ADMET and DMPK最新文献

Background and purpose: Methotrexate (MTX) is a widely used anti-cancer drug, but its overuse can lead to significant side effects. Therefore, it is very vital to design simple and sensitive analytical methods for its determination.

Experimental approach: In this work, an electrochemical sensor was prepared based on an ionic liquid (IL)/Ni-Co layered double hydroxide nanosheets (Ni-Co-LDH)-modified carbon paste electrode IL/Ni-Co-LDH/CPE. Cyclic voltammetry, differential pulse voltammetry, and chronoamperometry methods were applied to evaluate the performance of the designed sensor for MTX determination.

Key results: The IL/Ni-Co-LDH/CPE sensor exhibits a linear relationship between the peak current of the differential pulse voltammetry and MTX concentrations in the linear dynamic range of 0.02 to 140.0 μM, with a detection limit of 0.006 μM. The IL/Ni-Co-LDH/CPE sensor exhibited relative standard deviation values between 1.7 to 3.7 % for recovery tests on real samples, indicating the precision of the method.

Conclusion: The designed sensor with cost-effective and good performance could be valuable for therapeutic drug monitoring and clinical diagnostics.

Background and purpose: The food effects on oral drug absorption are challenging to predict from in vitro data. Food intake has been reported to reduce the oral absorption of several zwitterionic antihistamine drugs. However, the mechanism for this negative food effect has not been clear. The purpose of the present study was to evaluate the bile micelle and food binding of zwitterionic antihistamine drugs as a possible mechanism for the negative food effects on their oral drug absorption.

Experimental approach: Bilastine (BIL), cetirizine (CET), fexofenadine (FEX), and olopatadine (OLO) were employed as model drugs. The fed/fasted AUC ratios of BIL, CET, FEX, and OLO after oral administration are reported to be 0.60 to 0.7, 0.92, 0.76 to 0.85, and 0.84, respectively. The unbound fraction (f _u) of these drugs in the fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, containing 3 and 15 mM taurocholic acid, respectively) with or without FDA breakfast homogenate (BFH) was measured by dynamic dialysis.

Key results: The FeSSIF/ FaSSIF f_u ratios were 0.90 (BIL), 0.46 (CET), 0.76 (FEX), and 0.78 (OLO). In the presence of BFH, the f_u ratios were reduced to 0.52 (BIL), 0.22 (CET), 0.39 (FEX), and 0.44 (OLO).

Conclusion: Despite being zwitterion at pH 6.5, the antihistamine drugs were bound to bile micelles. Bile micelle and food binding were suggested to cause a negative food effect on the oral absorption of these drugs. However, the AUC ratio was not quantitatively predicted by using FeSSIF + BFH.

Background and purpose: The classical drug discovery toolbox continually expands beyond traditional rule of five (Ro5)-compliant small molecules to include new chemical modalities for difficult-to-drug targets. The paper focuses on the molecular properties essential to drive oral bioavailability within the bRo5 framework.

Experimental approach: The first part outlines the concept and methodologies for characterizing bRo5 physicochemical properties, including considerations on chameleonicity; in particular, the paper summarizes the content of the last author's talk presented during the IAPC-10 Meeting held in Belgrade in September 2023 (https://iapchem.org/index.php/iapc-10-home). The second part of the manuscript presents novel experimental and computational data on three proteolysis targeting chimeras (PROTACs) currently in clinical trials.

Key results: Molecular descriptors of ARV-110, ARV-471, and DT-2216 are reported and the main limitations of the applied experimental approaches are discussed. Moreover, a simple computational method shows how predicting the presence of chameleonic effects.

Conclusion: A full complete physicochemical characterization of three degraders in clinical trials is reported to highlight the differences in physicochemical descriptors between PROTACs dosed orally and intravenously.

Background and purpose: Chronic myeloid leukaemia (CML) is one of the most lethal types of leukaemia and can rapidly progress if not treated properly. Therefore, having an effective diagnostic strategy is crucial. Various methods are available for diagnosis, including electrochemical biosensors with aptamer bioreceptors.

Experimental approach: In this study, we immobilized the KK1D04 aptamer on a screen-printed carbon electrode (SPCE) supported by CeO₂ nanoparticles (CeO₂NPs) to detect K562 cells, a type of CML cell line. Several parameters were optimized to enhance the aptasensor response using the Box-Behnken experimental design.

Key results: The developed aptasensor demonstrated good performance with a limit of detection (LOD) and limit of quantification (LOQ) of 16 cells/mL and 3,882 cells/mL, respectively, in the K562 cell concentration range of 10² to 10⁶ cells/mL. The optimum experimental conditions were an aptamer concentration of 0.8 ppm, an aptamer incubation time of 36 minutes, and a K562 aptamer-cell incubation time of 13 minutes. The aptasensor also exhibits selectivity for K562 cells compared to Vero cells, THP1 cells, and Raji cells.

Conclusion: The aptasensor in this study demonstrated the potential to detect K562 cells. These results could contribute to the advancement of point-of-care (POC) devices for the detection of CML.

Background and purpose: Aiming to achieve light sedation via intranasal administration, this study showed that propofol (PPF) did not permeate across the rabbit nasal mucosa ex vivo from its marketed emulsion for injection.

Experimental approach: Dilution of the emulsion with methyl-β-cyclodextrin in saline solution increased propofol solubility in water and diffusion across the nasal epithelium.

Key results and conclusion: Despite these positive effects of the cyclodextrin, the amount of PPF permeated was minimal in 3 h, exceeding the formulation residence time in the nose. These results highlight the key role of formulation and the need for innovation in solubility and transmucosal transport enhancement techniques to optimize drug delivery and therapeutic efficacy.

Background and purpose: Interpenetrating polymer network (IPN) hydrogels are an adaptable category of materials, exhibiting remarkable promise for various biological applications due to their distinctive structural and functional attributes. This review delves into the synthesis of IPN hydrogels through both physical and chemical methodologies, elucidating how these techniques allow for precise tailoring of mechanical properties, swelling behaviour, and biocompatibility.

Experimental approach: We conducted an extensive literature review by searching well-established online research databases for articles published since 2009 to gather comprehensive data on IPN hydrogels.

Key results: Our review highlights several critical applications of IPN hydrogels in the biomedical field; i) Tissue engineering: IPN hydrogels are evaluated for their capacity to emulate the extracellular matrix, making them excellent scaffolds for tissue engineering; ii) Controlled drug release: The ability of IPN hydrogels to modulate drug release rates and protect bioactive molecules is explored. Their structure enables sustained and targeted delivery of therapeutic agents, enhancing treatment efficacy; iii) 3D bioprinting: The use of IPN hydrogels as bioinks for 3D bioprinting is assessed, demonstrating their capability to construct intricate, biomimetic structures with high precision; and iv) Regenerative medicine: the development of biomimetic IPN hydrogels for regenerative medicine, emphasizing their potential to closely replicate natural biological environments, thereby promoting effective tissue repair and regeneration.

Conclusion: IPN hydrogels emerge as a versatile and multifaceted platform with significant implications for advancing biomedical science and clinical therapies. Their diverse applications highlight their potential to revolutionize current biomedical practices and contribute to the development of innovative therapeutic solutions.

Background: Knee arthroscopy is a widely practiced orthopaedic procedure known for its minimally invasive approach, allowing quicker recovery times and less postoperative discomfort than traditional open surgeries. However, managing postoperative pain remains a critical aspect of patient care and satisfaction. The main objective of this research is to examine the relationships between patient demographics (age, gender, BMI) and early postoperative outcomes, including pain, physiotherapy, and walking.

Method: Randomized data collection, clinical trial study of 2 groups of patients. The patients were split into lidocaine 1 % 16 ml + methylprednisolone 160 mg 4 ml) and (methylprednisolone only 160 mg 4 ml) groups. All patients in both groups were queried about age, gender, BMI, and pain on the first, third, and 15th days following surgery. All patients were tested for physiotherapy on the second, third, and fourth postop days. After surgery, walking was tested on the third, fourth, and fifth days.

Results: Significant differences in postoperative pain relief and physiotherapy initiation times were observed. There are notable associations between treatment groups and recovery metrics, such as pain levels and mobility on various days' post-surgery. Significant demographic influences (age, gender, BMI) on recovery outcomes are observed, particularly in walking and pain at day 15 post-operation.

Conclusion: lidocaine and methylprednisolone improve postoperative pain relief and functional recovery in knee arthroscopy patients, with most experiencing reduced pain early post-surgery (early physiotherapy) and an expedited return to walking (decreased morbidity). Patients taking just methylprednisolone recovered slower. Age, gender, and BMI affected pain and walking abilities post-operation but not physiotherapy time, underscoring the personalised approach needed in postoperative treatment.

Background and purpose: This study aimed to improve the stability and prolonged gefitinib release from the nanoliposomes.

Experimental approach: Nanoliposomes were prepared by reverse-phase evaporation and optimized using Box-Behnken design to investigate the influence of sonication time (X ₁), tween 80 / soya phosphatidylcholine ratio (X ₂), and cholesterol/soya phosphatidylcholine ratio (X ₃) on nanoliposomes.

Key results: Optimized nanoliposomes were quasi-spherical shaped, with a mean dimension of 93.2 nm and an encapsulation efficiency of 87.56±0.17 %. Surface decoration of the optimized batch was done using different concentrations of chitosan. The optimal chitosan concentration required to adorn the nanoliposome surface was 0.01 %. In comparison to unadorned nanoliposomes (82.16±0.65 %), adorned nanoliposomes (78.04±0.35 %) released the drug consistently over 24 h via Fickian diffusion. The IC₅₀ values for surface-adorned nanoliposomes in A549 and H1299 cells were 6.53±0.75 and 4.73±0.46 μM, respectively. Cytotoxicity of the surface-decorated nanoliposomes may be due to their higher zeta potential and prolonged drug release. At the end of the sixth month, the samples stored at 4 °C were more stable than those stored at 25 °C and 45 °C. The stability of plain nanoliposomes has increased after chitosan coating. Thus, by using different concentrations of chitosan solution as coating material, we can develop a suitable sustained drug-release surface-adorned nanoliposomal formulation.

Conclusion: The developed nanoliposomes may offer a new path for melanoma clinics.

Background and purpose: Cotrimoxazole, a commonly prescribed antibiotic, has substantial resistance, especially in Indonesia, with its uropathogenic resistance reaching 67% in 2017. Although cotrimoxazole has been suggested to be co-administered with lactoferrin to enhance its antibacterial effectiveness and this practice has been widely adopted since the Covid-19 pandemic, the impact of lactoferrin on the pharmacokinetics of cotrimoxazole remains relatively unknown. This study aims to conduct a preliminary clinical investigation into the impact of lactoferrin supplementation on the pharmacokinetics of cotrimoxazole, focusing on the elimination rate and excretion of unchanged drug in urine.

Experimental approach: This study employed a blinded, cross-over, single-dose pharmacokinetics investigation, which included five healthy volunteers as participants. In the initial period, the first group received cotrimoxazole (80 mg trimethoprim and 400 mg sulfamethoxazole) along with a lactoferrin-containing supplement, while the second group only received cotrimoxazole. Subsequently, after a washout period, the conditions were reversed. Urine sampling was conducted at intervals from 0 to 24 hours post-medication, and drug levels in the urine were determined using high-performance liquid chromatography.

Key results: The population-based pharmacokinetic analysis revealed that the optimal model was the one-compartment model with first-order elimination and proportional residual error.

Conclusion: The findings show that the administration of lactoferrin-containing supplements did not significantly influence the covariate model and, therefore, did not alter the pharmacokinetics parameter of cotrimoxazole in urine with a single administration, implying that lactoferrin did not cause drug interaction problems when given simultaneously.

Background and purpose: Erectile dysfunction is a common issue among adult males involving difficulty in maintaining an erection, and it is often treated with fast-acting, low-side-effect drugs like avanafil (AVN), among other phosphodiesterase-5 inhibitors. Hence, developing fast, simple, and sensitive methods to detect AVN is crucial.

Experimental approach: This study conducts an electroanalytical inquiry and provides a new voltammetric method for accurately analyzing AVN utilizing a boron-doped diamond (BDD) electrode without any modifications.

Key results: In the Britton-Robinson buffer (BR, 0.04 mol L^-1, pH 4.0), cyclic voltammetry showed a clearly defined and irreversible anodic peak at around +1.44 V relative to Ag/AgCl. The pH of the solution was shown to have an impact on the voltammetric signals of the oxidation peaks. A good linear response for AVN quantification was achieved using square-wave voltammetry. This was done in a 0.04 mol L-1 BR (pH 4.0) solution at a potential of +1.33 V (vs. Ag/AgCl). The method exhibited a wide dynamic range of 0.5 to 30.0 μg mL^-1 (1.0 to 62 μmol L^-1) and a low limit of detection of 0.14 μg mL^-1 (0.29 μmol L^-1). The method proposed demonstrated suitability for determining AVN content in pharmaceutical formulations. The accuracy of the approach was demonstrated by comparing the results obtained using the developed method with those achieved using the UV-Vis spectrometry method.

Conclusion: Our method simplifies the analytical process by eliminating the need for electrode modification, reducing both time and resource requirements while enhancing overall feasibility.