ADMET and DMPK最新文献

Levodopa is routinely co-administered with carbidopa in the management of Parkinson's disease. Although the aforementioned combination therapy is effective, there may be fluctuating plasma levels of levodopa after oral administration. We formulated and evaluated the kinetic characteristics of the chitosan-pectin-based multiparticulate matrix of levodopa and carbidopa. Pectin was extracted from the cocoa husk, and the chitosan-pectin-based matrix was prepared by wet granulation. Formulations were evaluated for drug-excipient compatibility, drug content, precompression properties and in vitro release. For pharmacokinetic evaluation, rats were put into groups and administered either chitosan-pectin based matrix of levodopa/carbidopa, Sinemet^® CR or levodopa/carbidopa immediate release powder. Rats were administered the different formulations of levodopa/carbidopa (20/5 mg/kg) per os every 12 hours. The pharmacokinetic parameters of levodopa were estimated for the various treatment groups. The percentage content of levodopa and carbidopa in the various formulations was within the acceptance criteria. The AUC_0-24 for levodopa/carbidopa multiparticulate matrix (Formulation 3: 484.98 ± 18.70 μg.hr/mL); Formulation 4: 535.60 ± 33.04 μg.hr/mL), and C_max (Formulation 3: 36.28 ± 1.52 μg/mL; Formulation 4: 34.80 ± 2.19 μg/mL) were higher than Sinemet^® CR (AUC_0-24 262.84 ± 16.73 μg.hr/mL and C_max 30.62 ± 3.37 μg/mL). The t _1/2 of the new formulation was longer compared to Sinemet^® CR.

Drug discovery and development have become a very time-consuming and expensive process. Preclinical animal models have become the gold standard for studying drug pharmacokinetic and toxicity parameters. However, the involvement of a huge number of animal subjects and inter-species pathophysiological variations between animals and humans has provoked a lot of debate, particularly because of ethical concerns. Although many efforts are being established by biotech and pharmaceutical companies for screening new chemical entities in vitro before preclinical trials, failures during clinical trials are still involved. Currently, a large number of two- dimensional (2D) in vitro assays have been developed and are being developed by researchers for the screening of compounds. Although these assays are helpful in screening a huge library of compounds and have shown perception, there is a significant lack in predicting human Absorption, Distribution, Metabolism, Excretion and Toxicology (ADME-Tox). As a result, these assays cannot completely replace animal models. The recent inventions in three-dimensional (3D) cell culture-based assays like organoids and micro-physiological systems have shown great potential alternative tools for predicting the compound pharmacokinetic and pharmacodynamic fate in humans. In this comprehensive review, we have summarized some of the most commonly used 2D in vitro assays and emphasized the achievements in next-generation 3D cell culture-based systems for predicting the compound ADME-Tox.

In the present research, an advanced cellulose fiber paper (CFP) based biosensor is developed. This sensor is modified with nanocomposites containing poly(3,4-ethylene dioxythiophene) polystyrene sulfonate (PEDOT:PSS) as the main matrix and functionalized gold nanoparticles (PEDOT:PSS-AuNP@CFP) for the selective and sensitive detection of bacterial infection (BI)-specific biomarker procalcitonin (PCT). Scanning electronic microscopy, Fourier transform infrared spectroscopy, and X-ray diffraction are used to characterize the PEDOT:PSS-AuNP nanocomposite. This biosensor exhibits a high sensitivity of 1.34 μA (pg mL^-1)^-1 in the linear detection ranges of 1-20×10⁴ pg mL^-1, and a 24-day life span for PCT antigen detection. Anti-PCT antigenic protein is used for immobilization for PCT quantification. The results of electrochemical response studies showed that this conductive paper bioelectrode had good reproducibility, stability, and sensitivity in physiological ranges (1-20×10⁴ pg mL^-1). Further, the proposed bioelectrode is an alternative choice for point-of-care PCT detection.

In this work, an automated flow injection analysis (FIA) connected to a boron-doped diamond electrode (BDDE) was originally developed for the analysis of methimazole in pharmaceutical preparations. At a modification-free BDDE, methimazole was easilly oxidized. For the analysis of the mechanisms occurring at the electrode surface, cyclic voltammetry was employed to evaluate the impact of fundamental experimental parameters, such as pH and scan rate, on the BDDE response. For the quantitative detection, the FIA amperometric approach was constructed and used as a fast and sensitive method. The suggested approach provided a broad linear range of 0.5-50 μmol/L and a low detection limit of 10 nmol/L (signal-to-noise ratio = 3). Furthermore, the BDDE was successfully utilized to quantify methimazole in genuine samples from a variety of medicines, and its performance remained steady after more than 50 tests. The findings of amperometric measurements exhibit excellent repeatability, with relative standard deviations of less than 3.9 and 4.7 % for intra-day and inter-day, respectively. The findings indicated that, compared with traditional approaches, the suggested method has the following advantages: quick analysis time, simplicity, highly sensitive output, and no need for complicated operational processes.

Increased plasma concentrations of a variety of cellular enzymes (alanine transaminase, aspartate aminotransferase, alkaline phosphatase, amylase, etc.) are commonly used as routine screening tests for a range of conditions. An increased concentration usually is assumed to result from an increased rate of delivery to the plasma. Factors such as decreased metabolism or excretion or altered extravascular distribution usually are ignored. As a prelude to a detailed analysis of all the factors producing altered plasma enzyme levels, we have reviewed the relevant literature describing the pharmacokinetics (PK) of 13 of the commonly measured plasma proteins and developed a PK model that provides a simple physiological description of all the data. Our model starts with the general 3-compartment, 6-parameter system previously developed for albumin and interprets the fluxes in terms of unidirectional sieved protein convectional volume flows from the plasma to the two tissue compartments and equal lymph flows returning to the plasma. This greatly constrains the model such that each protein is characterized by only two adjustable parameters (plasma clearance and sieving factor). In addition to accurately fitting the plasma kinetics, the model can accurately describe the tissue and lymph protein PK. For example, it can describe the thoracic duct lymph protein concentration following an intravenous infusion or the plasma concentration following a subcutaneous tissue injection. This simple model provides a satisfactory framework for the PK of 12 of the 13 proteins investigated. The glycoprotein intestinal alkaline phosphatase is the exception, requiring the addition of a liver recycling compartment involving the asialoglycoprotein receptor.

A fast and facile electrochemical sensor for the detection of an important anticancer drug, 5-fluorouracil, is fabricated using CuFe₂O₄ nanoparticles modified screen printed graphite electrode (CuFe₂O₄ NPs/SPGE). The electrochemical activity of the modified electrode was characterized by chronoamperometry, cyclic voltammetry (CV) and differential pulse voltammetry (DPV) and linear sweep voltammetry (LSV) experiments. The CuFe₂O₄ NPs improved the electrochemical properties of the electrodes and enhanced their electroanalytical performance. Electrochemical measurements using differential pulse voltammetry showed a wide linear relationship between 5-fluorouracil concentration and peak height within the range 0.1 to 270.0 μM with a low detection limit (0.03 μM). Further, the sensor was testified with a urine sample and 5-fluorouracil injection sample, and the observed remarkable recovery results replicate its practical applicability.

Various applications of electrochemical sensors and biosensors have been reported in many fields. These include pharmaceuticals, drug detection, cancer detection, and analysis of toxic elements in tap water. Electrochemical sensors are characterised by their low cost, ease of manufacture, rapid analysis, small size and ability to detect multiple elements simultaneously. They also allow the reaction mechanisms of analytes, such as drugs, to be taken into account, giving a first indication of their fate in the body or their pharmaceutical preparation. Several materials are used in the construction of sensors, such as graphene, fullerene, carbon nanotubes, carbon graphite, glassy carbon, carbon clay, graphene oxide, reduced graphene oxide, and metals. This review covers the most recent progress in electrochemical sensors used to analyze drugs and metabolites in pharmaceutical and biological samples. We have highlighted carbon paste electrodes (CPE), glassy carbon electrodes (GCE), screen-printed carbon electrodes (SPCE) and reduced graphene oxide electrodes (rGOE). The sensitivity and analysis speed of electrochemical sensors can be improved by modifying them with conductive materials. Different materials used for modification have been reported and demonstrated, such as molecularly imprinted polymers, multiwalled carbon nanotubes, fullerene (C60), iron(III) nanoparticles (Fe₃O₄NP), and CuO micro-fragments (CuO MF). Manufacturing strategies and the detection limit of each sensor have been reported.

Background: An allergic reaction is the immune system's overreacting to a previously encountered, typically benign molecule, frequently a protein. Allergy reactions can result in rashes, itching, mucous membrane swelling, asthma, coughing, and other bizarre symptoms. To anticipate allergies, a wide range of principles and methods have been applied in bioinformatics. The sequence similarity approach's positive predictive value is very low and ineffective for methods based on FAO/WHO criteria, making it difficult to predict possible allergens.

Method: This work advocated the use of a deep learning model LSTM (Long Short-Term Memory) to overcome the limitations of traditional approaches and machine learning lower performance models in predicting the allergenicity of dietary proteins. A total of 2,427 allergens and 2,427 non-allergens, from a variety of sources, including the Central Science Laboratory and the NCBI are used. The data was divided 80:20 for training and testing purposes. These techniques have all been implemented in Python. To describe the protein sequences of allergens and non-allergens, five E-descriptors were used. E1 (hydrophilic character of peptides), E2 (length), E3(propensity to form helices), E4(abundance and dispersion), and E5 (propensity of beta strands) are used to make the variable-length protein sequence to uniform length using ACC transformation. A total of eight machine learning techniques have been taken into consideration.

Results: The Gaussian Naive Bayes as accuracy of 64.14 %, Radius Neighbour's Classifier with 49.2 %, Bagging Classifier was 85.8 %, ADA Boost was 76.9 %, Linear Discriminant Analysis has 76.13 %, Quadratic Discriminant Analysis was 84.2 %, Extra Tree Classifier was 90%, and LSTM is 91.5 %.

Conclusion: As the LSTM, has an AUC value of 91.5 % is regarded best in predicting allergens. A web server called ProAll-D has been created that successfully identifies novel allergens using the LSTM approach. Users can use the link https://doi.org/10.17632/tjmt97xpjf.1 to access the ProAll-D server and data.

Levothyroxine (LT-4) sodium has shown variable bioavailability following oral administration. This can be assigned to the significant influence of gastrointestinal conditions, food and drugs administered concomitantly on the rate and extent of absorption from the gastrointestinal tract. Thus, the aim of this research study was to establish an efficient transdermal delivery system of LT-4 sodium via the application of hyaluronic acid dissolving microneedles. Microneedles-based drug delivery system consists of sharp-tip needles that puncture the top layers of the skin in a minimally invasive manner to create physical channels through which therapeutic molecules can easily diffuse into/across the skin. Hyaluronic acid polymer at different ratios (5-60 %) was used to prepare microneedle arrays (100 needles per array) using a micromoulding technique. Characterisation tests were carried out to select the optimum formulation. F11 formula containing 50% w/v hyaluronic acid and 1% v/v Tween 80 formula showed an appropriate needle shape with dimensions of 432 ± 6.4 μm in height and a tip diameter of 9.8 ± 1.3 μm. The microneedle arrays demonstrated a suitable mechanical strength after applying a force of 32 N per array and an excellent insertion ability both in Parafilm M® and human skin. The in vivo dissolution of microneedles was started rapidly within 5 minutes following the insertion in the skin and completed at 1 hour. Ex vivo permeation study using human skin has shown a significant improvement in LT-4 sodium delivery across the skin compared to control preparations (drug solution and microneedle free film). The microneedle array F11 has significantly (P ≤ 0.05) increased LT-4 sodium permeation through the skin (cumulative permeated amount of 32 ± 2 μg/cm²) in comparison to the control solution (cumulative permeated amount of 0.7 ± 0.07 μg/cm²) and the microneedle free film (cumulative permeated amount of 0.1 ± 0.02 μg/cm²) over 7 hours. The findings from the irritation test revealed that mild erythema was produced from the application of microneedle arrays which disappeared within 24 hours. Accordingly, dissolving hyaluronic acid microneedles could be a feasible and effective approach to delivering LT-4 sodium transdermally without causing significant skin damage.