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1.
J Comput Aided Mol Des ; 35(2): 245-260, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33289903

RESUMEN

The alternative oxidase (AOX) is a monotopic diiron carboxylate protein that catalyses the oxidation of ubiquinol and the reduction of oxygen to water. Although a number of AOX inhibitors have been discovered, little is still known about the ligand-protein interaction and essential chemical characteristics of compounds required for a potent inhibition. Furthermore, owing to the rapidly growing resistance to existing inhibitors, new compounds with improved potency and pharmacokinetic properties are urgently required. In this study we used two computational approaches, ligand-protein docking and Quantitative Structure-Activity Relationships (QSAR) to investigate binding of AOX inhibitors to the enzyme and the molecular characteristics required for inhibition. Docking studies followed by protein-ligand interaction fingerprint (PLIF) analysis using the AOX enzyme and the mutated analogues revealed the importance of the residues Leu 122, Arg 118 and Thr 219 within the hydrophobic cavity. QSAR analysis, using stepwise regression analysis with experimentally obtained IC50 values as the response variable, resulted in a multiple regression model with a good prediction accuracy. The model highlighted the importance of the presence of hydrogen bonding acceptor groups on specific positions of the aromatic ring of ascofuranone derivatives, acidity of the compounds, and a large linker group on the compounds on the inhibitory effect of AOX.


Asunto(s)
Inhibidores Enzimáticos/química , Hidrocarburos Aromáticos/química , Proteínas Mitocondriales/antagonistas & inhibidores , Oxidorreductasas/antagonistas & inhibidores , Proteínas de Plantas/antagonistas & inhibidores , Secuencia de Aminoácidos , Evaluación Preclínica de Medicamentos , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Simulación del Acoplamiento Molecular , Oxidación-Reducción , Unión Proteica , Relación Estructura-Actividad Cuantitativa , Análisis de Regresión
2.
AAPS PharmSciTech ; 23(1): 42, 2021 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-34964076

RESUMEN

Solubility determination of poorly water-soluble drugs is pivotal for formulation scientists when they want to develop a liquid formulation. Performing such a test with different ratios of cosolvents with water is time-consuming and costly. The scarcity of solubility data for poorly water-soluble drugs increases the importance of developing correlation and prediction equations for these mixtures. Therefore, the aim of the current research is to determine the solubility of acetylsalicylic acid in binary mixtures of ethanol+water at 25 and 37°C. Acetylsalicylic acid is non-stable in aqueous solutions and readily hydrolyze to salicylic acid. So, the solubility of acetylsalicylic acid is measured in ethanolic mixtures by HPLC to follow the concentration of produced salicylic acid as well. Moreover, the solubility of acetylsalicylic acid is modeled using different cosolvency equations. The measured solubility data were also predicted using PC-SAFT EOS model. DSC results ruled out any changes in the polymorphic form of acetylsalicylic acid after the solubility test, whereas XRPD results showed some changes in crystallinity of the precipitated acetylsalicylic acid after the solubility test. Fitting the solubility data to the different cosolvency models showed that the mean relative deviation percentage for the Jouyban-Acree model was less than 10.0% showing that this equation is able to obtain accurate solubility data for acetylsalicylic acid in mixtures of ethanol and water. Also, the predicted data with an average mean relative deviation percentage (MRD%) of less than 29.65% show the capability of the PC-SAFT model for predicting solubility data. A brief comparison of the solubilities of structurally related solutes to acetylsalicylic acid was also provided.


Asunto(s)
Etanol , Agua , Aspirina , Solubilidad , Solventes
3.
AAPS PharmSciTech ; 21(3): 105, 2020 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-32180042

RESUMEN

This commentary is written in response to Pezzini's research group commentary, which claimed Liqui-Pellet and liquisolid pellet are not different. Despite some similarities, there are crucial differences separating these two technologies. Liqui-Pellet uses liqui-mass system (wet mass/paste admixture), and liquisolid pellet uses liquisolid system (flowable powder admixture). The understanding of the well-defined term 'liquisolid system' is crucial to understand what is and is not liquisolid formulation. Spireas, who is the inventor of liquisolid technology, clearly defined liquisolid system in his patent document and publications. Since his first publication in 1998, there are around 200 articles about liquisolid formulations (extracted from Scopus), and with no exception, every single one of them followed the original definition of liquisolid system. Liqui-Pellet does not use liquisolid system and so calling it the same as liquisolid pellet, which uses liquisolid system, is incorrect and misleading. The purpose of this commentary is to resolve misunderstanding and support furthering knowledge.


Asunto(s)
Química Farmacéutica , Polvos , Solubilidad , Comprimidos
4.
AAPS PharmSciTech ; 20(6): 231, 2019 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-31236781

RESUMEN

In spite of the major advantages that the liquisolid technology offers, particularly in tackling poor bioavailability of poorly water-soluble drugs (i.e., BCS Class II drugs), there are a few critical drawbacks. The inability of a high liquid load factor, poor flowability, poor compactibility, and an inability to produce a high dose dosage form of a reasonable size for swallowing are major hurdles, hampering this technology from being commercially feasible. An attempt was therefore made to overcome these drawbacks whilst maintaining the liquisolid inherent advantages. This resulted in the emerging next generation of oral dosage forms called the liqui-pellet. All formulations were incorporated into capsules as the final product. Solubility studies of naproxen were conducted in different liquid vehicles, namely polyethylene glycol 200, propylene glycol, Tween 80, Labrafil, Labrasol, and Kolliphor EL. The scanning electron microscopy studies indicated that the liquid vehicle tends to reduce the surface roughness of the pellet. X-ray powder diffraction (XRPD) indicated no significant differences in the crystalline structure or amorphous content between the physical mixture and the liqui-pellet formulation. This was due to the presence of a high concentration of amorphous Avicel in the formulation which overshadowed the crystalline structure of naproxen in the physical mixtures. Flowability and dissolution tests confirmed that this next-generation oral dosage form has excellent flowability, whilst maintaining the typical liquisolid enhanced drug release performance in comparison to its physical mixture counterpart. The liqui-pellet also had a high liquid load factor of 1, where ~ 29% of the total mass was the liquid vehicle. This shows that a high liquid load factor can be achieved in a liqui-pellet without compromising flowability. Overall, the results showed that the poor flowability of a liquisolid formulation could be overcomed with the liqui-pellet, which is believed to be a major advancement into the commercial feasibility of the liquisolid concept.


Asunto(s)
Formas de Dosificación , Preparaciones Farmacéuticas/administración & dosificación , Administración Oral , Disponibilidad Biológica , Difracción de Polvo , Solubilidad
5.
Xenobiotica ; 47(7): 614-631, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27485154

RESUMEN

1. Biliary excretion of compounds is dependant on several transporter proteins for the active uptake of compounds from the blood into the hepatocytes. Organic anion-transporting polypeptides (OATPs) are some of the most abundant transporter proteins in the sinusoidal membrane and have been shown to have substrate specificity similar to the structural characteristics of cholephilic compounds. 2. In this study, we sought to use measures of OATP binding as predictors of biliary excretion in conjunction with molecular descriptors in a quantitative structure-activity relationship (QSAR) study. Percentage inhibitions of three subtypes of OATPs were used as surrogate indicators of OATP substrates. Several statistical modelling techniques were incorporated including classification and regression trees, boosted trees, random forest and multivariate adaptive regression splines (MARS) in order to first develop QSARs for the prediction of OATP inhibition of compounds. The predicted OATP percentage inhibition using selected models were then used as features of the QSAR models for the prediction of biliary excretion of compounds in rat. 3. The results indicated that incorporation of predicted OATP inhibition improves accuracy of biliary excretion models. The best result was obtained from a simple regression tree that used predicted OATP1B1 percentage inhibition at the root node of the tree.


Asunto(s)
Eliminación Hepatobiliar , Transportadores de Anión Orgánico/metabolismo , Animales , Transporte Biológico , Hepatocitos/metabolismo , Hígado/metabolismo , Análisis Multivariante , Relación Estructura-Actividad Cuantitativa , Ratas
6.
Mol Pharm ; 12(1): 87-102, 2015 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-25397721

RESUMEN

The biopharmaceutical classification system (BCS) is now well established and utilized for the development and biowaivers of immediate oral dosage forms. The prediction of BCS class can be carried out using multilabel classification. Unlike single label classification, multilabel classification methods predict more than one class label at the same time. This paper compares two multilabel methods, binary relevance and classifier chain, for provisional BCS class prediction. Large data sets of permeability and solubility of drug and drug-like compounds were obtained from the literature and were used to build models using decision trees. The separate permeability and solubility models were validated, and a BCS validation set of 127 compounds where both permeability and solubility were known was used to compare the two aforementioned multilabel classification methods for provisional BCS class prediction. Overall, the results indicate that the classifier chain method, which takes into account label interactions, performed better compared to the binary relevance method. This work offers a comparison of multilabel methods and shows the potential of the classifier chain multilabel method for improved biological property predictions for use in drug discovery and development.


Asunto(s)
Biofarmacia/métodos , Química Farmacéutica/métodos , Modelos Teóricos , Administración Oral , Algoritmos , Células CACO-2 , Simulación por Computador , Descubrimiento de Drogas , Humanos , Imagenología Tridimensional , Permeabilidad , Análisis de Regresión , Reproducibilidad de los Resultados , Solubilidad
7.
J Pharm Pharm Sci ; 17(1): 92-105, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24735762

RESUMEN

PURPOSE: The prominent ATP-binding cassette (ABC) transporters ABCB1, ABCC1, and ABCG2 are involved in substance transport across physiological barriers and therefore in drug absorption, distribution, and elimination. They also mediate multi-drug resistance in cancer cells. Different flavonoids are known to interfere with different ABC transporters. Here, the effect of the furanoflavonol karanjin, a potential drug with antiglycaemic, gastroprotective, antifungal, and antibacterial effects, was investigated on ABCB1, ABCC1, and ABCG2-mediated drug transport in comparison to the flavonoids apigenin, genistein, and naringenin. METHODS: Cells expressing the relevant transporters (ABCB1: UKF-NB-3(ABCB1), UKF-NB-3(r)VCR¹°; ABCC1: G62, PC-3(r)VCR²°; ABCG2: UKF-NB-3(ABCG2)) were used in combination with specific fluorescent and cytotoxic ABC transporter substrates and ABC transporter inhibitors to study ABC transporter function. Moreover, the effects of the investigated flavonoids were determined on the ABC transporter ATPase activities. RESULTS: Karanjin interfered with drug efflux mediated by ABCB1, ABCC1, and ABCG2 and enhanced the ATPase activity of all three transporters. Moreover, karanjin exerted more pronounced effects than the control flavonoids apigenin, genistein, and naringenin on all three transporters. Most notably, karanjin interfered with ABCB1 at low concentrations being about 1 µM. CONCLUSIONS: Taken together, these findings should be taken into account during further consideration of karanjin as a potential drug for different therapeutic indications. The effects on ABCB1, ABCC1, and ABCG2 may affect the pharmacokinetics of co-administered drugs.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Benzopiranos/farmacología , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Proteínas de Neoplasias/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Adenosina Trifosfatasas/metabolismo , Apigenina/farmacología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Flavanonas/farmacología , Genisteína/farmacología , Humanos
8.
J Pharm Pharm Sci ; 17(1): 154-68, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24735766

RESUMEN

PURPOSE: The clinically approved oncogenic BRAF inhibitor PLX4032 (vemurafenib) was shown to be a substrate of the ATP-binding cassette (ABC) transporter ABCB1. Here, we compared PLX4032 and its structurally closely related precursor compound PLX4720 for their interference with ABCB1 and the ABCB1-mediated compound transport using docking and cell culture experiments. METHODS: For the docking study of PLX4032 and PLX4720 with ABCB1, we analysed binding of both compounds to mouse Abcb1a and to human ABCB1 using a homology model of human ABCB1 based on the 3D structure of Abcb1a. Naturally ABCB1 expressing cells including V600E BRAF-mutated and BRAF wild-type melanoma cells and cells transduced with a lentiviral vector encoding for ABCB1 were used as cell culture models. ABCB1 expression and function were studied by the use of fluorescent and cytotoxic ABCB1 substrates in combination with ABCB1 inhibitors. RESULTS: Docking experiments predicted PLX4032 to interact stronger with ABCB1 than PLX4720. Experimental studies using different cellular models and structurally different ABCB1 substrates confirmed that PLX4032 interfered stronger with ABCB1 function than PLX4720. For example, PLX4032 (20 µM) induced a 4-fold enhanced rhodamine 123 accumulation compared to PLX4720 (20 µM) in ABCB1-transduced UKF-NB-3 cells and reduced the IC50 for the cytotoxic ABCB1 substrate vincristine in this model by 21-fold in contrast to a 9-fold decrease induced by PLX4720. CONCLUSIONS: PLX4032 exerted stronger effects on ABCB1-mediated drug transport than PLX4720. This indicates that small changes in a molecule can substantially modify its interaction with ABCB1, a promiscuous transporter that transports structurally different compounds.


Asunto(s)
Antineoplásicos/farmacología , Indoles/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Sulfonamidas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/efectos de los fármacos , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adenosina Trifosfatasas/metabolismo , Animales , Antineoplásicos/administración & dosificación , Línea Celular , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Citometría de Flujo , Humanos , Indoles/administración & dosificación , Melanoma/tratamiento farmacológico , Ratones , Simulación del Acoplamiento Molecular , Sulfonamidas/administración & dosificación , Vemurafenib , Vincristina/administración & dosificación , Vincristina/uso terapéutico
9.
J Chem Inf Model ; 53(2): 461-74, 2013 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-23293925

RESUMEN

Class imbalance occurs frequently in drug discovery data sets. In oral absorption data sets, in the literature, there are considerably more highly absorbed compounds compared to poorly absorbed compounds. This produces models that are biased toward highly absorbed compounds which lack generalization to industry settings where more early stage drug candidates are poorly absorbed. This paper presents two strategies to cope with unbalanced class data sets: undersampling the majority high absorption class and misclassification costs using classification decision trees. The published data set by Hou et al. [J. Chem. Inf. Model.2007, 47, 208-218], which contained percentage human intestinal absorption of 645 drug and drug-like compounds, was used for the development and validation of classification trees using classification and regression tree (C&RT) analysis. The results indicate that undersampling the majority class, highly absorbed compounds, leads to a balanced distribution (50:50) training set which can achieve better accuracies for poorly absorbed compounds, whereas the biased training set achieved higher accuracies for highly absorbed compounds. The use of misclassification costs resulted in improved class predictions, when applied to reduce false positives or false negatives. Moreover, it was shown that the classical overall accuracy measure used in many publications is particularly misleading in the case of unbalanced data sets and more appropriate measures presented here may be used for a more realistic assessment of the classification models' performance. Thus, these strategies offer improvements to cope with unbalanced class data sets to obtain classification models applicable in industry.


Asunto(s)
Descubrimiento de Drogas/métodos , Absorción , Administración Oral , Bases de Datos Farmacéuticas , Árboles de Decisión , Humanos , Modelos Biológicos , Análisis de Regresión
10.
J Chem Inf Model ; 53(10): 2730-42, 2013 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-24050619

RESUMEN

There are currently thousands of molecular descriptors that can be calculated to represent a chemical compound. Utilizing all molecular descriptors in Quantitative Structure-Activity Relationships (QSAR) modeling can result in overfitting, decreased interpretability, and thus reduced model performance. Feature selection methods can overcome some of these problems by drastically reducing the number of molecular descriptors and selecting the molecular descriptors relevant to the property being predicted. In particular, decision trees such as C&RT, although they have an embedded feature selection algorithm, can be inadequate since further down the tree there are fewer compounds available for descriptor selection, and therefore descriptors may be selected which are not optimal. In this work we compare two broad approaches for feature selection: (1) a "two-stage" feature selection procedure, where a pre-processing feature selection method selects a subset of descriptors, and then classification and regression trees (C&RT) selects descriptors from this subset to build a decision tree; (2) a "one-stage" approach where C&RT is used as the only feature selection technique. These methods were applied in order to improve prediction accuracy of QSAR models for oral absorption. Additionally, this work utilizes misclassification costs in model building to overcome the problem of the biased oral absorption data sets with more highly absorbed than poorly absorbed compounds. In most cases the two-stage feature selection with pre-processing approach had higher model accuracy compared with the one-stage approach. Using the top 20 molecular descriptors from the random forest predictor importance method gave the most accurate C&RT classification model. The molecular descriptors selected by the five filter feature selection methods have been compared in relation to oral absorption. In conclusion, the use of filter pre-processing feature selection methods and misclassification costs produce models with better interpretability and predictability for the prediction of oral absorption.


Asunto(s)
Árboles de Decisión , Drogas en Investigación/farmacocinética , Modelos Estadísticos , Mucosa Bucal/metabolismo , Administración Oral , Algoritmos , Drogas en Investigación/síntesis química , Humanos , Relación Estructura-Actividad Cuantitativa
11.
Pharmaceutics ; 15(3)2023 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-36986844

RESUMEN

In vitro dissolution and permeability testing aid the simulation of the in vivo behavior of inhalation drug products. Although the regulatory bodies have specific guidelines for the dissolution of orally administered dosage forms (e.g., tablets and capsules), this is not the case for orally inhaled formulations, as there is no commonly accepted test for assessing their dissolution pattern. Up until a few years ago, there was no consensus that assessing the dissolution of orally inhaled drugs is a key factor in the assessment of orally inhaled products. With the advancement of research in the field of dissolution methods for orally inhaled products and a focus on systemic delivery of new, poorly water-soluble drugs at higher therapeutic doses, an evaluation of dissolution kinetics is proving crucial. Dissolution and permeability testing can determine the differences between the developed formulations and the innovator's formulations and serve as a useful tool in correlating in vitro and in vivo studies. The current review highlights recent advances in the dissolution and permeability testing of inhalation products and their limitations, including recent cell-based technology. Although a few new dissolution and permeability testing methods have been established that have varying degrees of complexity, none have emerged as the standard method of choice. The review discusses the challenges of establishing methods that can closely simulate the in vivo absorption of drugs. It provides practical insights into method development for various dissolution testing scenarios and challenges with dose collection and particle deposition from inhalation devices for dissolution tests. Furthermore, dissolution kinetic models and statistical tests to compare the dissolution profiles of test and reference products are discussed.

12.
Toxicology ; 485: 153412, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36584908

RESUMEN

There is increasing evidence that links mitochondrial off-target effects with organ toxicities. For this reason, predictive strategies need to be developed to identify mitochondrial dysfunction early in the drug discovery process. In this study, as a major mechanism of mitochondrial toxicity, first, the inhibitory activity of 35 compounds against succinate-cytochrome c reductase (SCR) was investigated. This in vitro study led to the generation of consistent experimental data for a diverse range of compounds, including pharmaceutical drugs and fungicides. Next, molecular docking and protein-ligand interaction fingerprinting (PLIF) analysis were used to identify significant residues and protein-ligand interactions for the Qo site of complex III and Q site of complex II. Finally, this data was used for the development of QSAR models using a regression-based approach to highlight structural and chemical features that might be responsible for SCR inhibition. The statistically validated QSAR models from this work highlighted the importance of low aqueous solubility, low ionisation, fewer 6-membered rings and shorter hydrocarbon alkane chains in the molecular structure for increased inhibition of SCR, hence mitochondrial toxicity. PLIF analysis highlighted two key residues for inhibitory activity of the Qo site of complex III: His 161 as H-bond acceptor and Pro 270 for arene interactions. Currently, there are limited structure-activity models published in the scientific literature for the prediction of mitochondrial toxicity. We believe this study helps shed light on the chemical space for the inhibition of mitochondrial electron transport chain (ETC).


Asunto(s)
Citocromos c , Ácido Succínico , Succinato Citocromo c Oxidorreductasa/metabolismo , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad Cuantitativa , Complejo III de Transporte de Electrones , Ligandos , Mitocondrias/metabolismo
13.
Biomedicines ; 11(2)2023 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-36830914

RESUMEN

With the current focus on 3D-printing technologies, it is essential to understand the processes involved in such printing methods and approaches to minimize the variability in dissolution behaviour to achieve better quality control outcomes. For this purpose, two formulations of theophylline tablets were prepared using hydroxypropyl cellulose (HPC) and ethyl cellulose (EC). Among the two types of tablets, three different methods (physical mixture (PM), hot-melt extrusion (HME) and 3D-printing fused deposition modelling (FDM)) were applied and their dissolution behaviours were studied under various conditions using a biodissolution tester. This was carried out at pH values of 1.2, 2.2, 5.8, 6.8, 7.2 and 7.5, mimicking the medium in the gastrointestinal tract. Dissolution tests under two dipping rates (10 dpm and 20 dpm) and two ionic strengths (0.2 M and 0.4 M) were conducted to mimic fed and fasting conditions. The dissolution efficiency (DE%), release rate, similarity factor (f2) and difference factor (f1) were calculated. When comparing the DE%, the formulation containing EC showed less sensitivity to changes in the dipping rate and ionic strength compared to the HPC formulation. As for the manufacturing method, 3D-printing FDM could improve the robustness of the dissolution behaviour of both formulations to dipping rate changes. However, for ionic strength changes, the effect of the manufacturing method was dependent on the formulation composition. For example, the 3D-printed tablets of the HPC formulation were more sensitive to changes in ionic strength compared to the EC-containing formulation. The release mechanism also changed after the thermal process, where n values in the Korsmeyer-Peppas model were much higher in the printing and HME methods compared to the PM. Based on the formulation composition, the 3D-printing method could be a good candidate method for tablets with a robust dissolution behaviour in the GI tract. Compared to HPC polymers, using hydrophobic EC polymers in printable formulations can result in a more robust dissolution behaviour in fed and fasting states.

14.
Biomedicines ; 11(12)2023 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-38137493

RESUMEN

Mitochondria are potential targets responsible for some drug- and xenobiotic-induced organ toxicities. However, molecular mechanisms of drug-induced mitochondrial toxicities are mostly unknown. Here, multiple in vitro assays were used to investigate the effects of 22 psychotropic drugs on mitochondrial function. The acute extracellular flux assay identified inhibitors of the electron transport chain (ETC), i.e., aripiprazole, phenytoin, and fluoxetine, an uncoupler (reserpine), substrate inhibitors (quetiapine, carbamazepine, buspirone, and tianeptine), and cytotoxic compounds (chlorpromazine and valproic acid) in HepG2 cells. Using permeabilized HepG2 cells revealed minimum effective concentrations of 66.3, 6730, 44.5, and 72.1 µM for the inhibition of complex-I-linked respiration for quetiapine, valproic acid, buspirone, and fluoxetine, respectively. Assessing complex-II-linked respiration in isolated rat liver mitochondria revealed haloperidol is an ETC inhibitor, chlorpromazine is an uncoupler in basal respiration and an ETC inhibitor under uncoupled respiration (IC50 = 135 µM), while olanzapine causes a mild dissipation of the membrane potential at 50 µM. This research elucidates some mechanisms of drug toxicity and provides some insight into their safety profile for clinical drug decisions.

15.
Biomedicines ; 10(6)2022 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-35740357

RESUMEN

The dissolution profile is of great importance in drug delivery and is affected by the manufacturing method. Thus, it is important to study the influence of the thermal process on drug release in emerging technologies such as 3D printing-fused deposition modeling (FDM). For this purpose, the characteristics of 3D printed tablets were compared to those of tablets prepared by other thermal methods such as hot-melt extrusion (HME) and non-thermal methods such as physical mixture (PM). Theophylline was used as a drug model and blends of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC) were used as a matrix former. The solid state of the drug in all formulations was investigated by differential scanning calorimetry, X-ray powder diffraction, and Fourier-transformed infrared spectroscopy. All studied tablets had the same weight and surface area/volume (SA/V). Dissolution data showed that, for some formulations, printed tablets interestingly had a faster release profile despite having the highest hardness values (>550 N) compared to HME and PM tablets. Porosity investigations showed that 100% infill printed tablets had the highest porosity (~20%) compared to HME (<10%) and PM tablets (≤11%). True density records were the lowest in printed tablets (~1.22 g/m3) compared to tablets made from both HME and PM methods (~1.26 g/m3), reflecting the possible increase in polymer specific volume while printing. This increase in the volume of polymer network may accelerate water and drug diffusion from/within the matrix. Thus, it is a misconception that the 3D printing process will always retard drug release based on increased tablet hardness. Hardness, porosity, density, solid-state of the drug, SA/V, weight, and formulation components are all factors contributing to the release profile where the total balance can either slow down or accelerate the release profile.

16.
Biomedicines ; 8(12)2020 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-33271759

RESUMEN

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterised by impairments in communication, social interaction, and the presence of restrictive and repetitive behaviours. Over the past decade, most of the research in ASD has focused on the contribution of genetics, with the identification of a variety of different genes and mutations. However, the vast heterogeneity in clinical presentations associated with this disorder suggests that environmental factors may be involved, acting as a "second hit" in already genetically susceptible individuals. To this regard, emerging evidence points towards a role for maternal immune system dysfunctions. This literature review considered evidence from epidemiological studies and aimed to discuss the pathological relevance of the maternal immune system in ASD by looking at the proposed mechanisms by which it alters the prenatal environment. In particular, this review focuses on the effects of maternal immune activation (MIA) by looking at foetal brain-reactive antibodies, cytokines and the microbiome. Despite the arguments presented here that strongly implicate MIA in the pathophysiology of ASD, further research is needed to fully understand the precise mechanisms by which they alter brain structure and behaviour. Overall, this review has not only shown the importance of the maternal immune system as a risk factor for ASD, but more importantly, has highlighted new promising pathways to target for the discovery of novel therapeutic interventions for the treatment of such a life-changing disorder.

17.
Drug Deliv Transl Res ; 10(1): 43-58, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31286452

RESUMEN

Liqui-pellet is a new dosage form stemming from pelletisation technology and concept from liquisolid technology. In spite of liqui-pellet overcoming a major hurdle in liquisolid technology through achieving excellent flow property with high liquid load factor, the formulation requires to be optimised in order to improve drug release rate. Liqui-pellets of naproxen containing Tween 80, Primojel, Avicel and Aerosil were extruded and spheronised. Flowability test confirmed that all liqui-pellet formulations have excellent-good flow property (Carr's index between 3.9-11.17%), including liqui-pellets with a high liquid load factor of 1.52, where 38% of the total mass is co-solvent. This shows a relatively high liquid load factor can be achieved in liqui-pellet without compromising the flowability, which is one of the key novelty of this work. It was found that the improved drug release rate was due to the remarkably improved disintegration of the supposedly non-disintegrating microcrystalline-based pellet; the optimised liqui-pellet seems to explode into fragments in the dissolution medium. At pH 1.2, the optimised formulation had ~ 10% more drug release than non-optimised formulation after 2 h, and at pH 7.4, the drug release of the optimised pellet was nearing 100% at ~ 15 min, whereas the none-optimised pellet only achieved ~ 79% drug release after 2 h. DSC and XRPD indicated an increase in the dissolution rate could be due to molecularly dispersion of naproxen in the pellets. Overall results showed that liqui-pellet exhibited an enhanced drug release and the capacity for high liquid load factor whilst maintaining excellent flowability, rendering it a potentially commercially feasible drug delivery system.


Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Formas de Dosificación , Naproxeno/administración & dosificación , Administración Oral , Antiinflamatorios no Esteroideos/farmacocinética , Naproxeno/farmacocinética , Solubilidad , Tensión Superficial , Tecnología Farmacéutica
18.
Carbohydr Polym ; 238: 116208, 2020 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-32299558

RESUMEN

Starch-based excipients are commonly used in oral solid dosage forms. The effect of particle size and pregelatinisation level of starch-based excipients on their water absorption behaviour have been evaluated. The results showed that starch-based excipients have type ii isotherms, indicating that the principal mechanism of sorption is the formation of monolayer coverage and multilayer water molecules (10-80 RH %). It was found that the particle size of starch-based excipients did not have any influence on the rate of water sorption, whereas the level of pregelatinisation changed the kinetics of water sorption-desorption. Results showed that the higher the degree of pregelatinisation, the higher the rate of water absorption, which is irrespective of particle size. SEM images showed that a partially gelatinised starch had a firm granular structure with small pores and channels on the surface while a fully gelatinised starch had more irregular and spongy like surface with a degree of fractured particles.


Asunto(s)
Excipientes/química , Almidón/química , Vapor , Absorción Fisicoquímica , Cinética , Modelos Químicos , Tamaño de la Partícula , Propiedades de Superficie
19.
J Mol Graph Model ; 26(5): 834-44, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17561422

RESUMEN

Histamine H3 receptors are presynaptic autoreceptors found in both central and peripheral nervous systems of many species. The central effects of these receptors suggest a potential therapeutic role for their antagonists in treatment of several neurological disorders such as epilepsy, schizophrenia, Alzheimer's and Parkinson's diseases. The purpose of this study was to identify the structural requirements for H3 antagonistic activity via quantitative structure-activity relationship (QSAR) studies and receptor modeling/docking techniques. A combination of partial least squares (PLS) and genetic algorithm (GA) was used in the QSAR approach to select the structural descriptors relevant to the receptor binding affinity of a series of 58 H3 antagonists. The descriptors were selected out of a pool of >1000 descriptors calculated by DRAGON, Hyperchem and ACD labs suite of programs. The resulting QSAR models for rat and human H3 binding affinities were validated using different strategies. QSAR models generated in the current work suggested the role of charge transfer interactions in the ligand-receptor interaction verified using the molecular modeling of the receptor and docking two antagonists to the binding site. The 3D model of human H3 receptor was built based on bovine rhodopsin structure and evaluated by molecular dynamics (MD) simulation in a mixed water-vacuum-water environment. The results were indicative of the stability of the model relating the observed structural changes during the MD simulation to the suggested ligand-receptor interactions. The results of this investigation are expected to be useful in the process of design and development of new potent H3 receptor antagonists.


Asunto(s)
Benzofuranos/química , Antagonistas de los Receptores Histamínicos/química , Modelos Moleculares , Pirrolidinas/química , Relación Estructura-Actividad Cuantitativa , Receptores Histamínicos H3/química , Secuencia de Aminoácidos , Animales , Bovinos , Línea Celular , Clonación Molecular , Humanos , Ligandos , Datos de Secuencia Molecular , Estructura Secundaria de Proteína , Ratas , Rodopsina/química , Alineación de Secuencia
20.
J Pharm Sci ; 96(12): 3334-51, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17626286

RESUMEN

This investigation is aimed at characterization of the mode of release from two different substitution types of HPMC and the effect of chemical structure of drugs using the QSPR (Quantitative - Structure-Property Relationship) technique. To this end, release profiles of HPMC matrices of several drugs containing the same formulation and compressed at a constant pressure were studied. QSPR method was used to establish statistically significant relationships between release parameters and the structural descriptors. Structural descriptors consisted of molecular mechanical, quantum mechanical and graph-theoretical parameters, as well as the partition coefficient and the aqueous solubility of the drugs. The results showed that the most important factors determining the release profile from both HPMC K4M and HPMC E4M matrices were the aqueous solubility of drugs (which could be substituted efficiently by dipole moment) and the size of the drug molecules. Comparison of drug release from matrices prepared using the two grades of HPMC showed very distinct differences for some drugs, as evaluated by the similarity factor. The results indicated that the source of the difference could be sought in the drug properties (as exemplified by the aqueous solubility and surface area) as well as the rate of erosion (that depends mainly on the polymer type).


Asunto(s)
Portadores de Fármacos , Metilcelulosa/análogos & derivados , Modelos Químicos , Modelos Estadísticos , Preparaciones Farmacéuticas/química , Relación Estructura-Actividad Cuantitativa , Tecnología Farmacéutica/métodos , Química Farmacéutica , Difusión , Composición de Medicamentos , Derivados de la Hipromelosa , Cinética , Metilcelulosa/química , Estructura Molecular , Peso Molecular , Presión , Solubilidad
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