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Journal of Controlled Release :... Oct 2014The oral bioavailability of numerous drugs is not only limited by poor solubility and/or poor membrane permeability as addressed by the biopharmaceutical classification... (Review)
Review
The oral bioavailability of numerous drugs is not only limited by poor solubility and/or poor membrane permeability as addressed by the biopharmaceutical classification system (BCS) but also by a pre-systemic metabolism taking place to a high extent in the intestine. Enzymes responsible for metabolic reactions in the intestine include cytochromes P450 (CYP450), transferases, peptidases and proteases. Furthermore, in the gut nucleases, lipases as well as glycosidases influence the metabolic pathway of drugs and nutrients. A crucial role is also played by the intestinal microflora able to metabolize a wide broad of pharmaceutical compounds. Strategies to provide a protective effect towards an intestinal pre-systemic metabolism are based on the co-administration of enzyme inhibitor being optimally immobilized on unabsorbable and undegradable polymeric excipients in order to keep them concentrated there where an inhibitory effect is needed. Furthermore, certain polymeric excipients such as polyacrylates exhibit per se enzyme inhibitory properties. In addition, by incorporating drugs in cyclodextrines, in self-emulsifying drug delivery systems (SEDDS) or liposomes a protective effect towards an intestinal enzymatic attack can be achieved. Being aware of the important role of this pre-systemic metabolism by integrating it in the BCS as third dimension and keeping strategies to overcome this enzymatic barrier in mind, the therapeutic efficacy of many orally given drugs can certainly be substantially improved.
Topics: Administration, Oral; Animals; Biocatalysis; Drug Delivery Systems; Humans; Pharmaceutical Preparations
PubMed: 25128718
DOI: 10.1016/j.jconrel.2014.08.004 -
Physical Review. E Mar 2020The molecular mechanism of specific interactions between double stranded DNA molecules has been investigated for many years. Problems remain in how confinement, ions,...
The molecular mechanism of specific interactions between double stranded DNA molecules has been investigated for many years. Problems remain in how confinement, ions, and condensing agents change the interactions. We consider how the orientational alignment of DNAs contributes to the interactions via free energy simulations. Here we report on the effective interactions between two parallel DNA double helices in 150-mM NaCl solution using all atom models. We calculate the potential of mean force (PMF) of DNA-DNA interactions as a function of two coordinates, interhelical separation of parallel double helices and relative rotation of a DNA molecule with respect to the other about the helical axis. We generate the two-dimensional PMF to better understand the effective interactions when a DNA molecule is in juxtaposition with another. The analysis of the ion and solvent distributions around the DNA and particularly in the interface region shows that certain alignments of the DNA pair enhance the interactions. At local free energy minima in distance and alignment, water molecules and Na^{+} ions form a hydrogen bonded network with the phosphates from each DNA. This network contributes an attractive energy component to the DNA-DNA interactions. Our results provide a molecular mechanism whereby local DNA-DNA interactions, depending on the helical orientation, give a potential mechanism for stabilizing pairing of much larger lengths of homologous DNA that have been seen experimentally. The study suggests an atomically detailed local picture of relevance to certain aspects of DNA condensation or aggregation.
Topics: DNA; Molecular Dynamics Simulation; Nucleic Acid Conformation; Rotation
PubMed: 32289903
DOI: 10.1103/PhysRevE.101.032414 -
American Journal of Health-system... Nov 2023With the implementation of a new electronic health record (EHR) system across Mayo Clinic, a project was approved to standardize and converge 9 region-specific...
PURPOSE
With the implementation of a new electronic health record (EHR) system across Mayo Clinic, a project was approved to standardize and converge 9 region-specific large-volume infusion pump (LVP) drug libraries for Baxter SIGMA Spectrum pumps.
SUMMARY
The objectives of the project were to (1) develop recommendations for identified variances in practice, (2) consolidate regional drug libraries into a converged enterprise library, (3) improve the drug library management process, and (4) maintain or exceed previous Dose Error Reduction System (DERS) compliance for infusions administered. Harmonization efforts with infusion pumps decreased the number of drug libraries maintained, reduced content maintenance time, and increased readiness for smart infusion pump-EHR interoperability. Seven of the 8 regions for which change in DERS compliance was assessed showed improved compliance relative to baseline in the 30-day postwashout period. Furthermore, when comparing pre- and postimplementation DERS compliance, the number of regions meeting the minimum compliance rate of 95% increased from 5 to 6 regions.
CONCLUSION
The project improved the drug library management process, allowed for DERS compliance to be accurately compared across regions, and ensured that patients across the enterprise receive the same standard of care with the administration of intravenous medications.
Topics: Humans; Pharmaceutical Preparations; Medication Errors; Infusions, Intravenous; Infusion Pumps; Reference Standards
PubMed: 37527506
DOI: 10.1093/ajhp/zxad172 -
Molecular Diversity May 2021The advent of computational methods for efficient prediction of the druglikeness of small molecules and their ever-burgeoning applications in the fields of medicinal...
The advent of computational methods for efficient prediction of the druglikeness of small molecules and their ever-burgeoning applications in the fields of medicinal chemistry and drug industries have been a profound scientific development, since only a few amounts of the small molecule libraries were identified as approvable drugs. In this study, a deep belief network was utilized to construct a druglikeness classification model. For this purpose, small molecules and approved drugs from the ZINC database were selected for the unsupervised pre-training step and supervised training step. Various binary fingerprints such as Macc 166 bit, PubChem 881 bit, and Morgan 2048 bit as data features were investigated. The report revealed that using an unsupervised pre-training phase can lead to a good performance model and generalizability capability. Accuracy, precision, and recall of the model for Macc features were 97%, 96%, and 99%, respectively. For more consideration about the generalizability of the model, the external data by expression and investigational drugs in drug banks as drug data and randomly selected data from the ZINC database as non-drug were created. The results confirmed the good performance and generalizability capability of the model. Also, the outcomes depicted that a large proportion of misclassified non-drug small molecules ascertain the bioavailability conditions and could be investigated as a drug in the future. Furthermore, our model attempted to tap potential opportunities as a drug filter in drug discovery.
Topics: Databases, Pharmaceutical; Deep Learning; Drug Discovery; Pharmaceutical Preparations
PubMed: 32193758
DOI: 10.1007/s11030-020-10065-7 -
The AAPS Journal Sep 2014Over the last few years, numerous ligand binding assay technologies that utilize real-time measurement have been introduced; however, an assemblage and evaluation of... (Review)
Review
Over the last few years, numerous ligand binding assay technologies that utilize real-time measurement have been introduced; however, an assemblage and evaluation of these technologies has not previously been published. Herein, we describe six emerging real-time measurement technologies: Maverick™, MX96 SPR™, NanoDLSay™, AMMP®/ViBE®, SoPrano™, and two Lab-on-a-Chip (LoC) microfluidic devices. The development stage gate of these technologies ranges from pre-commercial to commercially available. Due to the novelty, the application and utility of some of the technologies regarding bioanalysis are likely to evolve but it is our hope that this review will provide insight into the direction the development of real-time measurement technologies is moving and the vision of those that are taking us there. Following the technology discussions, a comprehensive summary table is presented.
Topics: Acoustics; Animals; Binding Sites; Drug Design; Equipment Design; Humans; Kinetics; Ligands; Microfluidic Analytical Techniques; Miniaturization; Nanotechnology; Pharmaceutical Preparations; Protein Binding; Surface Plasmon Resonance; Technology, Pharmaceutical
PubMed: 25060773
DOI: 10.1208/s12248-014-9643-2 -
Physical Review. E Nov 2018Estimation of mutual information between random variables has become crucial in a range of fields, from physics to neuroscience to finance. Estimating information...
Estimation of mutual information between random variables has become crucial in a range of fields, from physics to neuroscience to finance. Estimating information accurately over a wide range of conditions relies on the development of flexible methods to describe statistical dependencies among variables, without imposing potentially invalid assumptions on the data. Such methods are needed in cases that lack prior knowledge of their statistical properties and that have limited sample numbers. Here we propose a powerful and generally applicable information estimator based on non-parametric copulas. This estimator, called the non-parametric copula-based estimator (NPC), is tailored to take into account detailed stochastic relationships in the data independently of the data's marginal distributions. The NPC estimator can be used both for continuous and discrete numerical variables and thus provides a single framework for the mutual information estimation of both continuous and discrete data. By extensive validation on artificial samples drawn from various statistical distributions, we found that the NPC estimator compares well against commonly used alternatives. Unlike methods not based on copulas, it allows an estimation of information that is robust to changes of the details of the marginal distributions. Unlike parametric copula methods, it remains accurate regardless of the precise form of the interactions between the variables. In addition, the NPC estimator had accurate information estimates even at low sample numbers, in comparison to alternative estimators. The NPC estimator therefore provides a good balance between general applicability to arbitrarily shaped statistical dependencies in the data and shows accurate and robust performance when working with small sample sizes. We anticipate that the non-parametric copula information estimator will be a powerful tool in estimating mutual information between a broad range of data.
PubMed: 30984901
DOI: 10.1103/PhysRevE.98.053302 -
Global Public Health Apr 2020In the late 1990s antiretroviral pharmaceuticals began to be used in the United States and Western Europe to prevent HIV infection in contexts of occupational exposure....
In the late 1990s antiretroviral pharmaceuticals began to be used in the United States and Western Europe to prevent HIV infection in contexts of occupational exposure. One decade later, the application of Post Exposure Prophylaxis (PEP) and Pre-Exposure Prophylaxis (PrEP) had been extended to include cases of exposure to sexual assault, injection-drug use, and consensual sexual intercourse deemed at high risk. This article explores the implementation of biomedicalized HIV prevention protocols at a public healthcare clinic in Mexico City, building on sociological-feminist approaches in Science and Technology Studies (STS) and drawing on interviews with key actors, as well as digital ethnography. We emphasise the stratified biomedicalization or, said otherwise, the differences in PEP and PrEP accessibility and consumption among different populations and groups. We also describe the fragile grip of institutionalised biomedical solutions when alternative 'moral economies' intersect with them, particularly in contexts like Mexico, where governmental funding for experimental research on biomedical innovations has been limited. This text reveals both the existence of contrasting technoscientific interventions along class and gender differences, and the multiple and vivid ways by which individuals appropriate and interpret global biomedical practices.
Topics: Cities; HIV Infections; Humans; Medicalization; Mexico
PubMed: 31630626
DOI: 10.1080/17441692.2019.1679217 -
Pharmaceutical Research Sep 2021Lipophilic conjugates (LCs) of small molecule drugs have been used widely in clinical and pre-clinical studies to achieve a number of pharmacokinetic and therapeutic... (Review)
Review
Lipophilic conjugates (LCs) of small molecule drugs have been used widely in clinical and pre-clinical studies to achieve a number of pharmacokinetic and therapeutic benefits. For example, lipophilic derivatives of drugs are employed in several long acting injectable products to provide sustained drug exposure for hormone replacement therapy and to treat conditions such as neuropsychiatric diseases. LCs can also be used to modulate drug metabolism, and to enhance drug permeation across membranes, either by increasing lipophilicity to enhance passive diffusion or by increasing protein-mediated active transport. Furthermore, such conjugation strategies have been employed to promote drug association with endogenous macromolecular carriers (e.g. albumin and lipoproteins), and this in turn results in altered drug distribution and pharmacokinetic profiles, where the changes can be 'general' (e.g. prolonged plasma half-life) or 'specific' (e.g. enhanced delivery to specific tissues in parallel with the macromolecular carriers). Another utility of LCs is to enhance the encapsulation of drugs within engineered nanoscale drug delivery systems, in order to best take advantage of the targeting and pharmacokinetic benefits of nanomedicines. The current review provides a summary of the mechanisms by which lipophilic conjugates, including in combination with delivery vehicles, can be used to control drug delivery, distribution and therapeutic profiles. The article is structured into sections which highlight a specific benefit of LCs and then demonstrate this benefit with case studies. The review attempts to provide a toolbox to assist researchers to design and optimise drug candidates, including consideration of drug-formulation compatibility.
Topics: Animals; Drug Compounding; Drug Delivery Systems; Humans; Pharmaceutical Preparations; Prodrugs
PubMed: 34463935
DOI: 10.1007/s11095-021-03093-x -
AAPS PharmSciTech Oct 2019The deployment of oral multi-unit pellet formulation has gained significant attention in recent years conferring to numerous applications, especially in achieving... (Review)
Review
The deployment of oral multi-unit pellet formulation has gained significant attention in recent years conferring to numerous applications, especially in achieving modified release and acid resistance property. The fluidized bed coating, specifically Wurster technique is commercially utilized for pellet manufacturing, which is a complex process involving too many variables. Risk assessment tools can be employed to determine the critical variables affecting the pre-defined quality profile and screen out important parameters out of literally hundreds of variables to develop a robust product. The present review aims to describe possibly all the variables involved in Wurster coating process and application of FMEA in pellet manufacturing. A brief case study regarding applicability of FMEA to study the effects of critical factors is outlined. Risk assessment tools assist to reduce number of trials to manageable levels with aid of prior art, literature, and preliminary trials to develop an optimized product.
Topics: Chemistry, Pharmaceutical; Drug Implants; Pharmaceutical Preparations; Technology, Pharmaceutical
PubMed: 31654266
DOI: 10.1208/s12249-019-1516-7 -
International Journal of Pharmaceutics Feb 2018With the progression towards personalised and age-appropriate medicines, the production of drug loaded liposomes at the point of care would be highly desirable. In...
With the progression towards personalised and age-appropriate medicines, the production of drug loaded liposomes at the point of care would be highly desirable. In particular, liposomal solubilisation agents that can be produced rapidly and easily would provide a new option in personalised medicines. Such a process could also be used as a rapid tool for the formulation and pre-clinical screening of low soluble drugs. Within this paper, we outline a novel easy-to-use production method for point of use production of liposome solubilised drugs. Our results demonstrate that pre-formed multilamellar liposomes, stored in a fresh or frozen format, can be bilayer loaded with low solubility drugs using a simple bath sonication process. Sonication is undertaken in a sealed vial allowing the contents to remain sterile. Liposomes around 100 nm were prepared and these liposomes were able to increase the amount of drug dissolved by up to 10 fold. These liposomal solubilisation agents were stable in terms of size and drug solubilisation for up to 8 days when stored in the fridge making them an easy to use and robust small-scale tool for drug solubilisation.
Topics: Chemistry, Pharmaceutical; Liposomes; Particle Size; Pharmaceutical Preparations; Phospholipids; Point-of-Care Systems; Solubility; Sonication
PubMed: 29225099
DOI: 10.1016/j.ijpharm.2017.12.012