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Pharmacomicrobiomics: The Holy Grail to Variability in Drug Response?
Sharma, A, Buschmann, MM, Gilbert, JA
Clinical pharmacology and therapeutics. 2019;(2):317-328
Abstract
The human body, with 3.0 × 1013 cells and more than 3.8 × 1013 microorganisms, has nearly a one-to-one ratio of resident microbes to human cells. Initiatives like the Human Microbiome Project, American Gut, and Flemish Gut have identified associations between microbial taxa and human health. The study of interactions between microbiome and pharmaceutical agents, i.e., pharmacomicrobiomics, has revealed an instrumental role of the microbiome in modulating drug response that alters the therapeutic outcomes. In this review, we present our current comprehension of the relationship of the microbiome, host biology, and pharmaceutical agents such as cardiovascular drugs, analgesics, and chemotherapeutic agents to human disease and treatment outcomes. We also discuss the significance of studying diet-gene-drug interactions and further address the key challenges associated with pharmacomicrobiomics. Finally, we examine proposed models employing systems biology for the application of pharmacomicrobiomics and other -omics data, and provide approaches to elucidate microbiome-drug interactions to improve future translation to personalized medicine.
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Architectures and Mechanical Properties of Drugs and Complexes of Surface-Active Compounds at Air-Water and Oil-Water Interfaces.
Sarker, DK
Current drug discovery technologies. 2019;(1):11-29
Abstract
BACKGROUND Drugs can represent a multitude of compounds from proteins and peptides, such as growth hormones and insulin and on to simple organic molecules such as flurbiprofen, ibuprofen and lidocaine. Given the chemical nature of these compounds two features are always present. A portion or portions of the molecule that has little affinity for apolar surfaces and media and on the contrary a series of part or one large part that has considerable affinity for hydrophilic, polar or charged media and surfaces. A series of techniques are routinely used to probe the molecular interactions that can arise between components, such as the drug, a range of surface- active excipients and flavor compounds, for example terpenoids and the solvent or dispersion medium. RESULTS Fifty-eight papers were included in the review, a large number (16) being of theoretical nature and an equally large number (14) directly pertaining to medicine and pharmacy; alongside experimental data and phenomenological modelling. The review therefore simultaneously represents an amalgam of review article and research paper with routinely used or established (10) and well-reported methodologies (also included in the citations within the review). Experimental data included from various sources as diverse as foam micro-conductivity, interferometric measurements of surface adsorbates and laser fluorescence spectroscopy (FRAP) are used to indicate the complexity and utility of foams and surface soft matter structures for a range of purposes but specifically, here for encapsulation and incorporation of therapeutics actives (pharmaceutical molecules, vaccines and excipients used in medicaments). Techniques such as interfacial tensiometry, interfacial rheology (viscosity, elasticity and visco-elasticity) and nanoparticle particle size (hydrodynamic diameter) and charge measurements (zeta potential), in addition to atomic force and scanning electron microscopy have proven to be very useful in understanding how such elemental components combine, link or replace one another (competitive displacement). They have also proven to be both beneficial and worthwhile in the sense of quantifying the unseen actions and interplay of adsorbed molecules and the macroscopic effects, such as froth formation, creaming or sedimentation that can occur as a result of these interactions. CONCLUSION The disclosures and evaluations presented in this review confirm the importance of a theoretical understanding of a complex model of the molecular interactions, network and present a framework for the understanding of really very complex physical forms. Future therapeutic developers rely on an understanding of such complexity to garner a route to a more successful administration and formulation of a new generation of therapeutic delivery systems for use in medicine.
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The Role of the Phosphorus Atom in Drug Design.
Rodriguez, JB, Gallo-Rodriguez, C
ChemMedChem. 2019;(2):190-216
Abstract
Although the phosphorus atom is found in a variety of oxidation states, most of the phosphorus-containing molecules of pharmacological importance possess phosphorus in the form of phosphonate or phosphinate functional groups, or in a major oxidation state as a phosphate group. The most common occurrence of phosphorus in drugs is either in prodrugs or in compounds for which the phosphorus atom plays a role in the biological activity, such as in modified nucleotides, in metabolically stable analogues of metabolites bearing phosphate groups, and as bioisosteric analogues of carboxyl groups.
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Assessment of Pharmacokinetic Drug-Drug Interactions in Humans: In Vivo Probe Substrates for Drug Metabolism and Drug Transport Revisited.
Fuhr, U, Hsin, CH, Li, X, Jabrane, W, Sörgel, F
Annual review of pharmacology and toxicology. 2019;:507-536
Abstract
Pharmacokinetic parameters of selective probe substrates are used to quantify the activity of an individual pharmacokinetic process (PKP) and the effect of perpetrator drugs thereon in clinical drug-drug interaction (DDI) studies. For instance, oral caffeine is used to quantify hepatic CYP1A2 activity, and oral dagibatran etexilate for intestinal P-glycoprotein (P-gp) activity. However, no probe substrate depends exclusively on the PKP it is meant to quantify. Lack of selectivity for a given enzyme/transporter and expression of the respective enzyme/transporter at several sites in the human body are the main challenges. Thus, a detailed understanding of the role of individual PKPs for the pharmacokinetics of any probe substrate is essential to allocate the effect of a perpetrator drug to a specific PKP; this is a prerequisite for reliably informed pharmacokinetic models that will allow for the quantitative prediction of perpetrator effects on therapeutic drugs, also in respective patient populations not included in DDI studies.
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Emerging Research Paradigm for Infant Drug Exposure Through Breast Milk.
Ito, S
Current pharmaceutical design. 2019;(5):528-533
Abstract
BACKGROUND Information on drug secretion into milk is insufficient due to the exclusion of lactating women from clinical trials and drug development processes. As a result, non-adherence to the necessary drug therapy and discontinuation of breastfeeding occur, even if the predicted level of infant exposure is low. In contrast, inadvertent infant exposure to drugs in breast milk continues to happen due to lack of rational risk assessment, resulting in serious toxicity cases including death. This problem is multifactorial, but one of the key elements is the lack of pharmacokinetic information on drug secretion into milk and resultant infant exposure levels, the first line of evidence for risk assessment. METHODS Basic PK principles in drug excretion into milk were explained. The literature was scanned to identify approaches for PK data acquisition in this challenging field. RESULTS This review describes the feasibility to develop such approaches, and the knowledge gaps that still exist. A combination of population pharmacokinetics approach (to estimate averages and variations of drug concentration profiles in milk) and physiologically-based pharmacokinetics modeling of infants (to predict the population profiles of infant drug exposure levels) appears useful. CONCLUSIONS In order to facilitate participant enrollment and PK data acquisition in a timely manner, networks of investigators become crucial.
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Intermolecular Interactions between Drugs and Aminoalkyl Methacrylate Copolymer in Solution to Enhance the Concentration of Poorly Water-Soluble Drugs.
Higashi, K, Ueda, K, Moribe, K
Chemical & pharmaceutical bulletin. 2019;(9):906-914
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Abstract
An aminoalkyl methacrylate copolymer, Eudragit® E (EUD-E), has gained tremendous attention as a solid dispersion carrier because it efficiently stabilizes drugs in the amorphous state. Furthermore, EUD-E remarkably enhances drug dissolution in water. This review focuses on the interaction between drugs and EUD-E in solution, which contributes to the enhancement of drug concentration. Studies examining interactions between acidic drugs and EUD-E in organic solvents have revealed that the interaction occurs predominantly by electrostatic interaction, including hydrogen bonding and dipolar interactions. Other studies on interactions in aqueous solution found evidence for strong electrostatic interactions between acidic drugs and EUD-E in ion exchange experiments. 1H-NMR studies using high-resolution magic-angle spinning, nuclear Overhauser effect spectroscopy, diffusion, and relaxation time measurements successfully identified the interaction site and strength in aqueous solution. Hydrophobic and ionic interactions occurred between drugs and EUD-E. The conformation of EUD-E, which was affected by the ionic strength and pH of the aqueous media, also influenced the interaction. The knowledge discussed in this review will be helpful in designing solid dispersion formulations with EUD-E, which will efficiently enhance drug concentration and subsequent absorption into the body.
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Advances and challenges in studying noncoding RNA regulation of drug metabolism and development of RNA therapeutics.
Ning, B, Yu, D, Yu, AM
Biochemical pharmacology. 2019;:113638
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Abstract
Accumulating evidence has demonstrated that genome-derived noncoding RNAs (ncRNAs) play important roles in modulating inter-individual variations observed in drug metabolism and disposition by controlling the expression of genes coding drug metabolizing enzymes and transporters (DMETs) and relevant nuclear receptors (NRs). With the understanding of novel ncRNA regulatory mechanisms and significance in the control of disease initiation and progression, RNA-based therapies are under active investigation that may expand the druggable targets from conventional proteins to RNAs and the genome for the treatment of human diseases. Herein we provide an overview of research strategies, approaches and their limitations in biochemical and pharmacological studies pertaining to ncRNA functions in the regulation of drug and nutrient metabolism and disposition, and discussion on the promise and challenges in developing RNA therapeutics.
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Recent advances in nanotechnology for the treatment of metabolic syndrome.
Bahadori, E, Farjami, Z, Rezayi, M, Lngari, H, Darroudi, M, Avan, A, Ghayour-Mobarhan, M
Diabetes & metabolic syndrome. 2019;(2):1561-1568
Abstract
Metabolic syndrome is a main clinical challenge of global health which is growing universally. It would be resulted from over-consumption of energy, increased obesity, and lack of movement during life. The metabolic syndrome causes a five-fold increase in the risk of type 2 diabetes mellitus and a double increase in the risk of rising cardiovascular disease over the next 5-10 years. Based on this, more attention has been drawn to the diagnosis and treatment options of this disease. Nanotechnology is one of the preferred methods for improving this disease. This way is a natural development in many health domains, including synthetic and nanostructures. The use of nanoparticles with the purpose of increase the effectiveness of treatment, decrease the side effects and the amount of drug usage, through their small size, permeability and maintenance strength lead to their absorption by target organs. Meanwhile, different nanoparticles with consumption values and particle size have been investigated.
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Low colonic absorption drugs: risks and opportunities in the development of oral extended release products.
Xu, J, Lin, Y, Boulas, P, Peterson, ML
Expert opinion on drug delivery. 2018;(2):197-211
Abstract
INTRODUCTION Currently numerous drugs have been observed with lower colonic absorption than small intestine absorption, which can significantly impact in vivo performance of their oral extended release (ER) products. AREAS COVERED We reviewed over 300 publications, patents, book chapters, and commercial reports of drug products from regulatory agencies for low colonic absorption (LCA) drugs and critical findings are discussed. The focuses of this article are (1) current findings on the causes of low colonic absorption to support early assessment of LCA candidates, and (2) current knowledge on successful ER strategies and technical platforms used for LCA drugs in commercial drug products to facilitate oral ER product development. EXPERT OPINION Colonic drug absorption is one of the critical considerations in successful development of oral ER products. The root causes of low colonic absorption in many LCA drugs are still unclear. It is recommended to evaluate colonic drug absorption of drug candidate at early stage of oral ER product development. After evaluation, the selection of a formulation platform to develop an oral ER product needs to be carefully considered for LCA drugs. Based on the current commercial oral ER formulation platforms for LCA drugs, compounds are first divided into five types (I-V) and different ER formulation approaches with higher success rate are recommended for each type.
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Physiological and Pharmaceutical Knowledge in "Ninja" Society: Suggestions for Modern Anesthesiologists and Intensivists.
Takazawa, T, Tobe, M, Kimura, M, Suto, T, Ohta, J, Matsuoka, H, Yano, H, Saito, S
Journal of anesthesia history. 2018;(4):209-213
Abstract
Anesthesiologists and intensivists are modern professionals who provide conscious sedation and respiratory care and prescribe medicines with potential toxicity. Similarly, ninjas, covert agent soldiers who carried out special operations in medieval Japan, also had ample knowledge of toxicology, psychology, human consciousness and respiration. Although the extent of their knowledge remains largely unknown, that which has been described in the literature appears to be practical and scientifically explainable from the standpoint of modern medical science.