Section 6: Pharmaceutics, Pharmacokinetics, Drug Discovery
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PROVIDER: S-EPMC5519255 | biostudies-literature | 2017 Jul
REPOSITORIES: biostudies-literature
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Project description:The low solubility of active pharmaceutical ingredients (APIs) is a problem in pharmaceutical development. Several methodologies can be used to improve API solubility, including the use of eutectic systems in which one of the constituents is the API. This class of compounds is commonly called Therapeutic Deep Eutectic Systems (THEDES). THEDES has been gaining attention due to their properties such as non-toxicity, biodegradability, and being non-expensive and easy to prepare. Since the knowledge of the solid liquid diagram of the mixture and the ideal eutectic point is necessary to ascertain if a mixture is a deep eutectic or just a eutectic mixture that is liquid at ambient temperature, the systems studied in this work are called Therapeutic Liquid Eutectic Systems (THELES). Therefore, the strategy proposed in this work is to improve the solubility of chlorpropamide and tolbutamide by preparing THELES. Both APIs are sulfonylurea compounds used for the treatment of type 2 diabetes mellitus and have low solubility in water. To prepare the THELES, several coformers were tested, namely, tromethamine, L(+)-arginine, L-tryptophan, citric acid, malic acid, ascorbic acid, and p-aminobenzoic acid, in molar ratios of 1:1 and 1:2. To improve viscosity, water was added in different molar ratios to all systems. THELES were characterized by mid-infrared spectroscopy (MIR), and differential scanning calorimetry. Their viscosity, solubility, and permeability were also determined. Their stability at room temperature and 40 °C was accessed by MIR. Cytocompatibility was performed by metabolic activity and cell lysis evaluation, according to ISO10993-5:2009, and compared with the crystalline APIs. THELES with TRIS were successfully synthesized for both APIs. Results showed an increased solubility without a decrease in the permeability of the APIs in the THELES when compared with the pure APIs. The THELES were also considered stable for 8 weeks at ambient temperature. The cells studied showed that the THELES were not toxic for the cell lines used.
| S-EPMC8951776 | biostudies-literature
Project description:G-protein-coupled receptors (GPCRs) mediate many important physiological functions and are considered as one of the most successful therapeutic targets for a broad spectrum of diseases. The design and implementation of high-throughput GPCR assays that allow the cost-effective screening of large compound libraries to identify novel drug candidates are critical in early drug discovery. Early functional GPCR assays depend primarily on the measurement of G-protein-mediated 2nd messenger generation. Taking advantage of the continuously deepening understanding of GPCR signal transduction, many G-protein-independent pathways are utilized to detect the activity of GPCRs, and may provide additional information on functional selectivity of candidate compounds. With the combination of automated imaging systems and label-free detection systems, such assays are now suitable for high-throughput screening (HTS). In this review, we summarize the most widely used GPCR assays and recent advances in HTS technologies for GPCR drug discovery.
| S-EPMC3312097 | biostudies-other
Project description:Necroptosis is a programmed form of cell death. Receptor-interacting serine/threonine protein kinase l (RIPK1) is a crucial protein kinase that regulates the necroptosis pathway. Increased expression of death receptor family ligands such as tumor necrosis factor (TNF) increases the susceptibility of cells to apoptosis and necroptosis. RIPK1, RIPK3, and mixed-lineage kinase-like domain (MLKL) proteins mediate necrosis. RIPK1-mediated necroptosis further promotes cell death and inflammation in the pathogenesis of liver injury, skin diseases, and neurodegenerative diseases. The N-terminal kinase domain of RIPK1 is significant in the induction of cell death and can be used as a vital drug target for inhibitors. In this paper, we outline the pathways of necroptosis and the role RIPK1 plays in them and suggest that targeting RIPK1 in therapy may help to inhibit multiple cell death pathways.
| S-EPMC11850271 | biostudies-literature
Project description:Related to concerns about the role of obesity in the efficacy of contraceptive drugs, a review of the literature was carried out in regard to the pharmacokinetics of ethinyl estradiol and various progestins given by various routes of administration. Most studies show that obese women exhibit modestly lower plasma concentrations of these drugs (circa 30%) when given the same doses as normal-weight women. While the mechanism is uncertain, precedence in the literature suggests that this is due to body weight-related differences in metabolism rates. Confusing in some of the literature is that a few studies have reported erroneously calculated pharmacokinetic parameters after multiple dosing of oral contraceptives. A demonstration of appropriate pharmacokinetic methodology is provided.
| S-EPMC5422994 | biostudies-other
Project description:Continued discovery and development of new antiviral medications are paramount for global human health, particularly as new pathogens emerge and old ones evolve to evade current therapeutic agents. Great success has been achieved in developing effective therapies to suppress human immunodeficiency virus (HIV) and hepatitis B virus (HBV); however, the therapies are not curative and therefore current efforts in HIV and HBV drug discovery are directed toward longer-acting therapies and/or developing new mechanisms of action that could potentially lead to cure, or eradication, of the virus. Recently, exciting early clinical data have been reported for novel antivirals targeting respiratory syncytial virus (RSV) and influenza (flu). Preclinical data suggest that these new approaches may be effective in treating high-risk patients afflicted with serious RSV or flu infections. In this review, we highlight new directions in antiviral approaches for HIV, HBV, and acute respiratory virus infections.
| S-EPMC4765712 | biostudies-other
Project description:Vortioxetine is a novel antidepressant with multimodal activity currently approved for the treatment of major depressive disorder. Vortioxetine is orally administered once daily at 5- to 20-mg doses. The pharmacokinetics of vortioxetine are linear and dose proportional, with a mean terminal half-life of approximately 66 h and steady-state plasma concentrations generally achieved within 2 weeks of dosing. The mean absolute oral bioavailability of vortioxetine is 75%. No food effect on pharmacokinetics was observed. Vortioxetine is metabolized by cytochrome P450 enzymes and subsequently by uridine diphosphate glucuronosyltransferase. The major metabolite is pharmacologically inactive, and the minor pharmacologically active metabolite is not expected to cross the blood-brain barrier, making the parent compound primarily responsible for in-vivo activity. No clinically relevant differences were observed in vortioxetine exposure by sex, age, race, body size, and renal or hepatic function. Dose adjustment is only recommended for cytochrome P450 2D6 poor metabolizers based on polymorphism of the cytochrome P450 enzymes involved. Similarly, except for bupropion, a strong cytochrome P450 2D6 inhibitor, and rifampin, a broad cytochrome P450 inducer, co-administration of other drugs evaluated did not affect the vortioxetine exposure or safety profile in any clinically meaningful way. Pharmacodynamic studies demonstrated that vortioxetine achieved high levels of serotonin transporter occupancy in relevant brain areas, affected neurotransmitter levels in the cerebrospinal fluid, and modified abnormal resting state networks in the brain over the therapeutic dose range. Overall, vortioxetine can be administered in most populations studied to date without major dose adjustments; however, dose adjustments should be considered on a patient-by-patient basis.
| S-EPMC5973995 | biostudies-literature
Project description:The import of nuclear transcribed RNAs into mitochondria is an emerging area that presents tremendous opportunity to develop human metabolic therapeutics. However, our knowledge base is quite limited. Much remains to be discovered regarding specific RNA localization and mechanisms of import. In order to identify novel RNAs imported into mitochondria, all RNAs within the mitochondria were characterized using next generation sequencing technology. Several nuclear transcribed RNAs were found within mitochondrial RNA samples, including nuclear ribosomal RNAs, gamma satellite RNA and VL30 retroelement RNA. The presence of these RNAs within mitochondria coupled with RNA sequencing data (RNAseq) from other laboratories investigating mitochondrial RNA processing, lead us to hypothesize that nuclease treatment of mitoplasts is insufficient for removing contaminating cytoplasmic RNAs. In contrast to traditional methodology, mitochondrial import was evaluated by qRT-PCR after stepwise removal of the outer mitochondrial membrane and subsequent lysis of mitochondria. This allowed identification of RNAs lost from the mitochondria with the same kinetics as mtDNA-transcribed RNAs. This approach provided an improved evaluation of nuclear RNA enrichment within mitochondrial membranes in order to characterize nuclease protection and mitochondrial import and identify false-positive detection errors. qRT-PCR results confirmed the presence of VL30 retroelement RNA within mitochondria and question the hypothesis that the RNA component of RNase P is imported. These results illustrate a reliable approach for evaluating the presence of RNAs within mitochondria and open new avenues of investigation relating to mitochondrial RNA biology and in targeting mitochondrial based therapeutics.
2017-10-08 | GSE62170 | GEO
Project description:Drug discovery in the ovarian cancer arena continues to launch important new clinical trials. Many biologic agents are being studied in phase II and phase III clinical trials for recurrent disease. These agents include compounds that disrupt angiogenesis through a variety of mechanisms. Other oncogenic pathways are also specifically targeted such as PARP, MEK, and topoisomerase inhibitors which are currently being studied in phase III trials. Various cytotoxic agents, as well as therapeutic vaccines, are also under investigation, and continue to demonstrate promising new data. The relevant agents in the treatment of ovarian cancer which have demonstrated positive phase II activity will be discussed.
| S-EPMC4878024 | biostudies-other
Project description:The discovery of chlorothricin (1) defined a new family of microbial metabolites with potent antitumor antibiotic properties collectively referred to as spirotetronate polyketides. These microbial metabolites are structurally distinguished by the presence of a spirotetronate motif embedded within a macrocyclic core. Glycosylation at the periphery of this core contributes to the structural complexity and bioactivity of this motif. The spirotetronate family displays impressive chemical structures, potent bioactivities, and significant pharmacological potential. This review groups the family members based on structural and biosynthetic considerations and summarizes synthetic and biological studies that aim to elucidate their mode of action and explore their pharmacological potential.
| S-EPMC4380204 | biostudies-other
Project description:Embryonic stem (ES) cells and their differentiated progeny offer tremendous potential for regenerative medicine, even in the field of drug discovery. There is an urgent need for clinically relevant assays that make use of ES cells because of their rich biological utility. Attention has been focused on small molecules that allow the precise manipulation of cells in vitro, which could allow researchers to obtain homogeneous cell types for cell-based therapies and discover drugs for stimulating the regeneration of endogenous cells. Such therapeutics can act on target cells or their niches in vivo to promote cell survival, proliferation, differentiation, and homing. In the present paper, we reviewed the use of ES cell models for high-throughput/content drug screening and toxicity assessment. In addition, we examined the role of stem cells in large pharmaceutical companies' R&D and discussed a novel subject, nicheology, in stem cell-related research fields.
| S-EPMC4009932 | biostudies-other