scholarly journals Drug Disposition in the Lower Gastrointestinal Tract: Targeting and Monitoring

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 161
Author(s):  
Glenn Lemmens ◽  
Arno Van Camp ◽  
Stephanie Kourula ◽  
Tim Vanuytsel ◽  
Patrick Augustijns
Keyword(s):  
Drug Absorption ◽  
Drug Disposition ◽  
Drug Stability ◽  
Ussing Chamber ◽  
Dissolution Kinetics ◽  
Comprehensive Overview ◽  
Drug Molecules ◽  
Epithelial Physiology

The increasing prevalence of colonic diseases calls for a better understanding of the various colonic drug absorption barriers of colon-targeted formulations, and for reliable in vitro tools that accurately predict local drug disposition. In vivo relevant incubation conditions have been shown to better capture the composition of the limited colonic fluid and have resulted in relevant degradation and dissolution kinetics of drugs and formulations. Furthermore, drug hurdles such as efflux transporters and metabolising enzymes, and the presence of mucus and microbiome are slowly integrated into drug stability- and permeation assays. Traditionally, the well characterized Caco-2 cell line and the Ussing chamber technique are used to assess the absorption characteristics of small drug molecules. Recently, various stem cell-derived intestinal systems have emerged, closely mimicking epithelial physiology. Models that can assess microbiome-mediated drug metabolism or enable coculturing of gut microbiome with epithelial cells are also increasingly explored. Here we provide a comprehensive overview of the colonic physiology in relation to drug absorption, and review colon-targeting formulation strategies and in vitro tools to characterize colonic drug disposition.

Alkaloids as Anticancer Agents: A Review of Chinese Patents in Recent 5 Years

2020 ◽  
Vol 15 (1) ◽  
pp. 2-13 ◽  
Author(s):  
Hongyu Tao ◽  
Ling Zuo ◽  
Huanli Xu ◽  
Cong Li ◽  
Gan Qiao ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Cdk Inhibitors ◽  
Comprehensive Overview ◽  
P53 Expression ◽  
Study Results

Background: In recent years, many novel alkaloids with anticancer activity have been found in China, and some of them are promising for developing as anticancer agents. Objective: This review aims to provide a comprehensive overview of the information about alkaloid anticancer agents disclosed in Chinese patents, and discusses their potential to be developed as anticancer drugs used clinically. Methods: Anticancer alkaloids disclosed in Chinese patents in recent 5 years were presented according to their mode of actions. Their study results published on PubMed, and SciDirect databases were presented. Results: More than one hundred anticancer alkaloids were disclosed in Chinese patents and their mode of action referred to arresting cell cycle, inhibiting protein kinases, affecting DNA synthesis and p53 expression, etc. Conclusion: Many newly found alkaloids displayed potent anticancer activity both in vitro and in vivo, and some of the anticancer alkaloids acted as protein kinase inhibitors or CDK inhibitors possess the potential for developing as novel anticancer agents.

scholarly journals Generation of tetracycline-controllable CYP3A4-expressing Caco-2 cells by the piggyBac transposon system

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Moe Ichikawa ◽  
Hiroki Akamine ◽  
Michika Murata ◽  
Sumito Ito ◽  
Kazuo Takayama ◽  
...  
Keyword(s):  
Small Intestine ◽  
Drug Absorption ◽  
Cell Model ◽  
Negative Effects ◽  
Piggybac Transposon ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme ◽  
Cyp3a4 Expression

AbstractCaco-2 cells are widely used as an in vitro intestinal epithelial cell model because they can form a monolayer and predict drug absorption with high accuracy. However, Caco-2 cells hardly express cytochrome P450 (CYP), a drug-metabolizing enzyme. It is known that CYP3A4 is the dominant drug-metabolizing enzyme in human small intestine. In this study, we generated CYP3A4-expressing Caco-2 (CYP3A4-Caco-2) cells and attempted to establish a model that can simultaneously evaluate drug absorption and metabolism. CYP3A4-Caco-2 cells were generated by piggyBac transposon vectors. A tetracycline-controllable CYP3A4 expression cassette (tet-on system) was stably transduced into Caco-2 cells, thus regulating the levels of CYP3A4 expression depending on the doxycycline concentration. The CYP3A4 expression levels in CYP3A4-Caco-2 cells cultured in the presence of doxycycline were similar to or higher than those of adult small intestine. The CYP3A4-Caco-2 cells had enough ability to metabolize midazolam, a substrate of CYP3A4. CYP3A4 overexpression had no negative effects on cell proliferation, barrier function, and P-glycoprotein activity in Caco-2 cells. Thus, we succeeded in establishing Caco-2 cells with CYP3A4 metabolizing activity comparable to in vivo human intestinal tissue. This cell line would be useful in pharmaceutical studies as a model that can simultaneously evaluate drug absorption and metabolism.

scholarly journals 228 Antagonistic pH-selective VISTA antibody SNS-101 potentiates anti-PD-1/PD-L1-induced anti-tumor immunity

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A243-A243
Author(s):  
Thomas Thisted ◽  
Arnab Mukherjee ◽  
Kanam Malhotra ◽  
Zuzana Biesova ◽  
Yuliya Kleschenko ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cell ◽  
T Cell Activation ◽  
Drug Disposition ◽  
Checkpoint Inhibitors ◽  
Tumor Rejection ◽  
Therapeutic Window ◽  
Drug Candidate

BackgroundImmunotherapies, especially immune checkpoint inhibitors, have become a cornerstone of cancer treatment. Remarkable clinical responses have been observed blocking the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis across a spectrum of indications. However, innate and/or acquired resistance to anti-PD-1 blockade remains a major challenge. V-domain Ig suppressor of T-cell activation (VISTA) is a B7-family member, which promotes T-cell and myeloid quiescence and represents a promising target, particularly in combination with anti-PD-1/PD-L1 treatment. Recently, the interaction of VISTA with its receptor PSGL-1 was demonstrated to be significantly enhanced by the acidic tumor microenvironment (TME). As VISTA is highly expressed on myeloid cells, including those in the blood, antibodies binding VISTA at physiological pH 7.4 could result in rapid elimination from circulation through targeted-mediated drug disposition, making efficacious drug occupancy levels difficult to reach and potentially narrowing the therapeutic window. An antibody engineered to selectively bind and block VISTA at low pH in the TME may therefore be an ideal drug candidate.MethodsIn this study, fully human anti-VISTA antibodies were generated through pH-selective enrichment strategies of a yeast-based display library comprising highly diverse synthetic immune repertoires. The ‘parental’ antibodies have been extensively characterized using in vitro flow-cytometry, surface-plasmon resonance (SPR) and PSGL-1/VISTA inhibition assays in primary human CD4 and CD8 T-cells at pH 6.0 and pH 7.4. Eight parental antibodies were identified and tested for combinatorial efficacy with anti-PD-1 in vivo in human VISTA knock-in mice inoculated with syngeneic MC-38 tumors. These antibodies underwent further optimization for enhanced binding affinity at pH 6.0 and decreased binding at pH 7.4. ‘Progeny’ antibody ranking was based on the same in vitro and in vivo characterization as parental antibodies.ResultsEighty four parental antibodies were initially discovered. Flow-cytometry and SPR analysis revealed candidates displaying pH-dependent binding to endogenously expressed native VISTA on cells, and a PSGL-1/VISTA inhibition assay at pH 6.0 was run to identify and rank potent interface blockers. Eight candidate antibodies were tested in an in vivo intervention study in combination with anti-murine PD-1 demonstrating varied combinatorial efficacy with a subset leading to superior tumor rejection. Characterization of optimized progeny antibodies led to identification of anti-VISTA antibody SNS-101.ConclusionsEnrichment of highly diverse antibody libraries led to the identification of a pH-selective inhibitory anti-VISTA antibody SNS-101, which exerts excellent combinability with anti-PD-1 leading to superior anti-tumor activity in a mouse model.

scholarly journals A Review on the Enhancement of Calcium Phosphate Cement with Biological Materials in Bone Defect Healing

Polymers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 3075
Author(s):  
Sok Kuan Wong ◽  
Yew Hoong Wong ◽  
Kok-Yong Chin ◽  
Soelaiman Ima-Nirwana
Keyword(s):  
Calcium Phosphate ◽  
Calcium Phosphate Cement ◽  
Research Effort ◽  
Biological Materials ◽  
Biological Properties ◽  
Comprehensive Overview ◽  
Bone Defect Healing ◽  
Living Organisms

Calcium phosphate cement (CPC) is a promising material used in the treatment of bone defects due to its profitable features of self-setting capability, osteoconductivity, injectability, mouldability, and biocompatibility. However, the major limitations of CPC, such as the brittleness, lack of osteogenic property, and poor washout resistance, remain to be resolved. Thus, significant research effort has been committed to modify and reinforce CPC. The mixture of CPC with various biological materials, defined as the materials produced by living organisms, have been fabricated by researchers and their characteristics have been investigated in vitro and in vivo. This present review aimed to provide a comprehensive overview enabling the readers to compare the physical, mechanical, and biological properties of CPC upon the incorporation of different biological materials. By mixing the bone-related transcription factors, proteins, and/or polysaccharides with CPC, researchers have demonstrated that these combinations not only resolved the lack of mechanical strength and osteogenic effects of CPC but also further improve its own functional properties. However, exceptions were seen in CPC incorporated with certain proteins (such as elastin-like polypeptide and calcitonin gene-related peptide) as well as blood components. In conclusion, the addition of biological materials potentially improves CPC features, which vary depending on the types of materials embedded into it. The significant enhancement of CPC seen in vitro and in vivo requires further verification in human trials for its clinical application.

scholarly journals An In-Silico Study on Selected Organosulfur Compounds as Potential Drugs for SARS-CoV-2 Infection via Binding Multiple Drug Targets

2020 ◽  
Author(s):  
Liya Thurakkal ◽  
Satyam Singh ◽  
Sushabhan Sadhukhan ◽  
Mintu Porel
Keyword(s):  
Drug Targets ◽  
Target Prediction ◽  
Multiple Drug ◽  
Organosulfur Compounds ◽  
Potential Candidate ◽  
Health Crisis ◽  
Drug Molecules ◽  
Main Protease

The emerging paradigm shift from ‘one molecule, one target, for one disease’ towards ‘multi-targeted small molecules’ has paved an ingenious pathway in drug discovery in recent years. This idea has been extracted for the investigation of competent drug molecules for the unprecedented COVID-19 pandemic which became the greatest global health crisis now. Perceiving the importance of organosulfur compounds against SARS-CoV-2 from the drugs under clinical trials, a class of organosulfur compounds effective against SARS-CoV were selected and studied the interaction with multiple proteins of the SARS-CoV-2. One compound displayed inhibition against five proteins (both structural and non-structural) of the virus namely, main protease, papain-like protease, spike protein, helicase and RNA dependent RNA polymerase. Consequently, this compound emanates as a potential candidate for treating the virulent disease. The pharmacokinetics, ADMET properties and target prediction studies carried out in this work further inflamed the versatility of the compound and urge to execute <i>in-vitro</i> and <i>in-vivo</i> analysis on SARS-CoV-2 in the future.<br>

scholarly journals Induction and Maturation of Hepatocyte-Like Cells In Vitro: Focus on Technological Advances and Challenges

2021 ◽  
Vol 9 ◽  
Author(s):  
Ye Xie ◽  
Jia Yao ◽  
Weilin Jin ◽  
Longfei Ren ◽  
Xun Li
Keyword(s):  
Genetic Manipulation ◽  
Toxicity Testing ◽  
Basic Research ◽  
Drug Approval ◽  
Cell Types ◽  
Comprehensive Overview ◽  
Technological Advances ◽  
Degree Of Differentiation

Limited by the poor proliferation and restricted sources of adult hepatocytes, there is an urgent need to find substitutes for proliferation and cultivation of mature hepatocytes in vitro for use in disease treatment, drug approval, and toxicity testing. Hepatocyte-like cells (HLCs), which originate from undifferentiated stem cells or modified adult cells, are considered good candidates because of their advantages in terms of cell source and in vitro expansion ability. However, the majority of induced HLCs are in an immature state, and their degree of differentiation is heterogeneous, diminishing their usability in basic research and limiting their clinical application. Therefore, various methods have been developed to promote the maturation of HLCs, including chemical approaches, alteration of cell culture systems, and genetic manipulation, to meet the needs of in vivo transplantation and in vitro model establishment. This review proposes different cell types for the induction of HLCs, and provide a comprehensive overview of various techniques to promote the generation and maturation of HLCs in vitro.

Design and In-Vivo Evaluation of Risperidone Buccal Mucoadhesive Patches of Interpolymer Matrix

2021 ◽  
pp. 5305-5312
Author(s):  
Pradeep HK ◽  
Girish B ◽  
Nooruddeen K ◽  
Thimmasetty J ◽  
Venkateswarlu BS
Keyword(s):  
Drug Release ◽  
Drug Absorption ◽  
Kinetic Models ◽  
Phosphate Buffer Solution ◽  
Water Soluble ◽  
Content Uniformity ◽  
Human Beings ◽  
Insoluble Polymers

The buccal cavity is an alternate route for the administration of the drug. This route gained acceptance as increase in bioavailability is observed due to bypass of first pass metabolism. Solvent casting method was employed for the preparation of the risperidone mucoadhesive patches using different combinations of water soluble and water insoluble polymers using polyvinyl alcohol as a backing layer. Our main objective of this study was to understand the behaviour of water soluble and water insoluble polymers in combination on release pattern. Six different formulations of mucoadhesive patches were evaluated for physicochemical parameters like weight uniformity, content uniformity, thickness uniformity, surface pH, swelling studies, tensile strength, folding endurance, in-vitro drug release, and in-vivo drug absorption. Drug loaded mucoadhesive patches of various polymer bases had shown 35.64 to 72.33% drug release in 30 min in phosphate buffer solution of pH 6.6. In-vitro release data from patches were fit to different equations and kinetic models to explain release profiles. Kinetic models like Hixon-Crowell and Higuchi models were used. The formulation containing HPMC (15Cps) and polyvinyl pyrrolidone was considered as optimized based on the physicochemical and pharmaceutical properties. In-vivo studies in rabbits, carried out with prior permission from IAEC, showed 80.40% of drug release from the optimized patches. In-vivo and in-vitro correlations were found to be good. The drug absorption was found significant from the optimized formulation in healthy rabbits. The structure of the buccal membrane and permeability factors are similar in both human beings and rabbits. Therefore mucoadhesive patches of risperidone may be accepted with the important advantage of reduced risperidone dose.

A physiologically based biopharmaceutical analysis of zolpidem

2021 ◽  
Author(s):  
◽  
Rafael Leal Monteiro Paraiso
Keyword(s):  
Drug Development ◽  
Drug Absorption ◽  
Oral Absorption ◽  
Food Effect ◽  
Simulation Software ◽  
Oral Drug ◽  
Oral Drug Absorption ◽  
Physiologically Based

Computational oral absorption models, in particular PBBM models, provide a powerful tool for researchers and pharmaceutical scientists in drug discovery and formulation development, as they mimic and can describe the physiologically processes relevant to the oral absorption. PBBM models provide in vivo context to in vitro data experiments and allow for a dynamic understanding of in vivo drug disposition that is not typically provided by data from standard in vitro assays. Investigations using these models permit informed decision-making, especially regarding to formulation strategies in drug development. PBBM models, but can also be used to investigate and provide insight into mechanisms responsible for complex phenomena such as food effect in drug absorption. Although there are obviously still some gaps regarding the in silico construction of the gastrointestinal environment, ongoing research in the area of oral drug absorption (e.g. the UNGAP, AGE-POP and InPharma projects) will increase knowledge and enable improvement of these models. PBBM can nowadays provide an alternative approach to the development of in vitro–in vivo correlations. The case studies presented in this thesis demonstrate how PBBM can address a mechanistic understanding of the negative food effect and be used to set clinically relevant dissolution specification for zolpidem immediate release tablets. In both cases, we demonstrated the importance of integrating drug properties with physiological variables to mechanistically understand and observe the impact of these parameters on oral drug absorption. Various complex physiological processes are initiated upon food consumption, which can enhance or reduce a drug’s dissolution, solubility, and permeability and thus lead to changes in drug absorption. With improvements in modeling and simulation software and design of in vitro studies, PBBM modeling of food effects may eventually serve as a surrogate for clinical food effect studies for new doses and formulations or drugs. Furthermore, the application of these models may be even more critical in case of compounds where execution of clinical studies in healthy volunteers would be difficult (e.g., oncology drugs). In the fourth chapter we have demonstrated the establishment of the link between biopredictive in vitro dissolution testing (QC or biorelevant method) PBBM coupled with PD modeling opens the opportunity to set truly clinically relevant specifications for drug release. This approach can be extended to other drugs regardless of its classification according to the BCS. With the increased adoption of PBBM, we expect that best practices in development and verification of these models will be established that can eventually inform a regulatory guidance. Therefore, the application of Physiologically Based Biopharmaceutical Modelling is an area with great potential to streamline late-stage drug development and impact on regulatory approval procedures. Freie Schlagwörter / Tags

scholarly journals LC478, a Novel Di-Substituted Adamantyl Derivative, Enhances the Oral Bioavailability of Docetaxel in Rats

Pharmaceutics ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 135 ◽  
Author(s):  
Seung Han ◽  
Qili Lu ◽  
Kyeong Lee ◽  
Young Choi
Keyword(s):  
Oral Bioavailability ◽  
Oral Absorption ◽  
Ussing Chamber ◽  
Absolute Bioavailability ◽  
Time Curve ◽  
Glycoprotein P ◽  
Dose Concentration ◽  
Chamber Studies

P-glycoprotein (P-gp)-mediated efflux of docetaxel in the gastrointestinal tract mainly impedes its oral chemotherapy. Recently, LC478, a novel di-substituted adamantyl derivative, was identified as a non-cytotoxic P-gp inhibitor in vitro. Here, we assessed whether LC478 enhances the oral bioavailability of docetaxel in vitro and in vivo. LC478 inhibited P-gp mediated efflux of docetaxel in Caco-2 cells. In addition, 100 mg/kg of LC478 increased intestinal absorption of docetaxel, which led to an increase in area under plasma concentration-time curve (AUC) and absolute bioavailability of docetaxel in rats. According to U.S. FDA criteria (I, an inhibitor concentration in vivo tissue)/(IC50, inhibitory constant in vitro) >10 determines P-gp inhibition between in vitro and in vivo. The values 15.6–20.5, from (LC478 concentration in intestine, 9.37–12.3 μM)/(IC50 of LC478 on P-gp inhibition in Caco-2 cell, 0.601 μM) suggested that 100 mg/kg of LC478 sufficiently inhibited P-gp to enhance oral absorption of docetaxel. Moreover, LC478 inhibited P-gp mediated efflux of docetaxel in the ussing chamber studies using rat small intestines. Our study demonstrated that the feasibility of LC478 as an ideal enhancer of docetaxel bioavailability by P-gp inhibition in dose (concentration)-dependent manners.

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