14,625 results match your criteria pharmacokinetic profile


Si113-prodrugs selectively activated by plasmin against hepatocellular and ovarian carcinoma.

Eur J Med Chem 2021 Jun 17;223:113653. Epub 2021 Jun 17.

Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy; Lead Discovery Siena S.r.l., Via Vittorio Alfieri 31, 53019, Castelnuovo Berardenga, Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology Temple University, BioLife Science Building, Suite 333, 1900 North 12th Street, Philadelphia, PA, 19122, United States.

Si113, a pyrazolo[3,4-d]pyrimidine derivative, gained more attention as an anticancer agent due to its potent anticancer activity on both in vitro and in vivo hepatocellular carcinomas (HCC) and ovarian carcinoma models. But the drawback is the low water solubility which prevents its further development. In this context, we successfully overcame this limitation by synthesizing two novel prodrugs introducing the amino acid sequence D-Ala-Leu-Lys (TP). Read More

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Anticancer potential of indirubins in medicinal chemistry: Biological activity, structural modification, and structure-activity relationship.

Eur J Med Chem 2021 Jun 17;223:113652. Epub 2021 Jun 17.

Key Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province, Key Laboratory of Basic Pharmacology of Ministry of Education, School of Pharmacy, Zunyi Medical University, 6 West Xuefu Road, Zunyi, 563000, PR China. Electronic address:

Indirubin is the crucial ingredient of Danggui Longhui Wan and Qing-Dai, traditional Chinese medicine herbal formulas used for the therapy of chronic myelocytic leukemia in China for hundreds of years. Although the monomeric indirubin has been used in China for the treatment human chronic myelocytic leukemia. However, due to low water solubility, poor pharmacokinetic properties and low therapeutic effects are the major obstacle, and had significantly limited its clinical application. Read More

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Analysis of the toxicological and pharmacokinetic profile of Kaempferol-3-O-β-D-(6"-E-p-coumaryl) glucopyranoside - Tiliroside: in silico, in vitro and ex vivo assay.

Braz J Biol 2021 21;83:e244127. Epub 2021 Jun 21.

Universidade Federal da Paraíba - UFPB, Centro de Ciências da Saúde, Departamento de Fisiologia e Patologia, Pós-graduação em Desenvolvimento e Inovação Tecnológica de Medicamentos, João Pessoa, PB, Brasil.

Tiliroside is a glycosidic flavonoid present in many plants species including Helicteres velutina K. Schum (Malvaceae sensu lato), commonly known in Brazil as "pitó". This molecule has been shown to have many biological activities, however no study has been carried out to investigate the toxicity of this substance. Read More

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Pharmacokinetics of enflicoxib in dogs: Effects of prandial state and repeated administration.

J Vet Pharmacol Ther 2021 Jun 23. Epub 2021 Jun 23.

Welab Barcelona, Barcelona Science Park (PCB), Barcelona, Spain.

The pharmacokinetics of enflicoxib were evaluated in both a bioavailability study and a multi-dose safety study in Beagle dogs. When administered at 8 mg/kg, the oral bioavailability (F) of enflicoxib was 44.1% in fasted dogs, but F increased to 63. Read More

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Simultaneous Quantification of Four Compounds in Rat Plasma by HPLC-MS/MS and Its Application to Pharmacokinetic Study after Oral Administration of Pomegranate Flowers.

J Chromatogr Sci 2021 Jun 23. Epub 2021 Jun 23.

University of Chinese Academy of Sciences, Beijing 100049, China.

Pomegranate flowers (PFs) were reported to possess various biological activities such as antidiabetic, anti-inflammatory and hepatoprotective activities, and using to treat diabetes. Although chemical constituents and pharmacological activities of PFs have been studied, unfortunately, there was no report on the pharmacokinetic profile of PFs in vivo. In this study, a selective high-performance liquid chromatography triple quadrupole tandem mass spectrometry (HPLC-QQQ-MS/MS) method was developed and validated for simultaneous quantification of four compounds (corilagin, ellagic acid, gallic acid and brevifolincarboxylic acid) in rat plasma after oral administration of PFs. Read More

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An evaluation of ledipasvir + sofosbuvir for the treatment of chronic Hepatitis C infection.

Expert Opin Pharmacother 2021 Jun 23. Epub 2021 Jun 23.

Department of Clinical Pharmacy and Translational Science, University of Tennessee Health Science Center College of Pharmacy.

Introduction: Hepatitis C (HCV) is viral disease with a global impact. Over the last 10 years, the treatment of this disease has evolved. Treatment guidelines have evolved to adopt new medications for HCV. Read More

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Pharmacodynamics and pharmacokinetics of a copper intrauterine contraceptive system releasing ulipristal acetate: a randomized proof-of-concept study.

Contraception 2021 Jun 19. Epub 2021 Jun 19.

Population Council. 1230 York Avenue, New York City, NY, 10065, USA.

Objectives: To assess pharmacodynamic and pharmacokinetic outcomes of a novel copper (Cu) intrauterine system (IUS) releasing ulipristal acetate (UPA) in healthy women.

Study Design: In this single-blinded, randomized proof-of-concept study, ovulatory women received one of three Cu-IUSs releasing low-dose UPA (5, 20 or 40 µg/d) for 12 weeks. The study included a baseline cycle, three 4-week treatment-cycles and two recovery cycles. Read More

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Pharmacokinetics and brain sigma 1 (σ1) receptor occupancy of MR309, a selective σ1 receptor antagonist.

Br J Clin Pharmacol 2021 Jun 22. Epub 2021 Jun 22.

Mundipharma Research Limited, Cambridge, UK.

Background And Purpose: Preclinical studies of MR309, a selective sigma1 receptor (σ1R) antagonist, support a potential role in treating neuropathic pain. We report two studies that provide insight into the pharmacokinetics (PK) and brain σ1R binding of MR309.

Experimental Approach: Steady-state PK of MR309 (400 mg QD and 200 mg BID for 10 days; EudraCT 2015-001818-99 [PK study]) and the relationship between MR309 plasma exposure and brain σ1R occupancy (EudraCT 2017-000670-11 [PET study]) were investigated in healthy volunteers. Read More

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Population Pharmacokinetics and Dose Optimization of Vancomycin in Critically Ill Children.

Eur J Drug Metab Pharmacokinet 2021 Jun 22. Epub 2021 Jun 22.

Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, 7925, South Africa.

Background And Objective: Critically ill children may exhibit varied vancomycin pharmacokinetic parameters mainly due to altered protein binding, extracellular volume, and renal elimination. The objective of this study was to assess the pharmacokinetics of vancomycin in critically ill children and determine the optimum dose regimen.

Methods: This was a cross-sectional study of critically ill children admitted to a pediatric intensive care unit. Read More

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Panitumumab: A Review of Clinical Pharmacokinetic and Pharmacology Properties After Over a Decade of Experience in Patients with Solid Tumors.

Adv Ther 2021 Jun 18. Epub 2021 Jun 18.

Clinical Pharmacology, Modeling and Simulation, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA, 94080, USA.

Panitumumab is a fully human monoclonal antibody that binds to the epidermal growth factor receptor (EGFR), thereby inhibiting the growth and survival of tumors expressing EGFR. Panitumumab received approval in the USA in 2006 for the treatment of wild-type RAS (defined as wild-type in both KRAS and NRAS) metastatic colorectal cancer. Over the last 10 years, the pharmacokinetic and pharmacodynamic profile of panitumumab has been studied to further evaluate its safety, efficacy, and optimal dosing regimen. Read More

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Bridge Functionalisation of Bicyclo[1.1.1]pentane Derivatives.

Angew Chem Int Ed Engl 2021 Jun 20. Epub 2021 Jun 20.

GlaxoSmithKline Research and Development, Medicinal Chemistry, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, SG1 2NY, Stevenage, UNITED KINGDOM.

"Escaping from flatland", by increasing the saturation level and three-dimensionality of drug-like compounds, can enhance their potency, selectivity and pharmacokinetic profile. One approach that has attracted considerable recent attention is the bioisosteric replacement of aromatic rings, internal alkynes and tert-butyl groups with bicyclo[1.1. Read More

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Investigation of the impact of grapefruit juice, pomegranate juice and tomato juice on pharmacokinetics of brexpiprazole in rats using UHPLC-QTOF-MS.

Biomed Chromatogr 2021 Jun 18:e5201. Epub 2021 Jun 18.

Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), An Institute of National Importance, Government of India, Gandhinagar, Gujarat, India.

Brexpiprazole (BRX) is approved for the treatment of schizophrenia and major depressive disorders and it is mainly metabolized by CYP3A4 and CYP2D6. Grapefruit juice (GFJ), pomegranate juice (PJ) and tomato juice (TJ) have the potential to inhibit CYP3A4 enzymes in the body. However, fruit juice-drug interactions between BRX and GFJ, PJ and TJ are not studied extensively. Read More

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Nanodelivery of a self-assembling prodrug with exceptionally high drug loading potentiates chemotherapy efficacy.

Int J Pharm 2021 Jun 16;605:120805. Epub 2021 Jun 16.

The First Affiliated Hospital, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, School of Medicine, Zhejiang University, Hangzhou 310003, PR China. Electronic address:

Nanomedicines have achieved several successful clinical applications for cancer therapy over the past decades. To date, numerous nanomedicine formats and design rationales have been proposed to improve pharmaceutical delivery and treatment efficacy. Despite these advances, the achievement of high drug loading and loading efficiencies of drug payloads in nanocarriers remains a technical challenge. Read More

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HIPEC Methodology and Regimens: The Need for an Expert Consensus.

Ann Surg Oncol 2021 Jun 17. Epub 2021 Jun 17.

Department of Surgical Oncology, Centre Hospitalier Lyon-sud, Lyon, France.

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) is performed with a wide variation in methodology, drugs, and other elements vital to the procedure. Adoption of a limited number of regimens could increase the collective experience of peritoneal oncologists, make comparison between studies more meaningful, and lead to a greater acceptance of results from randomized trials. This study aimed to determine the possibility of standardizing HIPEC methodology and regimens and to identify the best method of performing such a standardization. Read More

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Use of Physiologically Based Pharmacokinetic Modeling for Predicting Drug-Food Interactions: Recommendations for Improving Predictive Performance of Low Confidence Food Effect Models.

AAPS J 2021 Jun 17;23(4):85. Epub 2021 Jun 17.

DMPK and Translational Modeling, AbbVie Inc., North Chicago, Illinois, USA.

Food can alter drug absorption and impact safety and efficacy. Besides conducting clinical studies, in vitro approaches such as biorelevant solubility and dissolution testing and in vivo dog studies are typical approaches to estimate a drug's food effect. The use of physiologically based pharmacokinetic models has gained importance and is nowadays a standard tool for food effect predictions at preclinical and clinical stages in the pharmaceutical industry. Read More

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Preclinical evaluation of a novel antibody-drug conjugate targeting DR5 for lymphoblastic leukemia therapy.

Mol Ther Oncolytics 2021 Jun 29;21:329-339. Epub 2021 Apr 29.

Yantai Obioadc Biomedical Technology Ltd., Yantai, China.

Acute lymphoblastic leukemia (ALL) is an aggressive hematological neoplasm resulting from immature lymphoid precursors. An antibody-drug conjugate (ADC), coupling a small molecule covalently with a targeting antibody, can specifically kill tumor cells. Death receptor 5 (DR5) is considered as a promising anti-tumor drug target. Read More

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Discovery of Arylsulfonamide Na1.7 Inhibitors: IVIVC, MPO Methods, and Optimization of Selectivity Profile.

ACS Med Chem Lett 2021 Jun 1;12(6):1038-1049. Epub 2021 Jun 1.

Discovery Chemistry, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.

The voltage-gated sodium channel Na1.7 continues to be a high-profile target for the treatment of various pain afflictions due to its strong human genetic validation. While isoform selective molecules have been discovered and advanced into the clinic, to date, this target has yet to bear fruit in the form of marketed therapeutics for the treatment of pain. Read More

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Discovery of Orally Bioavailable Ligand Efficient Quinazolindiones as Potent and Selective Tankyrases Inhibitors.

ACS Med Chem Lett 2021 Jun 13;12(6):1005-1010. Epub 2021 May 13.

Virtual PoC DPU, Alternative Discovery and Development, IVIVT, Platform Technologies and Sciences, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.

We report herein the discovery of quinazolindiones as potent and selective tankyrase inhibitors. Elucidation of the structure-activity relationship of the lead compound led to truncated analogues that have good potency in cells, pharmacokinetic (PK) properties, and excellent selectivity. Compound exhibited excellent potencies in cells and proliferation studies, good selectivity, activities, and an excellent PK profile. Read More

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Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2.

ACS Med Chem Lett 2021 Jun 25;12(6):969-975. Epub 2021 May 25.

Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.

To improve the metabolic stability profile of BMS-741672 (), we undertook a structure-activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to the identification of (BMS-753426) as a potent and orally bioavailable antagonist of CCR2. Compared to previous clinical candidate , the -butyl amine showed significant improvements in pharmacokinetic properties, with lower clearance and higher oral bioavailability. Read More

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Obstructive Jaundice doesn't Change the Population Pharmacokinetics of Etomidate in Patients who Underwent Bile Duct Surgery.

Curr Drug Deliv 2021 Jun 16. Epub 2021 Jun 16.

Department of Anesthesiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pudian Road, Shanghai, China.

Background: Etomidate is commonly used in the induction of anesthesia. We have previously confirmed that etomidate requirements are significantly reduced in patients with obstructive jaundice and that etomidate anesthesia during endoscopic retrograde cholangiopancreatography (ERCP) results in more stable hemodynamics when compared with propofol. The aim of the present study is to investigate whether obstructive jaundice affects the pharmacokinetics of etomidate in patients who underwent bile duct surgery. Read More

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Development of [F]AldoView as the First Highly Selective Aldosterone Synthase PET Tracer for Imaging of Primary Hyperaldosteronism.

J Med Chem 2021 Jun 17. Epub 2021 Jun 17.

Centre for Radiopharmaceutical Chemistry, University College London, 5 Gower Place, London WC1E 6BS, U.K.

The purpose of this study was to synthesize a fluorine-18 labeled, highly selective aldosterone synthase (CYP11B2) inhibitor, [F]AldoView, and to assess its potential for the detection of aldosterone-producing adenomas (APAs) with positron emission tomography in patients with primary hyperaldosteronism (PHA). Using dibenzothiophene sulfonium salt chemistry, [F]AldoView was obtained in high radiochemical yield in one step from [F]fluoride. In mice, the tracer showed a favorable pharmacokinetic profile, including rapid distribution and clearance. Read More

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Development of a Prototype, Once-Daily, Modified-Release Formulation for the Short Half-Life RIPK1 Inhibitor GSK2982772.

Pharm Res 2021 Jun 16. Epub 2021 Jun 16.

GlaxoSmithKline, 980 Great West Road, Brentford, Middlesex, TW8-9GS, UK.

Purpose: GSK2982772 is a selective inhibitor of receptor-interacting protein kinase-1, with a 2-3 h half-life. This study evaluated if a once-daily modified-release formulation of GSK2982772 could be developed with no significant food effect.

Methods: Part A evaluated the pharmacokinetics of GSK2982772 following fasted single-dose (120 mg) administration of two matrix minitab formulations (MT-8 h and MT-12 h) vs 120 mg immediate release (IR) and MT-12 h with a high-fat meal. Read More

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A helicase-primase drug candidate with sufficient target tissue exposure affects latent neural herpes simplex virus infections.

Sci Transl Med 2021 Jun;13(598)

Innovative Molecules GmbH, Leopoldshöher Str. 7, 32107 Bad-Salzuflen, Germany.

More than 50% of the world population is chronically infected with herpesviruses. Herpes simplex virus (HSV) infections are the cause of herpes labialis (cold sores), genital herpes, and sight-impairing keratitis. Less frequently, life-threatening disseminated disease (encephalitis and generalized viremia) can also occur, mainly in immunocompromised patients and newborns. Read More

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Therapeutic review of cabotegravir/rilpivirine long-acting antiretroviral injectable and implementation considerations at an HIV specialty clinic.

Pharmacotherapy 2021 Jun 15. Epub 2021 Jun 15.

Indiana University Health, Indianapolis, Indiana, USA.

Cabotegravir/rilpivirine (CAB/RPV) was recently approved by the US Food and Drug Administration (FDA) as the first complete parenteral antiretroviral (ART) regimen for treatment of people living with HIV (PLWH). As a monthly intramuscular (IM) injection, this therapy constitutes a major departure from the traditional paradigm of oral therapy requiring (at least) daily administration that has defined HIV treatment for decades. Composed of a second-generation integrase inhibitor (INSTI) and nonnucleoside reverse transcriptase inhibitor (NNRTI), CAB/RPV has achieved high rates of sustained virologic suppression with a favorable safety profile for treatment-experienced PLWH following oral lead-in (OLI) during several clinical trials. Read More

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Discovery and Optimization of a Novel 2-Pyrazolo[3,4-d]pyrimidine Derivative as a Potent Irreversible Pan-Fibroblast Growth Factor Receptor Inhibitor.

J Med Chem 2021 Jun 15. Epub 2021 Jun 15.

The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China.

Fibroblast growth factor receptors (FGFRs) have become promising therapeutic targets in various types of cancers. In fact, several selective irreversible inhibitors capable of covalently reacting with the conserved cysteine of FGFRs are currently being evaluated in clinical trials. In this article, we optimized and discovered a novel lead compound with remarkable inhibitory effects against FGFR (1-3), which is a derivative of 2-pyrazolo[3,4-d]pyrimidine. Read More

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Current opinion on the pharmacogenomics of paclitaxel-induced toxicity.

Expert Opin Drug Metab Toxicol 2021 Jun 15. Epub 2021 Jun 15.

Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.

: Paclitaxel is a microtubule stabilizer that is currently one of the most utilized chemotherapeutic agents. Its efficacy in breast, uterine, lung and other neoplasms made its safety profile enhancement a subject of great interest. Neurotoxicity is the most common paclitaxel-associated toxicities. Read More

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Targeted and modular architectural polymers employing bioorthogonal chemistry for quantitative therapeutic delivery.

Chem Sci 2020 Mar 6;11(12):3268-3280. Epub 2020 Mar 6.

Centre for Advanced Imaging, The University of Queensland Brisbane QLD 4072 Australia

There remain several key challenges to existing therapeutic systems for cancer therapy, such as quantitatively determining the true, tissue-specific drug release profile , as well as reducing side-effects for an increased standard of care. Hence, it is crucial to engineer new materials that allow for a better understanding of the pharmacokinetic/pharmacodynamic behaviours of therapeutics. We have expanded on recent "click-to-release" bioorthogonal pro-drug activation of antibody-drug conjugates (ADCs) to develop a modular and controlled theranostic system for quantitatively assessing site-specific drug activation and deposition from a nanocarrier molecule, by employing defined chemistries. Read More

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A Chemically Defined, Xeno- and Blood-Free Culture Medium Sustains Increased Production of Small Extracellular Vesicles From Mesenchymal Stem Cells.

Front Bioeng Biotechnol 2021 26;9:619930. Epub 2021 May 26.

Cells for Cells, Santiago, Chile.

Cell therapy is witnessing a notable shift toward cell-free treatments based on paracrine factors, in particular, towards small extracellular vesicles (sEV), that mimic the functional effect of the parental cells. While numerous sEV-based applications are currently in advanced preclinical stages, their promised translation depends on overcoming the manufacturing hurdles posed by the large-scale production of purified sEV. Unquestionably, the culture medium used with the parental cells plays a key role in the sEV's secretion rate and content. Read More

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Direct Oral Anticoagulants: From Randomized Clinical Trials to Real-World Clinical Practice.

Front Pharmacol 2021 26;12:684638. Epub 2021 May 26.

Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.

Direct oral anticoagulants (DOACs) are a more manageable alternative than vitamin K antagonists (VKAs) to prevent stroke in patients with nonvalvular atrial fibrillation and to prevent and treat venous thromboembolism. Despite their widespread use in clinical practice, there are still some unresolved issues on optimizing their use in particular clinical settings. Herein, we reviewed the current clinical evidence on uses of DOACs from pharmacology and clinical indications to safety and practical issues such as drugs and food interactions. Read More

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Pharmacokinetic Study of Oral C-Radiolabeled Hyzetimibe, A New Cholesterol Absorption Inhibitor.

Front Pharmacol 2021 28;12:665372. Epub 2021 May 28.

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.

Hyzetimibe is a candidate drug being investigated as the second-in-class cholesterol absorption inhibitor; it lowers plasma levels of low-density lipoprotein cholesterol (LDL-C) by blocking the Niemann-Pick C1-like 1 protein, a transporter mainly expressed in the intestine that allows dietary cholesterol to enter the body from the intestinal lumen. Previous studies on the metabolism of hyzetimibe in healthy volunteers were not enough to show the biotransformation and excretion pathway; in particular, whether hyzetimibe maintains pharmacological action for duration sufficient to pass through the hepatic-intestinal circulation remains unknown. Furthermore, it remains unclear whether the differences between the chemical structures of ezetimibe and hyzetimibe would result in different pharmacokinetic characteristics. Read More

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