Natural Products as a Foundation for Drug Discovery.
Authors: Beutler JA
Abstract
Many natural products have been used as drugs for the treatment of diverse indications. Although most U.S. pharmaceutical companies have reduced or eliminated their in-house natural-product research over the years, new approaches for compound screening and chemical synthesis are resurrecting interest in exploring the therapeutic value of natural products. The aim of this commentary is to review emerging strategies and techniques that have made natural products a viable strategic choice for inclusion in drug discovery programs. Published 2019. U.S. Government.
PMID: 3153...
Source: Current Protocols in Pharmacology - September 22, 2019 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Transgenic Tumor Models for Evaluating CAR T-Cell Immunotherapies.
Authors: Aranda F, Barajas M, Huarte E
Abstract
Chimeric antigen receptor (CAR) T-cell therapy against tumor antigens involves a recombinant immunoreceptor that combines an antibody-derived targeting fragment with signaling domains capable of activating T cells and fusion of this receptor domain to a costimulatory domain (typically CD28 or 4-1BB). Clinical trials of CAR T-cell therapeutics targeting CD19 antigens for relapsed or refractory B-cell malignancies have shown unparalleled results and consequently have recently been approved by the U.S. Food and Drug Administration. However, the lack of efficacy ...
Source: Current Protocols in Pharmacology - September 22, 2019 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Cerebral Open Flow Microperfusion to Monitor Drug Transport Across the Blood-Brain Barrier.
This article comprehensively describes the experimental setup and procedures, perfusate requirements, critical parameters, common problems that may occur, and their causes and solutions. Typical results from a cOFM sampling experiment are presented and discussed. This protocol provides a tool for performing pharmacokinetic and pharmacodynamic studies in mouse or rat brain with an intact BBB. © 2019 by John Wiley & Sons, Inc.
PMID: 31145555 [PubMed - as supplied by publisher] (Source: Current Protocols in Pharmacology)
Source: Current Protocols in Pharmacology - June 2, 2019 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Investigating the Mitochondrial Permeability Transition Pore in Disease Phenotypes and Drug Screening.
Authors: Bhosale G, Duchen MR
Abstract
Mitochondria act as 'sinks' for Ca2+ signaling, with mitochondrial Ca2+ uptake linking physiological stimuli to increased ATP production. However, mitochondrial Ca2+ overload can induce a cellular catastrophe by opening of the mitochondrial permeability transition pore (mPTP). This pore is a large conductance pathway in the inner mitochondrial membrane that causes bioenergetic collapse and appears to represent a final common path to cell death in many diseases. The role of the mPTP as a determinant of disease outcome is best established in ischemia/reperfusion injury ...
Source: Current Protocols in Pharmacology - May 14, 2019 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Determination of Dermal Pharmacokinetics by Microdialysis Sampling in Rats.
Authors: Voelkner NMF, Voelkner A, Derendorf H
Abstract
The evaluation of absorption and availability at the site of action of a drug candidate is an important element of drug discovery and development, as clinical response is a function of the bioavailability of the active agent and its continued presence at the site of action. Evaluation of dermal pharmacokinetics facilitates the selection of new compounds or chemical structures for advancement as possible clinical candidates. An advantage of microdialysis is that it allows the measurement of compound concentrations at the site of action without disturbi...
Source: Current Protocols in Pharmacology - April 28, 2019 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Evaluation of Compound Activity in Primary Human Intestinal Organoids Using Gene Expression and Histology.
Authors: Marchelletta R, Yu J, Moon C, Kim MM
Abstract
Human intestinal organoids have enabled performance of functional epithelial studies and modeling of human diseases of the intestine. This unit describes 1) a method to isolate and culture crypts from human intestinal tissue, 2) use of combinatorial methods to expand stem cell-enriched spheroids and differentiate them into organoids composed of various intestinal epithelial cell types, and 3) methods to stimulate these organoids with and measure their responsiveness to external stimuli. To validate the differentiation, organoids can be stained to quali...
Source: Current Protocols in Pharmacology - March 29, 2019 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Translational Use of a Standardized Full Human Skin Organ Culture Model in Autoimmune Blistering Diseases.
Authors: Burmester IAK, Emtenani S, Johns JG, Ludwig RJ, Hammers CM, Hundt JE
Abstract
The full human skin organ culture (HSOC) model is a standardized test system for evaluating pharmacological substances on human skin in vitro. The acantholysis associated with pemphigus vulgaris (PV), a severe and potentially life-threatening autoimmune skin blistering disease, can be induced in HSOC by injecting a bi-specific anti-desmoglein (dsg) 1 and 3 single-chain antibody variable fragment (scFv). Compared to cell culture experiments (e.g., induction of dsg3-internalization or keratinocyte dissociation using HaCaT ...
Source: Current Protocols in Pharmacology - March 9, 2019 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity.
Authors: Mullane K, Williams M
Abstract
The only drugs currently approved for the treatment of Alzheimer's Disease (AD) are four acetylcholinesterase inhibitors and the NMDA antagonist memantine. Apart from these drugs, which have minimal to no clinical benefit, the 40-year search for effective therapeutics to treat AD has resulted in a clinical failure rate of 100% not only for compounds that prevent brain amyloid deposition or remove existing amyloid plaques but also those acting by a variety of other putative disease-associated mechanisms. This indicates that the preclinical data generated from current ...
Source: Current Protocols in Pharmacology - February 26, 2019 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Drug Discovery for Pemphigoid Diseases.
This article describes antibody transfer and immunization-induced PD mouse models currently employed for translational PD research. © 2019 by John Wiley & Sons, Inc.
PMID: 30786171 [PubMed - as supplied by publisher] (Source: Current Protocols in Pharmacology)
Source: Current Protocols in Pharmacology - February 22, 2019 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Murine Models of Pancreatitis Leading to the Development of Pancreatic Cancer.
Authors: Leal AS, Liby KT
Abstract
Chronic or repeated episodes of acute pancreatic inflammation, or pancreatitis, are risk factors for the development of pancreatic cancer. Pancreatic cancer is characterized by a strong fibro-inflammatory tumor microenvironment. In pancreatitis, the same fibro-inflammatory reaction is observed concurrently with a loss of normal pancreatic cells. Mouse models are commonly employed to study the progression of pancreatitis and pancreatic cancer, with genetic and pharmacological tools used to elucidate cellular and acellular interactions within pancreatic tumors. Described in...
Source: Current Protocols in Pharmacology - October 18, 2018 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Modeling Chronic Graft Versus Host Disease in Mice Using Allogeneic Bone Marrow and Splenocyte Transfer.
Authors: Schroeder MA, Ashami K, Staser K
Abstract
This unit describes a method for allogeneic bone marrow and splenocyte transfer for the modeling of chronic graft versus host disease (cGVHD) in mice. Preclinical models provide clinically relevant platforms for mechanistic and therapeutic studies that may inform the treatment of patients suffering from cGVHD, a common and potentially severe complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). Most murine models of cGVHD depend on the transfer of major histocompatibility complex (MHC)-mismatched bone marrow and whole splenocytes (...
Source: Current Protocols in Pharmacology - September 12, 2018 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
The Irwin Test/Functional Observational Battery (FOB) for Assessing the Effects of Compounds on Behavior, Physiology, and Safety Pharmacology in Rodents.
Authors: Mathiasen JR, Moser VC
Abstract
The modified Irwin procedure or functional observational battery (FOB) can be used to achieve several goals. New chemical entities (NCEs) can be behaviorally screened for nervous system effects at a variety of doses to identify potential therapeutic uses and in the selection of appropriate doses for subsequent assays. NCEs can also be evaluated in the behavioral battery and compared with reference standards to assess liabilities in a new compound class, with an estimated therapeutic index being suggested by the doses used in comparison to therapeutic doses. For the ...
Source: Current Protocols in Pharmacology - September 5, 2018 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Screening Strategies for the Discovery of Ion Channel Monoclonal Antibodies.
Authors: Colley CS, England E, Linley JE, Wilkinson TCI
Abstract
Ion channels play crucial roles in physiology by modulation of cellular functions that include electrical excitability, secretion, cell migration, and gene transcription. They are an important target class for drug discovery and have historically been targeted using small molecule approaches. A significant opportunity exists to target these channels with antibodies and alternative forms of biologics. Antibodies display high specificity, selectivity, and affinity for their target antigen, thus having the potential to target ion channels very p...
Source: Current Protocols in Pharmacology - September 1, 2018 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Overview of Transporters in Pharmacokinetics and Drug Discovery.
Authors: Zhang Y
Abstract
Transporters play important roles in absorption, distribution, metabolism, and elimination (ADME) processes, as well as drug pharmacokinetics (PK) and pharmacodynamics (PD). They are also important in maintaining the homeostasis of endogenous compounds and nutrients in the body. Increasing evidences also suggest that they are important in mediating drug-drug interactions (DDIs). While the significance of transporters in drug pharmacodynamics and DDIs are beyond the scope of this overview, the basic concepts of transporters, their contributions in membrane permeation processes, and...
Source: Current Protocols in Pharmacology - September 1, 2018 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Protocols for Measuring Glutamate Uptake: Dose-Response and Kinetic Assays in In Vitro and Ex Vivo Systems.
This article presents detailed descriptions of procedures and troubleshooting tips for basic in vitro and ex vivo uptake assays for the functional characterization of glutamate transporters and the assessment of the effect of compounds that modulate their activity. Assays are performed in cell lines that transiently or stably express a particular transporter under investigation, in primary cultures of astrocytes, or in ex vivo synaptosomal preparations that endogenously express these transporters. Two main assays are described, including dose-response assays to measure potencies of test compounds for stimulation or inhibit...
Source: Current Protocols in Pharmacology - August 29, 2018 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
