Assessment of substance abuse liability in rodents: self-administration, drug discrimination, and locomotor sensitization.
Authors: Paterson NE
Abstract
Assessing abuse liability is a crucial step in the development of a novel chemical entity (NCE) with central nervous system (CNS) activity or with chemical or pharmacological properties in common with known abused substances. Rodent assessment of abuse liability is highly attractive due to its relatively low cost and high predictive validity. Described in this unit are three rodent assays commonly used to provide data on the potential for abuse liability based on the acute effects of NCEs: specifically, self-administration, drug discrimination, and locomotor sensitization. As ...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Assessment of P-glycoprotein substrate and inhibition potential of test compounds in MDR1-transfected MDCK cells.
Authors: C L Lam K, Rajaraman G
Abstract
P-glycoprotein (P-gp) is the most widely studied drug transporter due to its potential role in drug disposition and efficacy, and drug-drug interactions (DDI). It is abundantly expressed in both the intestinal wall and blood-brain barrier where it serves as a drug permeability barrier while simultaneously facilitating drug elimination in the liver and kidney. It is also abundantly expressed in tumors where it can facilitate the elimination of chemotherapeutics, a phenomenon known as multidrug resistance (MDR). Clinically relevant DDIs involving P-gp are well documen...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Assessment of the time-dependent inhibition (TDI) potential of test compounds with human liver microsomes by IC50 shift method using a nondilution approach.
Authors: de Ron L, Rajaraman G
Abstract
Time-dependent inhibition (TDI) of hepatic cytochrome P450 (CYP) enzymes is increasingly implicated in the majority of clinically relevant drug-drug interactions (DDIs). A time-dependent inhibitor or its reactive metabolite irreversibly inactivates CYP enzymes, thereby inhibiting the metabolism of other drugs. As the majority of marketed drugs are metabolized by CYP enzymes, their inhibition has important clinical consequences, such as in decreasing the metabolic clearance of a co-administered drug (victim drug). This could be life threatening, as such an effect narr...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Parallel chemistry in the 21st century.
Authors: Long A
Abstract
The tool chest of techniques, methodologies, and equipment for conducting parallel chemistry is larger than ever before. Improvements in the laboratory and developments in computational chemistry have enabled compound library design at the desks of medicinal chemists. This unit includes a brief background in combinatorial/parallel synthesis chemistry, along with a discussion of evolving technologies for both solid- and solution-phase chemistry. In addition, there are discussions on designing compound libraries, acquisition/procurement of compounds and/or reagents, the chemistry and...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Guidelines for the care and use of laboratory animals in biomedical research.
Authors: Jones-Bolin S
Abstract
This unit provides a general overview on topics related to the practical care and use of laboratory animals in biomedical research. These topics are briefly described and provide Web sites and/or research articles that can be accessed for more detailed information. While the primary focus is on the care and use of rats and mice bred for biomedical research, many of the Web sites listed provide information on other species used for this purpose.
PMID: 23258596 [PubMed - indexed for MEDLINE] (Source: Current Protocols in Pharmacology)
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Use of electrophysiological methods in the study of recombinant and native neuronal ligand-gated ion channels.
Authors: Thomas P, Smart TG
Abstract
Detailed in this unit are protocols for studying the effects of externally and internally applied agents on the behavior of ligand-gated ion channels (LGICs), specifically the GABA(A) receptor. These assays include a number of electrophysiological techniques applied to whole-cell and excised patch recordings of recombinant and native GABA(A) receptor subtypes used in the generation and analysis of a pharmacological data. Although applied to GABA(A) receptors, these techniques are equally applicable to other LGICs. The analysis is extended to incorporate consideration of...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Overview of human primary tumorgraft models: comparisons with traditional oncology preclinical models and the clinical relevance and utility of primary tumorgrafts in basic and translational oncology research.
Authors: Lum DH, Matsen C, Welm AL, Welm BE
Abstract
Laboratory models that accurately replicate human tumor initiation and characteristics are integral to advancing knowledge in cancer research. However, comparative studies between commonly employed laboratory models and human tumors have demonstrated that some models have molecular and genomic alterations dissimilar to the cancer type they attempt to replicate. In contrast, several recent comparative studies suggest that because patient-derived tumors grown in mice maintain many of the important characteristics of the original tumor, they represent an im...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
α-Adrenoceptor assays.
Authors: Abel PW, Jain N
Abstract
α-Adrenoceptors mediate responses to activation of both peripheral sympathetic nerves and central noradrenergic neurons. They also serve as autoreceptors that modulate the release of norepinephrine (NE) and other neurotransmitters. There are two major classes of α-adrenoceptors, the α(1)- and α(2). Each class is subdivided into three subtypes: α(1A), α(1B), α(1D), and α(2A), α(2B), α(2C). Described in this unit are in vitro isolated tissue methods used to study α-adrenoceptor functions and to identify novel ligands for these receptors. Detailed protocols describ...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Water maze testing to identify compounds for cognitive enhancement.
Authors: Rose GM, Rowe WB
Abstract
The water maze task is widely used to evaluate spatial learning and memory in rodents. The basic paradigm requires an animal to swim in a pool until it finds a hidden escape platform. The animals learn to find the platform using extra-maze cues and, after several training trials, are able to swim directly to it from any starting location. Memory for the platform location is assessed by examining swimming behavior with the platform removed from the maze, while sensory, motor and motivational aspects of the task can be examined by making the platform visible to the animals....
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Patient-derived models of human breast cancer: protocols for in vitro and in vivo applications in tumor biology and translational medicine.
Authors: DeRose YS, Gligorich KM, Wang G, Georgelas A, Bowman P, Courdy SJ, Welm AL, Welm BE
Abstract
Research models that replicate the diverse genetic and molecular landscape of breast cancer are critical for developing the next-generation therapeutic entities that can target specific cancer subtypes. Patient-derived tumorgrafts, generated by transplanting primary human tumor samples into immune-compromised mice, are a valuable method to model the clinical diversity of breast cancer in mice, and are a potential resource in personalized medicine. Primary tumorgrafts also enable in vivo testing of therapeu...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Discovery of biologically active oncologic and immunologic small molecule therapies using zebrafish: overview and example of modulation of T cell activation.
Authors: Trede NS, Heaton W, Ridges S, Sofla H, Cusick M, Bearss D, Jones D, Fujinami RS
Abstract
Zebrafish models continue to gain popularity as in vivo models for drug discovery. Described in this overview are advantages and challenges of zebrafish drug screening, as well as a novel in vivo screen for immunomodulatory compounds using transgenic, T cell reporting zebrafish larvae designed for discovery of compounds targeting T cell leukemia. This assay system allows rapid screening of large numbers of compounds while avoiding the pitfalls of assays based on cell cultures, which lack biologic context and a...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
The human kinome and kinase inhibition.
Authors: Duong-Ly KC, Peterson JR
Abstract
Protein and lipid kinases play key regulatory roles in a number of biological processes. Unsurprisingly, activating mutations in kinases have been linked to a number of disorders and diseases, most notably cancers. Thus, kinases have emerged as promising clinical targets. There are more than 500 human protein kinases and about 20 lipid kinases. Most protein kinases share a highly conserved domain, the eukaryotic protein kinase (ePK) domain, which contains the ATP and substrate-binding sites. Many inhibitors in clinical use bind to the highly conserved ATP binding ...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Cigarette smoke exposure as a model of inflammation associated with COPD.
Authors: Eltom S, Stevenson C, Birrell MA
Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation resulting from inflammation-driven pathologies in the lungs that are a consequence of smoking over many years. Given that the disease is increasing globally, understanding the mechanism by which cigarette smoke (CS) causes lung inflammation and exploiting that knowledge to develop effective treatments is urgently required. Animal models of CS exposure are commonly used to examine the inflammatory processes that may be involved in the development of COPD. The pro...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Overview of determination of biopharmaceutical properties for development candidate selection.
Authors: Yazdanian M
Abstract
The physicochemical and biopharmaceutical properties of putative drug molecules impact their performance in both in vitro and in vivo studies. The design and selection of molecules with drug-like properties assists in the selection of drug candidates with a higher probability of success in the development process. Described in this overview are commonly used approaches for measuring compound solubility, permeability, and partitioning in drug discovery and development. The utility of these methods in the drug discovery process and product development is discussed. The evaluatio...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Predicting drug-induced QT prolongation and torsades de pointes: a review of preclinical endpoint measures.
Authors: Townsend C, Brown BS
Abstract
Compound-induced prolongation of the cardiac QT interval is a major concern in drug development and this unit discusses approaches that can predict QT effects prior to undertaking clinical trials. The majority of compounds that prolong the QT interval block the cardiac rapid delayed rectifier potassium current, IKr (hERG). Described in this overview are different ways to measure hERG, from recent advances in automated electrophysiology to the quantification of channel protein trafficking and binding. The contribution of other cardiac ion channels to hERG data interpre...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
