| 1. |
- Bjork, K, et al.
(författare)
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Modulation of monoamine receptors by adaptor proteins and lipid rafts: role in some effects of centrally acting drugs and therapeutic agents
- 2011
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Ingår i: Annual review of pharmacology and toxicology. - : Annual Reviews. - 1545-4304 .- 0362-1642. ; 51, s. 211-242
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Tidskriftsartikel (refereegranskat)abstract
- The monoamines and their cognate receptors are widespread in the central nervous system and are vital for normal brain function. Dysfunction in these systems underlies several psychiatric and neurological disease states, and consequently monoamines are targets of a host of pharmacotherapies. This review provides an overview on how monoamine receptors are regulated by adaptor proteins and lipid rafts with emphasis on interactions in nerve cells. Monoamine receptors have prominent intracellular loops that provide binding sites for adaptor proteins. Receptor function is further modulated by cholesterol and submembranous microdomains termed lipid rafts. These interactions determine several facets of G protein–coupled receptor (GPCR) function including trafficking, localization, and signaling. Possible roles of adaptor proteins and lipid rafts in disease states and in mediating actions of drugs and therapeutic agents are also discussed.
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| 2. |
- Carlsson, Arvid, 1923, et al.
(författare)
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Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence
- 2001
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Ingår i: Annu Rev Pharmacol Toxicol. - 0362-1642. ; 41, s. 237-60
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Forskningsöversikt (refereegranskat)abstract
- In spite of its proven heuristic value, the dopamine hypothesis of schizophrenia is now yielding to a multifactorial view, in which the other monoamines as well as glutamate and GABA are included, with a focus on neurotransmitter interactions in complex neurocircuits. The primary lesion(s) in schizophrenia does not necessarily involve any of these neurotransmitters directly but could deal with a more general defect, such as a faulty connectivity of developmental origin. Nevertheless, a precise identification of neurotransmitter aberrations in schizophrenia will probably provide clues for a better understanding of the disease and for the development of new treatment and prevention strategies.
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| 3. |
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| 4. |
- Civelli, Olivier, et al.
(författare)
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G Protein-Coupled Receptor Deorphanizations
- 2013
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Ingår i: Annual Review of Pharmacology and Toxicology. - : Annual Reviews. - 0362-1642 .- 1545-4304. ; 53, s. 127-146
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Forskningsöversikt (refereegranskat)abstract
- G protein-coupled receptors (GPCRs) are major regulators of intercellular interactions. They initiate these actions by being activated by a wide variety of natural ligands. Historically, ligands were discovered first, but the advent of molecular biology reversed this trend. Most GPCRs are identified on the basis of their DNA sequences and thus are initially unmatched to known natural ligands. They are termed orphan GPCRs. Discovering their ligands-i.e., "deorphanizing" the GPCRs-gave birth to the field of reverse pharmacology. This review discusses the present status of GPCR deorphanization, presents a few examples of successes and surprises, and highlights difficulties encountered in these efforts.
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| 5. |
- Darwich, Adam S., et al.
(författare)
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Model-Informed Precision Dosing: Background, Requirements, Validation, Implementation, and Forward Trajectory of Individualizing Drug Therapy
- 2021
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Ingår i: Annual Review of Pharmacology and Toxicology. - : Annual Reviews Inc.. - 0362-1642 .- 1545-4304. ; 61:36, s. 1-21
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Tidskriftsartikel (refereegranskat)abstract
- Model-informed precision dosing (MIPD) has become synonymous with modern approaches forindividualizing drug therapy, in which the characteristics of each patient are considered as opposedto applying a one-size-fits-all alternative. This review provides a brief account of the currentknowledge, practices, and opinions on MIPD while defining an achievable vision for MIPDin clinical care based on available evidence.We begin with a historical perspective on variabilityin dose requirements and then discuss technical aspects of MIPD, including the need for clinicaldecision support tools, practical validation, and implementation of MIPD in health care.Wealso discuss novel ways to characterize patient variability beyond the common perceptions of geneticcontrol. Finally, we address current debates on MIPD from the perspectives of the new drugdevelopment, health-care economics, and drug regulations.
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| 6. |
- Ewart, L, et al.
(författare)
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Application of Microphysiological Systems to Enhance Safety Assessment in Drug Discovery
- 2018
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Ingår i: Annual review of pharmacology and toxicology. - : Annual Reviews. - 1545-4304 .- 0362-1642. ; 58, s. 65-82
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Tidskriftsartikel (refereegranskat)abstract
- Enhancing the early detection of new therapies that are likely to carry a safety liability in the context of the intended patient population would provide a major advance in drug discovery. Microphysiological systems (MPS) technology offers an opportunity to support enhanced preclinical to clinical translation through the generation of higher-quality preclinical physiological data. In this review, we highlight this technological opportunity by focusing on key target organs associated with drug safety and metabolism. By focusing on MPS models that have been developed for these organs, alongside other relevant in vitro models, we review the current state of the art and the challenges that still need to be overcome to ensure application of this technology in enhancing drug discovery.
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| 7. |
- Fredholm, BB, et al.
(författare)
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Actions of adenosine at its receptors in the CNS: insights from knockouts and drugs
- 2005
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Ingår i: Annual review of pharmacology and toxicology. - : Annual Reviews. - 0362-1642 .- 1545-4304. ; 45, s. 385-412
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Tidskriftsartikel (refereegranskat)abstract
- ▪ Abstract Adenosine and its receptors have been the topic of many recent reviews ( 1 – 26 ). These reviews provide a good summary of much of the relevant literature—including the older literature. We have, therefore, chosen to focus the present review on the insights gained from recent studies on genetically modified mice, particularly with respect to the function of adenosine receptors and their potential as therapeutic targets. The information gained from studies of drug effects is discussed in this context, and discrepancies between genetic and pharmacological results are highlighted.
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| 8. |
- Gencheva, R, et al.
(författare)
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Thioredoxin Reductase Inhibition for Cancer Therapy
- 2022
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Ingår i: Annual review of pharmacology and toxicology. - : Annual Reviews. - 1545-4304 .- 0362-1642. ; 62, s. 177-196
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Tidskriftsartikel (refereegranskat)abstract
- The cytosolic selenoprotein thioredoxin reductase 1 (TrxR1, TXNRD1), and to some extent mitochondrial TrxR2 (TXNRD2), can be inhibited by a wide range of electrophilic compounds. Many such compounds also yield cytotoxicity toward cancer cells in culture or in mouse models, and most compounds are likely to irreversibly modify the easily accessible selenocysteine residue in TrxR1, thereby inhibiting its normal activity to reduce cytosolic thioredoxin (Trx1, TXN) and other substrates of the enzyme. This leads to an oxidative challenge. In some cases, the inhibited forms of TrxR1 are not catalytically inert and are instead converted to prooxidant NADPH oxidases, named SecTRAPs, thus further aggravating the oxidative stress, particularly in cells expressing higher levels of the enzyme. In this review, the possible molecular and cellular consequences of these effects are discussed in relation to cancer therapy, with a focus on outstanding questions that should be addressed if targeted TrxR1 inhibition is to be further developed for therapeutic use.
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| 9. |
- Haeggstrom, JZ, et al.
(författare)
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Structures of Leukotriene Biosynthetic Enzymes and Development of New Therapeutics
- 2023
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Ingår i: Annual review of pharmacology and toxicology. - : Annual Reviews. - 1545-4304 .- 0362-1642. ; 63, s. 407-428
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Tidskriftsartikel (refereegranskat)abstract
- Leukotrienes are potent immune-regulating lipid mediators with patho-genic roles in inflammatory and allergic diseases, particularly asthma. These autacoids also contribute to low-grade inflammation, a hallmark of cardiovascular, neurodegenerative, metabolic, and tumor diseases. Biosynthesis of leukotrienes involves release and oxidative metabolism of arachidonic acid and proceeds via a set of cytosolic and integral membrane enzymes that are typically expressed by cells of the innate immune system. In activated cells, these enzymes traffic and assemble at the endoplasmic and perinuclear membrane, together comprising a biosynthetic complex. Here we describe recent advances in our molecular understanding of the protein components of the leukotriene-synthesizing enzyme machinery and also briefly touch upon the leukotriene receptors. Moreover, we discuss emerging opportunities for pharmacological intervention and development of new therapeutics.
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| 10. |
- Langguth, B, et al.
(författare)
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Therapeutic Approaches to the Treatment of Tinnitus
- 2019
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Ingår i: Annual review of pharmacology and toxicology. - : Annual Reviews. - 1545-4304 .- 0362-1642. ; 59, s. 291-313
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Tidskriftsartikel (refereegranskat)abstract
- Tinnitus is a highly prevalent condition that is associated with hearing loss in most cases. In the absence of external stimuli, phantom perceptions of sounds emerge from alterations in neuronal activity within central auditory and nonauditory structures. Pioneering studies using lidocaine revealed that tinnitus is susceptible to pharmacological interventions. However, lidocaine is not effective in all patients, and no other drug has been identified with clear efficacy for the long-term treatment of tinnitus. In this review, we present recent advances in tinnitus research, including more detailed knowledge of its pathophysiology and involved neurotransmitter systems. Moreover, we summarize results from animal and clinical treatment studies as well as from studies that identified tinnitus as a side effect of pharmacological treatments. Finally, we focus on challenges in the development of pharmacological compounds for the treatment of tinnitus, namely the limitations of available animal models and of standardized clinical research methodologies.
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| 11. |
- Lauschke, VM, et al.
(författare)
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Pharmacoepigenetics and Toxicoepigenetics: Novel Mechanistic Insights and Therapeutic Opportunities
- 2018
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Ingår i: Annual review of pharmacology and toxicology. - : Annual Reviews. - 1545-4304 .- 0362-1642. ; 58, s. 161-185
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Tidskriftsartikel (refereegranskat)abstract
- Pharmacological treatment and exposure to xenobiotics can cause substantial changes in epigenetic signatures. The majority of these epigenetic changes, caused by the compounds in question, occur downstream of transcriptional activation mechanisms, whereby the epigenetic alterations can create a transcriptional memory and stably modulate cell function. The increasing understanding of epigenetic mechanisms and their importance in disease has prompted the development of therapeutic interventions that target epigenetic modulatory mechanisms, particularly in oncology where inhibitors of epigenetic-modifying proteins (epidrugs) have been successfully used in treatment, mostly in combination with standard-of-care chemotherapy, either provoking direct cytotoxicity or inhibiting resistance to anticancer drugs. In addition, emerging methods for detecting epigenetically modified DNA in bodily fluids may provide information about tumor phenotype or drug treatment success. However, it is important to note that many technical pitfalls, such as the nondeconvolution of methylcytosine and hydroxymethylcytosine, compromise epigenetic analyses and the interpretation of results. In this review, we provide an update on the field, with an emphasis on the novel therapeutic opportunities made possible by epidrugs.
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| 12. |
- Molina, DM, et al.
(författare)
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The Cellular Thermal Shift Assay: A Novel Biophysical Assay for In Situ Drug Target Engagement and Mechanistic Biomarker Studies
- 2016
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Ingår i: Annual review of pharmacology and toxicology. - : Annual Reviews. - 1545-4304 .- 0362-1642. ; 56, s. 141-161
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Tidskriftsartikel (refereegranskat)abstract
- A drug must engage its intended target to achieve its therapeutic effect. However, conclusively measuring target engagement (TE) in situ is challenging. This complicates preclinical development and is considered a key factor in the high rate of attrition in clinical trials. Here, we discuss a recently developed, label-free, biophysical assay, the cellular thermal shift assay (CETSA), which facilitates the direct assessment of TE in cells and tissues at various stages of drug development. CETSA also reveals biochemical events downstream of drug binding and therefore provides a promising means of establishing mechanistic biomarkers. The implementation of proteome-wide CETSA using quantitative mass spectrometry represents a novel strategy for defining off-target toxicity and polypharmacology and for identifying downstream mechanistic biomarkers. The first year of CETSA applications in the literature has focused on TE studies in cell culture systems and has confirmed the broad applicability of CETSA to many different target families. The next phase of CETSA applications will likely encompass comprehensive animal and patient studies, and CETSA will likely serve as a very valuable tool in many stages of preclinical and clinical drug development.
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| 13. |
- Orrenius, S, et al.
(författare)
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Autophagy in toxicology: cause or consequence?
- 2013
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Ingår i: Annual review of pharmacology and toxicology. - : Annual Reviews. - 1545-4304 .- 0362-1642. ; 53, s. 275-297
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Tidskriftsartikel (refereegranskat)abstract
- Research on autophagy and its effects on cell metabolism and physiology has increased dramatically during recent years. Multiple forms of autophagy have been characterized, and many of the genes involved in the regulation of this process have been identified. The importance of autophagy for embryonic development and maintenance of tissue homeostasis in the adult organism has been demonstrated convincingly, and several human diseases have been linked to deficiencies in autophagy. Most often, autophagy serves as a protective mechanism, but persistent activation of autophagy can result in cell death. This is true for many toxic agents. In fact, there are ample examples of cross talk between autophagy and other modes of cell death after exposure to toxicants. However, the relative contribution of autophagy to the overall toxicity of these compounds is not always clear, and further research is needed to clarify the toxicological significance of this process.
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| 14. |
- Orrenius, S, et al.
(författare)
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Mitochondrial oxidative stress: implications for cell death
- 2007
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Ingår i: Annual review of pharmacology and toxicology. - : Annual Reviews. - 0362-1642 .- 1545-4304. ; 47, s. 143-183
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Tidskriftsartikel (refereegranskat)abstract
- In addition to the established role of the mitochondria in energy metabolism, regulation of cell death has emerged as a second major function of these organelles. This seems to be intimately linked to their generation of reactive oxygen species (ROS), which have been implicated in mtDNA mutations, aging, and cell death. Mitochondrial regulation of apoptosis occurs by mechanisms, which have been conserved through evolution. Thus, many lethal agents target the mitochondria and cause release of cytochrome c and other pro-apoptotic proteins into the cytoplasm. Cytochrome c release is initiated by the dissociation of the hemoprotein from its binding to the inner mitochondrial membrane. Oxidation of cardiolipin reduces cytochrome c binding and increases the level of soluble cytochrome c in the intermembrane space. Subsequent release of the hemoprotein occurs by pore formation mediated by pro-apoptotic Bcl-2 family proteins, or by Ca2+ and ROS-triggered mitochondrial permeability transition, although the latter pathway might be more closely associated with necrosis. Taken together, these findings have placed the mitochondria in the focus of current cell death research.
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| 15. |
- Orrenius, S, et al.
(författare)
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Role of Cell Death in Toxicology: Does It Matter How Cells Die?
- 2019
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Ingår i: Annual review of pharmacology and toxicology. - : Annual Reviews. - 1545-4304 .- 0362-1642. ; 59, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- My research activity started with studies on drug metabolism in rat liver microsomes in the early 1960s. The CO-binding pigment (cytochrome P450) had been discovered a few years earlier and was subsequently found to be involved in steroid hydroxylation in adrenal cortex microsomes. Our early studies suggested that it also participated in the oxidative demethylation of drugs catalyzed by liver microsomes, and that prior treatment of the animals with phenobarbital caused increased levels of the hemoprotein in the liver, and similarly enhanced rates of drug metabolism. Subsequent studies of cytochrome P450-mediated metabolism of toxic drugs in freshly isolated rat hepatocytes characterized critical cellular defense systems and identified mechanisms by which accumulating toxic metabolites could damage and kill the cells. These studies revealed that multiple types of cell death could result from the toxic injury, and that it is important to know which type of cell death results from the toxic injury.
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| 16. |
- Pollard, K. Michael, et al.
(författare)
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Mechanisms of Environment-Induced Autoimmunity
- 2021
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Ingår i: Annual Review of Pharmacology and Toxicology. - : ANNUAL REVIEWS. - 0362-1642 .- 1545-4304. - 9780824304614 ; 61, s. 135-157
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Forskningsöversikt (refereegranskat)abstract
- Although numerous environmental exposures have been suggested as triggers for preclinical autoimmunity, only a few have been confidently linked to autoimmune diseases. For disease-associated exposures, the lung is a common site where chronic exposure results in cellular toxicity, tissue damage, inflammation, and fibrosis. These features are exacerbated by exposures to particulate material, which hampers clearance and degradation, thus facilitating persistent inflammation. Coincident with exposure and resulting pathological processes is the posttranslational modification of self-antigens, which, in concert with the formation of tertiary lymphoid structures containing abundant B cells, is thought to promote the generation of autoantibodies that in some instances demonstrate major histocompatibility complex restriction. Under appropriate gene-environment interactions, these responses can have diagnostic specificity. Greater insight into the molecular and cellular requirements governing this process, especially those that distinguish preclinical autoimmunity from clinical autoimmune disease, may facilitate determination of the significance of environmental exposures in human autoimmune disease.
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| 17. |
- Rask-Andersen, Mathias, et al.
(författare)
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The druggable genome : Evaluation of drug targets in clinical trials suggests major shifts in molecular class and indication
- 2014
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Ingår i: Annual Review of Pharmacology and Toxicology. - : Annual Reviews. - 0362-1642 .- 1545-4304. ; 54, s. 9-26
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Tidskriftsartikel (refereegranskat)abstract
- The largest innovations within pharmaceutical development come through new compounds that have unique and novel modes of action. These innovations commonly involve expanding the protein space targeted by pharmaceutical agents. At present, information about drugs and drug targets is available online via public databases such as DrugBank and the Therapeutic Targets Database. However, this information is biased, understandably so, toward established drugs and drug-target interactions. To gain a better overview of the drug-targeted portion of the human proteome and the directions of current drug development, we developed a data set of clinical trial drug-target interactions based on CenterWatch's Drugs in Clinical Trials Database, one of the largest databases of its kind. Our curation identified 475 potentially novel clinical trial drug targets. This review aims to identify trends in drug development based on the potentially novel targets currently being explored in clinical trials.
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| 18. |
- Riazifar, M., et al.
(författare)
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Stem Cell Extracellular Vesicles: Extended Messages of Regeneration
- 2017
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Ingår i: Annual Review of Pharmacology and Toxicology. - : Annual Reviews. - 0362-1642 .- 1545-4304. - 9780824304577 ; , s. 125-154
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Stem cells are critical to maintaining steady-state organ homeostasis and regenerating injured tissues. Recent intriguing reports implicate extracellular vesicles (EVs) as carriers for the distribution of morphogens and growth and differentiation factors from tissue parenchymal cells to stem cells, and conversely, stem cell-derived EVs carrying certain proteins and nucleic acids can support healing of injured tissues. We describe approaches to make use of engineered EVs as technology platforms in therapeutics and diagnostics in the context of stem cells. For some regenerative therapies, natural and engineered EVs from stem cells may be superior to single-molecule drugs, biologics, whole cells, and synthetic liposome or nanoparticle formulations because of the ease of bioengineering with multiple factors while retaining superior biocompatibility and biostability and posing fewer risks for abnormal differentiation or neoplastic transformation. Finally, we provide an overview of current challenges and future directions of EVs as potential therapeutic alternatives to cells for clinical applications.
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| 19. |
- Shvedova, AA, et al.
(författare)
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Close encounters of the small kind: adverse effects of man-made materials interfacing with the nano-cosmos of biological systems
- 2010
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Ingår i: Annual review of pharmacology and toxicology. - : Annual Reviews. - 1545-4304 .- 0362-1642. ; 50, s. 63-88
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Tidskriftsartikel (refereegranskat)abstract
- Engineered nanomaterials have unique physico-chemical properties that make them promising for many technological and biomedical applications, including tissue regeneration, drug and gene delivery, and in vivo monitoring of disease processes. However, with the burgeoning capabilities to manipulate structures at the nano-scale, intentional as well as unintentional human exposures to engineered nanomaterials are set to increase. Nanotoxicology is an emerging discipline focused on understanding the properties of engineered nanomaterials and their interactions with biological systems, and may be viewed as the study of the undesirable interference between man-made nanomaterials and cellular nanostructures or nanomachines. In this review, we discuss recognition of engineered nanomaterials by the immune system, our primary defense system against foreign invasion. Moreover, as oxidative stress is believed to be one of the major deleterious consequences of exposure to nanomaterials, we explore triggering of pro- and antioxidant pathways as well as biomarkers of oxidative stress. Finally, we highlight in vivo studies of the toxicological outcomes of engineered nanomaterials, including carbon nanotubes, with an emphasis on inflammation and genotoxic responses.
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| 20. |
- Smith, CIE, et al.
(författare)
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Therapeutic Oligonucleotides: State of the Art
- 2019
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Ingår i: Annual review of pharmacology and toxicology. - : Annual Reviews. - 1545-4304 .- 0362-1642. ; 59, s. 605-630
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Tidskriftsartikel (refereegranskat)abstract
- Oligonucleotides (ONs) can interfere with biomolecules representing the entire extended central dogma. Antisense gapmer, steric block, splice-switching ONs, and short interfering RNA drugs have been successfully developed. Moreover, antagomirs (antimicroRNAs), microRNA mimics, aptamers, DNA decoys, DNAzymes, synthetic guide strands for CRISPR/Cas, and innate immunity-stimulating ONs are all in clinical trials. DNA-targeting, triplex-forming ONs and strand-invading ONs have made their mark on drug development research, but not yet as medicines. Both design and synthetic nucleic acid chemistry are crucial for achieving biologically active ONs. The dominating modifications are phosphorothioate linkages, base methylation, and numerous 2′-substitutions in the furanose ring, such as 2′-fluoro, O-methyl, or methoxyethyl. Locked nucleic acid and constrained ethyl, a related variant, are bridged forms where the 2′-oxygen connects to the 4′-carbon in the sugar. Phosphorodiamidate morpholino oligomers, carrying a modified heterocyclic backbone ring, have also been commercialized. Delivery remains a major obstacle, but systemic administration and intrathecal infusion are used for treatment of the liver and brain, respectively.
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