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Publisher: Elsevier   (Total: 3185 journals)

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Showing 1 - 200 of 3185 Journals sorted alphabetically
Academic Pediatrics     Hybrid Journal   (Followers: 37, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 25, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 100, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 28, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 37, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 5)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 7)
Acta Astronautica     Hybrid Journal   (Followers: 427, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 28, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 3)
Acta de Investigación Psicológica     Open Access   (Followers: 3)
Acta Ecologica Sinica     Open Access   (Followers: 10, SJR: 0.18, CiteScore: 1)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 292, SJR: 3.263, CiteScore: 6)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 6, SJR: 0.504, CiteScore: 1)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.542, CiteScore: 1)
Acta Oecologica     Hybrid Journal   (Followers: 12, SJR: 0.834, CiteScore: 2)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription  
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 2, SJR: 0.307, CiteScore: 0)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 1, SJR: 1.793, CiteScore: 6)
Acta Poética     Open Access   (Followers: 4, SJR: 0.101, CiteScore: 0)
Acta Psychologica     Hybrid Journal   (Followers: 27, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access   (Followers: 1)
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.052, CiteScore: 2)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3, SJR: 0.374, CiteScore: 1)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.344, CiteScore: 1)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 7, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 8)
Acute Pain     Full-text available via subscription   (Followers: 15, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 17, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 9, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 11, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 23)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 179, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 12, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.694, CiteScore: 3)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 16, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 28, SJR: 0.126, CiteScore: 0)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 11, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 11, SJR: 1.551, CiteScore: 4)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 24, SJR: 2.089, CiteScore: 5)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 15, SJR: 0.572, CiteScore: 2)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.61, CiteScore: 7)
Advances in Botanical Research     Full-text available via subscription   (Followers: 2, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 32, SJR: 3.043, CiteScore: 6)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 1.453, CiteScore: 2)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 1.992, CiteScore: 5)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 5)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 14)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 28, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 10, SJR: 1.316, CiteScore: 2)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 26, SJR: 1.562, CiteScore: 3)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 20, SJR: 1.977, CiteScore: 8)
Advances in Computers     Full-text available via subscription   (Followers: 14, SJR: 0.205, CiteScore: 1)
Advances in Dermatology     Full-text available via subscription   (Followers: 15)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 13)
Advances in Digestive Medicine     Open Access   (Followers: 11)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 7)
Advances in Drug Research     Full-text available via subscription   (Followers: 26)
Advances in Ecological Research     Full-text available via subscription   (Followers: 43, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 29, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 8)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 49, SJR: 5.39, CiteScore: 8)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 1)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 62, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Genetics     Full-text available via subscription   (Followers: 20, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 10, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 24, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 12, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 23)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 3, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 36, SJR: 4.433, CiteScore: 6)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 10, SJR: 1.163, CiteScore: 2)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 2, SJR: 1.938, CiteScore: 3)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6, SJR: 0.176, CiteScore: 0)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 3)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.682, CiteScore: 2)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 8)
Advances in Marine Biology     Full-text available via subscription   (Followers: 19, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 12, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 7, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 23)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.182, CiteScore: 0)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 4)
Advances in Oncobiology     Full-text available via subscription   (Followers: 2)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 17, SJR: 1.875, CiteScore: 4)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.174, CiteScore: 0)
Advances in Parasitology     Full-text available via subscription   (Followers: 5, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 25, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 17)
Advances in Pharmacology     Full-text available via subscription   (Followers: 16, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.574, CiteScore: 1)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.109, CiteScore: 1)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 10)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 19)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 0.791, CiteScore: 2)
Advances in Psychology     Full-text available via subscription   (Followers: 66)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (Followers: 1, SJR: 0.263, CiteScore: 1)
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.101, CiteScore: 0)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 6)
Advances in Space Research     Full-text available via subscription   (Followers: 413, SJR: 0.569, CiteScore: 2)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Surgery     Full-text available via subscription   (Followers: 12, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 36, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 20)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 15)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 51, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 365, SJR: 0.796, CiteScore: 3)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.42, CiteScore: 2)
African J. of Emergency Medicine     Open Access   (Followers: 6, SJR: 0.296, CiteScore: 0)
Ageing Research Reviews     Hybrid Journal   (Followers: 11, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 468, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (Followers: 1, SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 17, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 31, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 44, SJR: 1.272, CiteScore: 3)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 4)
Agriculture and Natural Resources     Open Access   (Followers: 3)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 57, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 6, SJR: 0.26, CiteScore: 0)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.19, CiteScore: 0)
Alcohol     Hybrid Journal   (Followers: 12, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 11)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 2, SJR: 0.604, CiteScore: 3)
Alexandria J. of Medicine     Open Access   (Followers: 1, SJR: 0.191, CiteScore: 1)
Algal Research     Partially Free   (Followers: 11, SJR: 1.142, CiteScore: 4)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.504, CiteScore: 1)
Allergology Intl.     Open Access   (Followers: 5, SJR: 1.148, CiteScore: 2)
Alpha Omegan     Full-text available via subscription   (SJR: 3.521, CiteScore: 6)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 10, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 52, SJR: 4.66, CiteScore: 10)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 4, SJR: 1.796, CiteScore: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 4, SJR: 1.108, CiteScore: 3)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 6)
American Heart J.     Hybrid Journal   (Followers: 57, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 62, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 45, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 11)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 13, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 34, SJR: 7.45, CiteScore: 8)
American J. of Infection Control     Hybrid Journal   (Followers: 29, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 35, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 48)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3, SJR: 1.967, CiteScore: 2)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 233, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 66, SJR: 3.184, CiteScore: 4)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 5, SJR: 0.265, CiteScore: 0)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.289, CiteScore: 1)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, CiteScore: 1)
American J. of Pathology     Hybrid Journal   (Followers: 30, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 28, SJR: 2.164, CiteScore: 4)
American J. of Surgery     Hybrid Journal   (Followers: 39, SJR: 1.141, CiteScore: 2)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.767, CiteScore: 1)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 7)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.144, CiteScore: 3)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 63, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 20, SJR: 0.411, CiteScore: 1)
Anales de Cirugia Vascular     Full-text available via subscription   (Followers: 1)
Anales de Pediatría     Full-text available via subscription   (Followers: 3, SJR: 0.277, CiteScore: 0)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription  
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 5, SJR: 4.849, CiteScore: 10)
Analytica Chimica Acta     Hybrid Journal   (Followers: 44, SJR: 1.512, CiteScore: 5)
Analytica Chimica Acta : X     Open Access  
Analytical Biochemistry     Hybrid Journal   (Followers: 200, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 12, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 14)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 23, SJR: 0.683, CiteScore: 2)
Angiología     Full-text available via subscription   (SJR: 0.121, CiteScore: 0)
Angiologia e Cirurgia Vascular     Open Access   (Followers: 1, SJR: 0.111, CiteScore: 0)
Animal Behaviour     Hybrid Journal   (Followers: 207, SJR: 1.58, CiteScore: 3)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 6, SJR: 0.937, CiteScore: 2)
Animal Reproduction Science     Hybrid Journal   (Followers: 7, SJR: 0.704, CiteScore: 2)

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Similar Journals
Journal Cover
Advances in Pharmacology
Journal Prestige (SJR): 1.536
Citation Impact (citeScore): 3
Number of Followers: 16  
 
  Full-text available via subscription Subscription journal
ISSN (Print) 1054-3589
Published by Elsevier Homepage  [3185 journals]
  • Medications development for food-based and drug use disorders
    • Abstract: Publication date: Available online 3 June 2019Source: Advances in PharmacologyAuthor(s): Fernando B. de Moura, Stephen J. Kohut, Jack Bergman Despite decades of research, few medications have gained Food and Drug Administration (FDA) approval for the management of substance abuse disorder. The paucity of successful medications can be attributed, in part, to the lack of clearly identified neurobiological targets for addressing the core pathology of addictive behavior. Commonalities in the behavioral and brain processes involved in the rewarding effects of drugs and foods has prompted the evaluation of candidate medications that target neural pathways involved in both drug and eating disorders. Here, pharmacological strategies for the development of novel medications for drug addiction are presented in the context of potential overlapping neurobiological targets identified for eating disorders (e.g., obesity, overeating, binge-eating) and substance abuse. Mechanisms discussed in this chapter include modulators of the gut-brain axis (e.g., leptin, ghrelin, cholecystokinin, cocaine- and amphetamine-regulated transcript, and pancreatic peptides) and neurotransmitter systems (e.g., opioids, cannabinoids, dopamine, serotonin, and acetylcholine).
       
  • Nitric oxide: Antidepressant mechanisms and inflammation
    • Abstract: Publication date: Available online 24 May 2019Source: Advances in PharmacologyAuthor(s): Mehdi Ghasemi Millions of individuals worldwide suffers from mood disorders, especially major depressive disorder (MDD), which has a high rate of disease burden in society. Although targeting the biogenic amines including serotonin, and norepinephrine have provided invaluable links with the pharmacological treatment of MDD over the last four decades, a growing body of evidence suggest that other biologic systems could contribute to the pathophysiology and treatment of MDD. In this chapter, we highlight the potential role of nitric oxide (NO) signaling in the pathophysiology and thereby treatment of MDD. This has been investigated over the last four decades by showing that (i) levels of NO are altered in patients with major depression; (ii) modulators of NO signaling exert antidepressant effects in patients with MDD or in the animal studies; (iii) NO signaling could be targeted by a variety of antidepressants in animal models of depression; and (iv) NO signaling can potentially modulate the inflammatory pathways that underlie the pathophysiology of MDD. These findings, which hypothesize an NO involvement in MDD, can provide a new insight into novel therapeutic approaches for patients with MDD in the future.
       
  • GPCR drug discovery-moving beyond the orthosteric to the allosteric domain
    • Abstract: Publication date: Available online 14 May 2019Source: Advances in PharmacologyAuthor(s): Christian C. Felder Allosteric modulation of G protein coupled receptors (GPCRs) is rapidly becoming a standard option for development of therapeutics headed to the clinic. Although GPCRs represent about 35% of marketed drugs, to date only two allosteric modulators have been approved for human use. However, many are now in early clinical development are can provide unique regulation of GPCRs including high selectivity along with physiologic temporal and spatial signaling. These molecules bind to a site that is distinct from the site where the endogenous agonist binds yet can provide robust modulation effects that span from the positive to the negative. Along with classical chemogenomic techniques, newer technology is being directly applied to their development including three dimensional biophysical structure-function analysis and in silico molecular dynamic simulations. The goal is to provide rationally designed molecules from well informed physical and in silico data to speed the discovery and development of the next generation therapeutics. In this chapter an example of the evolution of allosteric drug discovery targeting the muscarinic receptor family should serve to inform of progress in this exciting area of research and early drug development.
       
  • Obsessive compulsive disorder (OCD): Current treatments and a framework
           for neurotherapeutic research
    • Abstract: Publication date: Available online 2 May 2019Source: Advances in PharmacologyAuthor(s): Erik Z. Woody, Kurt Leroy Hoffman, Henry Szechtman We briefly review current approaches to the diagnosis and treatment of OCD, noting their lack of a strong theoretical foundation. In keeping with the Research Domain Criteria project (RDoC) calls for reconceptualizing psychopathology in ways that better link up with normal brain systems, we advance an adaptationist, brain-network perspective on OCD and propose that OCD represents a dysfunction in the stopping dynamics of a normal brain network that evolved to handle potential danger. We then illustrate how this theoretical perspective can be used to organize possibilities for research on neurotherapeutics for OCD and suggest novel directions for future work.
       
  • Lipid rafts in psychiatry
    • Abstract: Publication date: Available online 2 May 2019Source: Advances in PharmacologyAuthor(s): Nathan H. Wray, Mark M. Rasenick Lipid microenvironments in the plasma membrane are known to influence many signal transduction pathways. Several of those pathways are critical for both the etiology and treatment of depression. Further, several signaling proteins are modified, covalently, by lipids, a process that alters their interface with the microenvironments mentioned above. This review presents a brief discussion of the interface of the above elements as well as a discussion about the participation of lipids and lipid moieties in the action of antidepressants.
       
  • Idiosyncratic Drug-Induced Liver Injury in Patients: Detection, Severity
           Assessment, and Regulatory Implications
    • Abstract: Publication date: Available online 30 April 2019Source: Advances in PharmacologyAuthor(s): Paul B. Watkins Idiosyncratic Drug-Induced Liver Injury (IDILI) is a rare but potentially life-threatening event that is caused by drugs that, at usual therapeutic doses, do not cause any biochemical or clinical evidence of liver injury in the majority of treated patients. The most common clinical phenotypes of IDILI are “acute hepatitis,” “mixed hepatocellular-cholestatic hepatitis,” and “cholestatic hepatitis” and these are distinguished by clinical, biochemical and histologic characteristics. Anti-microbials, herbals and dietary supplements are now the agents most often implicated in the US Drug-Induced Liver Injury Network registry. There are several scales that have been used to characterize the severity of IDILI events. There are no reliable means to accurately predict the course of an IDILI event at presentation. In clinical trials, the “gold standard” liver safety signal is the occurrence of “Hy's Law Cases.” Making the diagnosis of IDILI, and when a patient is taking multiple drugs, identifying the most likely culprit can be challenging, but many drugs cause IDILI with characteristic clinical and biochemical presentations, or “signatures.” In a clinical trial, it is sometimes possible to identify an overlooked “signature” of IDILI by characterizing more minor, asymptomatic, and transient elevations in liver chemistries. This observation can be helpful in assessing causation in rare serious liver events occurring in the clinical trial, or first recognized post-marketing.
       
  • Rapid-acting antidepressants
    • Abstract: Publication date: Available online 24 April 2019Source: Advances in PharmacologyAuthor(s): Jeffrey M. Witkin, Anna E. Martin, Lalit K. Golani, Nina Z. Xu, Jodi L. Smith Conventional antidepressants (biogenic amine mechanisms) are not fully efficacious (e.g., symptoms remain after treatment, not all patients respond), produce effects only after weeks of daily dosing, and do not impact all disease symptoms. In contrast, a new class of antidepressants has been emerging since 2006 that has demonstrated rapid onset, large effect size, activity after only a single or few dose applications, and positive impact in treatment refractory patients and against some treatment-resistant symptoms (e.g., anhedonia). Rapid-acting antidepressant drug action has been demonstrated in controlled clinical studies for ketamine, a few other NMDA receptor antagonists, and scopolamine. Less clinical data are currently available for psychedelic drugs such as psilocybin, lysergic acid diethylamide, and ayahuasca. The mechanisms of action of rapid-acting antidepressants are not fully understood. However, a general triggering mechanism appears to involve the potentiation of AMPA receptor function. Although the durability of antidepressant effects of ketamine and scopolamine is limited, psychedelic drugs have been reported to produce effects for many months. The primary impediment to generating a medicine of this type for depressed patients is side effects and the lack of methods to ensure enduring antidepressant effects. Thus, further exploration of drug possibilities continues. Esketamine ((S)-ketamine) was recently FDA approved. Compounds currently in clinical development include the NMDA receptor antagonist (R)-ketamine, the NMDA receptor modulator, GLYX-13 (Rapastinel), and the AMPA receptor potentiator TAK-653. Additional pharmacological classes have produced effects in the preclinical laboratory to suggest their potential as rapid-acting agents. These include mGlu2/3 receptor antagonists, AMPA receptor potentiators, and negative allosteric modulators of GABAA(α5) receptors. In all cases, molecules exist that could be used to provide clinical proof of concept testing.
       
  • mGlu2/3 receptor antagonists
    • Abstract: Publication date: Available online 24 April 2019Source: Advances in PharmacologyAuthor(s): Shigeyuki Chaki Abnormalities of glutamatergic transmission are implicated in neuropsychiatric disorders. Among the glutamate receptors, metabotropic (mGlu) 2/3 receptors have recently gained much attention as molecular targets for the treatment of several neuropsychiatric disorders including depression and anxiety. Both orthosteric and allosteric antagonists of mGlu2/3 receptors have been synthesized, and their therapeutic potential has been examined. These research activities have demonstrated the promise of mGlu2/3 receptor antagonists as potential treatment agents for the above-mentioned neuropsychiatric disorders. In particular, it has been considered that the antidepressant effects of mGlu2/3 receptor antagonists are worthy of pursuing, since the antidepressant profiles as well as synaptic/neural mechanisms involved in the actions of mGlu2/3 receptor antagonists are similar to those of ketamine, which has been demonstrated to show potent, rapid and sustained efficacy in patients with depression, even those resistant to the conventionally prescribed antidepressants. In this chapter, the general pharmacology of mGlu2/3 receptor antagonists and their therapeutic potential are reviewed. In particular, I focus on the usefulness of mGlu2/3 receptor antagonists as novel antidepressants, in comparison with ketamine.
       
  • Role of MEIS1 in RLS: From GWAS to functional studies in mice
    • Abstract: Publication date: Available online 9 April 2019Source: Advances in PharmacologyAuthor(s): Aaro V. Salminen, Daniel D. Lam, Juliane Winkelmann MEIS1 is a transcription factor playing an important role in the development of several organs, including central and peripheral nervous systems. A genetic locus spanning the MEIS1 coding region has been associated with the risk of RLS in genome-wide association studies, with increasing evidence that MEIS1 is the causal RLS gene. The RLS-linked genetic signal has been mapped to an intronic regulatory element within MEIS1. This element plays a role in the ganglionic eminences of the developing forebrain, with the RLS risk allele related to a reduced activation of the enhancer. This suggests that the ganglionic eminences play an important role in the development of genetic susceptibility to RLS. In addition, rare variants within MEIS1 have been shown to contribute to the disease risk. These variants were identified first in RLS families and later found in further RLS cases by targeted sequencing. Some of these variants alone are sufficient to suppress MEIS1 function in neural development, providing further evidence of the importance of neurodevelopmental processes in the pathological mechanism of MEIS1 in RLS. Heterozygous Meis1 inactivation in mice causes hyperactivity at the onset of the inactive period, consistent with human RLS. In addition, these mice revealed an effect of MEIS1 on the dopaminergic system at both the spinal and supraspinal level. More studies are needed in human genetics to determine the exact role of MEIS1 variants in the risk of RLS, as well as in functional genetics and animal studies to further elucidate the pathological mechanism of MEIS1 in RLS.
       
  • Mechanisms and Biomarkers of Liver Regeneration After Drug-Induced Liver
           Injury
    • Abstract: Publication date: Available online 21 March 2019Source: Advances in PharmacologyAuthor(s): Melissa M. Clemens, Mitchell R. McGill, Udayan Apte Liver, the major metabolic organ in the body, is known for its remarkable capacity to regenerate. Whereas partial hepatectomy (PHx) is a popular model for the study of liver regeneration, the liver also regenerates after acute injury, but less is known about the mechanisms that drive it.Recent studies have shown that liver regeneration is critical for survival in acute liver failure (ALF), which is usually due to drug-induced liver injury (DILI). It is sometimes assumed that the signaling pathways involved are similar to those that regulate regeneration after PHx, but there are likely to be critical differences. A better understanding of regeneration mechanisms after DILI and hepatotoxicity in general could lead to development of new therapies for ALF patients and new biomarkers to predict patient outcome. Here, we summarize what is known about the mechanisms of liver regeneration and repair after hepatotoxicity. We also review the literature in the emerging field of liver regeneration biomarkers.
       
  • Pharmacological treatments of augmentation in RLS patients
    • Abstract: Publication date: Available online 20 March 2019Source: Advances in PharmacologyAuthor(s): Claudia Trenkwalder, Walter Paulus Augmentation, a treatment-induced paradoxical worsening of the symptoms of restless legs syndrome (RLS) that is caused by long-term dopaminergic therapy, in particular with higher doses, remains the major challenge of RLS treatment. The mainstay of treatment continues to be preventing augmentation, either by starting RLS therapy with alternative drugs or by sensitizing physicians about the absolute necessity of respecting approved dosages of dopaminergic drugs when treating RLS and never exceeding the maximum recommended dosages. In the case of a positive diagnosis of augmentation, treatment consists of reducing or eliminating dopaminergic therapy, ensuring that serum ferritin is clearly higher than the level assumed to be necessary from a hematological point of view and/or switching treatment to alternative drugs such as α2δ ligands, opiates, or to combination therapy.
       
  • Iron uptake at the blood-brain barrier is influenced by sex and genotype
    • Abstract: Publication date: Available online 22 March 2019Source: Advances in PharmacologyAuthor(s): Quinn W. Wade, Brian Chiou, James R. Connor Iron transport to the brain is a critically important and highly regulated process necessary for proper brain function. This review aims to summarize iron uptake mechanisms in the brain and the importance of sex and genotype on this uptake. In restless legs syndrome (RLS), brain iron uptake has been hypothesized to be dysregulated, leading to the clinically observed brain iron deficiency, so this review specifically comments on this disorder. The review covers transferrin-bound transport and the more recently discovered role of ferritin in brain iron delivery. Studies on the impact of sex, MEIS1 (associated with RLS), and H63D gene variants have revealed critical regulatory mechanisms and driving factors that significantly impact iron transport that may considerably affect the clinical treatment of RLS. RLS has provided insights into the gaps in knowledge underlying brain iron uptake mechanisms and their regulation, which in turn have provided insights into the pathophysiology of RLS.
       
  • Caenorhabditis elegans and its applicability to studies on RLS
    • Abstract: Publication date: Available online 14 March 2019Source: Advances in PharmacologyAuthor(s): Pan Chen, Omamuyovwi Meashack Ijomone, Kun He Lee, Michael Aschner Restless legs syndrome (RLS) is a common neurological disorder in the United States. This disorder is characterized by an irresistible urge to move the legs, although the symptoms vary in a wide range. The pathobiology of RLS has been linked to iron (Fe) deficiency and dopaminergic (DAergic) dysfunction. Several genetic factors have been reported to increase the risk of RLS. Caenorhabditis elegans (C. elegans) is a well-established animal model with a fully sequenced genome, which is highly conserved with mammals. Given the detailed knowledge of its genomic architecture, ease of genetic manipulation and conserved biosynthetic and metabolic pathways, as well as its small size, ease of maintenance, speedy generation time and large brood size, C. elegans provides numerous advantages in studying RLS-associated gene-environment interactions. Here we will review current knowledge about RLS symptoms, pathology and treatments, and discuss the application of C. elegans in RLS study, including the worm homologous genes and methods that could be performed to advance the pathophysiology RLS.
       
  • Non-dopaminergic vs. dopaminergic treatment options in restless legs
           syndrome
    • Abstract: Publication date: Available online 14 March 2019Source: Advances in PharmacologyAuthor(s): Vivian Wanner, Celia Garcia Malo, Sofía Romero, Irene Cano-Pumarega, Diego García-Borreguero Two types of drugs have been extensively investigated for the treatment of restless legs syndrome (RLS)/Willis-Ekbom disease (WED): dopamine agonists and α2δ ligands to the α2δ subunit of calcium channels. Comparative studies show that both classes of drugs are similarly effective in treating RLS symptoms over the short- and long-term. While dopamine agonists are more effective in treating periodic limb movements (PLMs), α2δ ligands are more effective in consolidating sleep. However, given the fact that dopamine agonists cause high rates of augmentation of symptoms, recent international guidelines recommend that whenever possible the initial treatment of choice should be an α2δ ligand. In fact, the most effective preventive strategy involves not using dopaminergic agents unless absolutely necessary. Indeed, should dopaminergic treatment be needed to handle the symptoms effectively, then it is recommended that the dopaminergic load be reduced by using the lowest effective dose for the shortest possible period of time. However, it must be taken into account that the only α2δ ligand approved for RLS/WED is gabapentin enacarbil, which is not yet available in Europe.Furthermore, recent studies have also reported on the efficacy of opioids as a second-line treatment of RLS/WED, following treatment failure with dopamine agonists. Recent guidelines have taken these new data into account and highlight that a low dose of an opioid (prolonged-release oxycodone or methadone) may be considered in patients with very severe augmentation of symptoms.Alternative non-dopaminergic treatment concepts based on glutamatergic and adenosinergic mechanisms are currently in development, and are likely to provide encouraging therapeutic alternatives.
       
  • Biomarkers of Drug-Induced Liver Injury
    • Abstract: Publication date: Available online 6 March 2019Source: Advances in PharmacologyAuthor(s): Mitchell R. McGill, Hartmut Jaeschke Drug-induced liver injury (DILI) is a major clinical and regulatory challenge. As a result, interest in DILI biomarkers is growing. So far, considerable progress has been made in identification of biomarkers for diagnosis (acetaminophen-cysteine protein adducts), prediction (genetic biomarkers), and prognosis (microRNA-122, high mobility group box 1 protein, keratin-18, glutamate dehydrogenase, mitochondrial DNA). Many of those biomarkers also provide mechanistic insight. The purpose of this chapter is to review major advances in DILI biomarker research over the last decade, and to highlight some of the challenges involved in implementation. Although much work has been done, more liver-specific biomarkers, more DILI-specific biomarkers, and better prognostic biomarkers for survival are all still needed. Furthermore, more work is needed to define reference intervals and medical decision limits.
       
  • Role and Mechanisms of Autophagy in Alcohol-induced Liver Injury
    • Abstract: Publication date: Available online 24 February 2019Source: Advances in PharmacologyAuthor(s): Xiaojuan Chao, Wen-Xing Ding Alcoholic liver disease (ALD) is one of the major causes of chronic liver disease worldwide. Currently, no successful treatments are available for ALD. The pathogenesis of ALD is characterized as simple steatosis, fibrosis, cirrhosis, alcoholic hepatitis (AH), and eventually hepatocellular carcinoma (HCC). Autophagy is a highly conserved intracellular catabolic process, which aims at recycling cellular components and removing damaged organelles in response to starvation and stresses. Therefore, autophagy is considered as an important cellular adaptive and survival mechanism under various pathophysiological conditions. Recent studies from our lab and others suggest that chronic alcohol consumption may impair autophagy and contribute to the pathogenesis of ALD. In this chapter, we summarize recent progress on the role and mechanisms of autophagy in the development of ALD. Understanding the roles of autophagy in ALD may offer novel therapeutic avenues against ALD by targeting these pathways.
       
  • Acetaminophen hepatotoxicity: A mitochondrial perspective
    • Abstract: Publication date: Available online 21 February 2019Source: Advances in PharmacologyAuthor(s): Anup Ramachandran, Hartmut Jaeschke Acetaminophen (APAP) is a highly effective analgesic, which is safe at therapeutic doses. However, an overdose can cause hepatotoxicity and even liver failure. APAP toxicity is currently the most common cause of acute liver failure in the United States. Decades of research on mechanisms of liver injury have established the role of mitochondria as central players in APAP-induced hepatocyte necrosis and this chapter examines the various facets of the organelle's involvement in the process of injury as well as in resolution of damage. The injury process is initiated by formation of a reactive metabolite, which binds to sulfhydryl groups of cellular proteins including mitochondrial proteins. This inhibits the electron transport chain and leads to formation of reactive oxygen species, which induce the activation of redox-sensitive members of the MAP kinase family ultimately causing activation of c-Jun N terminal kinase, JNK. Translocation of JNK to the mitochondria then amplifies mitochondrial dysfunction, ultimately resulting in mitochondrial permeability transition and release of mitochondrial intermembrane proteins, which trigger nuclear DNA fragmentation. Together, these events result in hepatocyte necrosis, while adaptive mechanisms such as mitophagy remove damaged mitochondria and minimize the extent of the injury. This oscillation between recovery and necrosis is predominant in cells at the edge of the necrotic area in the liver, where induction of mitochondrial biogenesis is important for liver regeneration. All these aspects of mitochondria in APAP hepatotoxicity, as well as their relevance to humans with APAP overdose and development of therapeutic approaches will be examined in detail in this chapter.
       
  • Cell Death in Drug-Induced Liver Injury
    • Abstract: Publication date: Available online 20 February 2019Source: Advances in PharmacologyAuthor(s): Andrea Iorga, Lily Dara Drug-induced liver injury (DILI) is an important cause of liver toxicity which can have varying clinical presentations, the most severe of which being acute liver failure. Hepatocyte death as a cause of drug toxicity is a feature of DILI. There are multiple cell death subroutines; some, like apoptosis, necroptosis, autophagy, and necrosis have been extensively studied, while others such as pyroptosis and ferroptosis have been more recently described. The mode of cell death in DILI depends on the culprit drug, as it largely dictates the mechanism and extent of injury. The main cell death subroutines in DILI are apoptosis and necrosis, with mitochondrial involvement being pivotal for the execution of both. A few drugs such as acetaminophen (APAP) can cause direct, dose-dependent toxicity, while the majority of drugs cause idiosyncratic DILI (IDILI). IDILI is an unpredictable form of liver injury that is not dose dependent, occurs in individuals with a genetic predisposition, and presents with variable latency. APAP-induced programmed necrosis has been extensively studied. However, the mechanisms and pathogenesis of cell death from drugs causing IDILI are harder to elucidate due to the complex and multifactorial nature of the disease. Cell death in IDILI is likely death receptor-mediated apoptosis and the result of an activated innate and adaptive immune system, compounded by other host factors such as genetics, gender, age, and capacity for immune tolerance. This chapter will review the different modes of cell death, namely apoptosis, necrosis, necroptosis, autophagy, pyroptosis, and ferroptosis and their pertinence to DILI.
       
  • Drug-induced liver injury in obesity and nonalcoholic fatty liver disease
    • Abstract: Publication date: Available online 20 February 2019Source: Advances in PharmacologyAuthor(s): Julien Allard, Dounia Le Guillou, Karima Begriche, Bernard Fromenty Obesity is commonly associated with nonalcoholic fatty liver (NAFL), a benign condition characterized by hepatic lipid accumulation. However, NAFL can progress in some patients to nonalcoholic steatohepatitis (NASH) and then to severe liver lesions including extensive fibrosis, cirrhosis and hepatocellular carcinoma. The entire spectrum of these hepatic lesions is referred to as nonalcoholic fatty liver disease (NAFLD). The transition of simple fatty liver to NASH seems to be favored by several genetic and environmental factors. Different experimental and clinical investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs may cause more severe and/or more frequent acute liver injury in obese individuals whereas others may trigger the transition of simple fatty liver to NASH or may worsen hepatic lipid accumulation, necroinflammation and fibrosis. This review presents the available information regarding drugs that may cause a specific risk in the context of obesity and NAFLD. These drugs, which belong to different pharmacological classes, include acetaminophen, halothane, methotrexate, rosiglitazone and tamoxifen. For some of these drugs, experimental investigations confirmed the clinical observations and unveiled different pathophysiological mechanisms which may explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Because obese people often take several drugs for the treatment of different obesity-related diseases, there is an urgent need to identify the main pharmaceuticals that may cause acute liver injury on a fatty liver background or that may enhance the risk of severe chronic liver disease.
       
  • D3 and D1 receptors: The Yin and Yang in the treatment of restless legs
           syndrome with dopaminergics
    • Abstract: Publication date: Available online 18 February 2019Source: Advances in PharmacologyAuthor(s): Stefan Clemens, Imad Ghorayeb Dopaminergic treatments targeting the D3 receptor subtype to reduce the symptoms of RLS show substantial initial clinical benefits but fail to maintain their efficacy over time. Sensorimotor circuits in the spinal cord are the gateway for the sensory processing of the symptoms and critical for the associated leg movements that relieve the symptoms and the periodic limb movements that often develop during sleep. There is a high preponderance of the inhibitory D3 receptor in the sensory-processing areas of the spinal cord (dorsal horn), whereas the motor areas in the ventral horn more strongly express the excitatory D1 receptor subtype. D3 and D1 receptors can form functional heteromeric ensembles that influence each other. In the spinal cord, long-term treatment with D3 receptor agonists is associated with the upregulation of the D1 receptor subtype and block of D1 receptor function at this stage can restore the D3 receptor effect. Alternate scenarios for a role of dopamine involve a role for the D5 receptor in regulating motor excitability and for the D4 receptor subtype in controlling D3-like effects. A model emerges that proposes that the behavioral changes in RLS, while responsive to D3 receptor agonists, may be ultimately be the result of unmasked increased D1-like receptor activities.
       
  • The heterotetrameric structure of the adenosine A1-dopamine D1 receptor
           complex: Pharmacological implication for Restless Legs Syndrome
    • Abstract: Publication date: Available online 13 February 2019Source: Advances in PharmacologyAuthor(s): Antoni Cortés, Verònica Casadó-Anguera, Estefanía Moreno, Vicent Casadó Dopaminergic and purinergic signaling play a pivotal role in neurological diseases associated with motor symptoms, including Parkinson's disease (PD), multiple sclerosis, amyotrophic lateral sclerosis, Huntington disease, Restless Legs Syndrome (RLS), spinal cord injury (SCI), and ataxias. Extracellular dopamine and adenosine exert their functions interacting with specific dopamine (DR) or adenosine (AR) receptors, respectively, expressed on the surface of target cells. These receptors are members of the family A of G protein-coupled receptors (GPCRs), which is the largest protein superfamily in mammalian genomes. GPCRs are target of about 40% of all current marketed drugs, highlighting their importance in clinical medicine. The striatum receives the densest dopamine innervations and contains the highest density of dopamine receptors. The modulatory role of adenosine on dopaminergic transmission depends largely on the existence of antagonistic interactions mediated by specific subtypes of DRs and ARs, the so-called A2AR–D2R and A1R–D1R interactions. Due to the dopamine/adenosine antagonism in the CNS, it was proposed that ARs and DRs could form heteromers in the neuronal cell surface. Therefore, adenosine can affect dopaminergic signaling through receptor–receptor interactions and by modulations in their shared intracellular pathways in the striatum and spinal cord. In this work we describe the allosteric modulations between GPCR protomers, focusing in those of adenosine and dopamine within the A1R–D1R heteromeric complex, which is involved in RLS. We also propose that the knowledge about the intricate allosteric interactions within the A1R–D1R heterotetramer, may facilitate the treatment of motor alterations, not only when the dopamine pathway is hyperactivated (RLS, chorea, etc.) but also when motor function is decreased (SCI, aging, PD, etc.).
       
  • D3 receptor agonist efficacy in RLS/WED
    • Abstract: Publication date: Available online 12 February 2019Source: Advances in PharmacologyAuthor(s): Francesca Casoni, Andrea Galbiati, Luigi Ferini-Strambi Restless Legs Syndrome/Willis Ekbom Disease (RLS/WED) is a sleep related movement disorder characterized by an irresistible urge to move the limbs frequently associated with uncomfortable sensations that usually begin or worsen during inactivity and may be relieved by movement. The pathophysiology of the disorder involves several biological system; in particular, dopaminergic pathway and iron physiology have been extensively studied. Being a chronic condition, long-term treatments are required for an adequate management and strong evidence support the employment of dopamine agonists. D3 receptor agonists are of particular interest, because they act on receptors that are widely expressed in the spinal cord with an inhibitory action on sensory system. Pramipexole, rotigotine and ropinirole act on D3 receptors, even if not selectively, and are effective in reducing sensorimotor symptoms and improving sleep quality. However, despite an initial amelioration patients frequently experience augmentation, i.e., a worsening of symptoms induced by dopamine agonists. This can be explained by the activity of D1 receptor and by the non-selectiveness of D3 agonist drugs. Higher dopamine concentrations tend to activate the excitatory D1-like receptor that are associated with increased motor activity. The development of drugs that selectively target D3 receptors will be fundamental to provide alternative therapeutic strategies and to reduce the occurrence of augmentation.
       
  • Idiopathic Restless Legs Syndrome treatment: Progress and pitfalls'
    • Abstract: Publication date: Available online 12 February 2019Source: Advances in PharmacologyAuthor(s): Imad Ghorayeb The pathophysiology of Restless Legs Syndrome (RLS) remains uncertain. Although the dopaminergic and/or the iron breakdown homeostasis hypotheses are still considered to be the mainstay of the RLS underlying mechanism, therapeutic intervention aiming to alleviate RLS syndrome through dopamine agonists use and iron stores recovery failed so far to show short-term remarkable efficacy, and controlled trials to establish sustained long-term efficacy, tolerability and safety are lacking.Here we review available literature dealing with pharmacological treatment of RLS and consider some rational aspects of RLS pathophysiology that may support the use of available drug classes in treating this condition.
       
  • Evaluation and Treatment of Acetaminophen Toxicity
    • Abstract: Publication date: Available online 22 January 2019Source: Advances in PharmacologyAuthor(s): Erik S. Fisher, Steven C. Curry A review of the typical clinical course, diagnosis and treatment of acetaminophen toxicity is provided. For an acute overdose, most adults must ingest about 12 g or more acetaminophen (APAP) before risk of serious hepatotoxicity is of concern. A nomogram of serum APAP concentration vs hours post-ingestion can assist in determining risk of liver injury and need for treatment. However, histories concerning the time of ingestion and the amount of drug ingested are usually unreliable. Peak serum transaminase activities usually occur 48–96 h after acute ingestion. It is possible for patients to present in liver failure days after ingestion with undetectable serum APAP concentrations. Patients who have chronically ingested excessive APAP doses and develop hepatotoxicity usually present with such, and renal failure is more common in this population. Current treatment centers on administration of N-acetylcysteine (NAC) to prevent hepatotoxicity, though NAC also improves outcomes in patients who present with acute liver failure. When given early after APAP ingestion, NAC's main mechanism of action is to maintain intracellular glutathione stores so to detoxify the electrophilic APAP metabolite, NAPQI. NAC is generally well-tolerated when given intravenously, with the main concern being anaphylactoid reactions. These reactions usually occur during loading doses and are easily treated with discontinuation of the NAC infusion, administration of antihistamines, and then restarting the loading dose at a slower infusion rate. There is concern that current NAC dosing is not large enough to adequately treat large APAP ingestions. Patients with acute liver failure may be candidates for orthotopic liver transplantation.
       
  • Mechanisms of Idiosyncratic Drug-Induced Liver Injury
    • Abstract: Publication date: Available online 18 January 2019Source: Advances in PharmacologyAuthor(s): Jack Uetrecht Idiosyncratic drug-induced liver injury (IDILI) is a significant problem. Little is known with certainty about the mechanisms of IDILI. However, there is growing evidence that most IDILI is immune mediated and caused by reactive metabolites. The two major and complementary hypotheses that link reactive metabolite formation with the induction of an immune response that can lead to IDILI are the hapten and danger hypotheses. Specifically, a reactive metabolite can bind to proteins and make them foreign; however, without activation of antigen presenting cells (APCs), the immune response will be immune tolerance. Not all reactive metabolites are associated with the same risk of causing IDILI. If the reactive metabolite can also cause some cell damage, this can lead to the release of danger-associated molecular pattern molecules (DAMPs) that activate APCs. Other hypotheses for the mechanism of IDILI include mitochondrial injury, inhibition of the bile salt export pump, and endoplasmic reticulum stress. These mechanisms may be complementary to the danger hypothesis in that they may cause the release of DAMPs. None of these hypotheses has been adequately tested. Previous animal models have had characteristics very different from IDILI in humans and are unlikely to involve the same mechanism. However, impairment of immune tolerance has led to a model with characteristics very similar to IDILI in humans. This will make it possible to rigorously test hypotheses. A better mechanistic understanding of IDILI should lead to better methods to screen drug candidates for IDILI risk and treat IDILI when it occurs.
       
  • The neurophysiology of hyperarousal in RLS: Hints for a role of
           glutamate/GABA
    • Abstract: Publication date: Available online 18 January 2019Source: Advances in PharmacologyAuthor(s): Giuseppe Lanza, Raffale Ferri Restless legs syndrome (RLS) is a common sensory-motor circadian disorder, whose basic components include urge to move the legs, unpleasant sensory experience, and periodic leg movements during sleep, all associated with an enhancement of the individual's arousal state. Brain iron deficiency (BID) is considered to be a key initial pathobiological factor, based on alterations of iron acquisition by the brain, also moderated by genetic factors. In addition to the well-known dopaminergic involvement in RLS, previous studies pointed out that BID brings also a hyperglutamatergic state that influences a dysfunctional cortico-striatal-thalamic-cortical circuit in genetically vulnerable individuals. However, the enhancement of arousal mechanisms in RLS may also be explained by functional changes of the ascending arousal systems and by deficitary GABA-mediated inhibitory control. Very recently, it was also suggested that BID induces a hypoadenosinergic state in RLS, thus possibly providing a link for a putative unified pathophysiological mechanism accounting for both hyperarousal and sensory-motor signs. Consequently, RLS might be viewed as a multitransmitter neurochemical disorder, globally resulting in enhanced excitability and decreased inhibition. In this framework, understanding the complex interaction of different neuronal circuits in generating the symptoms of RLS is mandatory both for a better diagnostic refinement and for an innovative therapeutic support. Notably, multiple neurotransmission dysfunction, either primary or triggered by BID, may also bridge the gap between RLS and other chronic pain disorders. This chapter summarizes the current experimental and clinical findings into a heuristic model of the electrophysiology and neurochemistry underlying RLS.
       
  • Adenosine mechanisms and hypersensitive corticostriatal terminals in
           restless legs syndrome. Rationale for the use of inhibitors of adenosine
           transport
    • Abstract: Publication date: Available online 18 January 2019Source: Advances in PharmacologyAuthor(s): Sergi Ferré, César Quiroz, William Rea, Xavier Guitart, Diego García-Borreguero Our working hypothesis is that a hypoadenosinergic state is a main pathogenetic factor that determines the sensory-motor symptoms and hyperarousal of restless legs syndrome (RLS). We have recently demonstrated that brain iron deficiency (BID) in rodents, a well-accepted animal model of RLS, is associated with a generalized downregulation of adenosine A1 receptors (A1R) in the brain and with hypersensitivity of corticostriatal glutamatergic terminals. Here, we first review the experimental evidence for a pivotal role of adenosine and A1R in the control of striatal glutamatergic transmission and the rationale for targeting putative downregulated striatal A1R in RLS patients, which is supported by recent clinical results obtained with dipyridamole, an inhibitor of the nucleoside transporters ENT1 and ENT2. Second, we perform optogenetic-microdialysis experiments in rats to demonstrate that A1R determine the sensitivity of corticostriatal glutamatergic terminals and the ability of dipyridamole to counteract optogenetically-induced corticostriatal glutamate release in both animals with BID and controls. Thus, a frequency of optogenetic stimulation that was ineffective at inducing cortico-striatal glutamate release in control rats became effective with the local perfusion of a selective A1R antagonist. Furthermore, in animals with and without BID, the striatal application of dipyridamole blocked the optogenetic-induced glutamate release and decreased basal levels of glutamate, which was counteracted by the A1R antagonist. The results support the clinical application of ENT1 inhibitors in RLS.
       
 
 
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