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Publisher: Elsevier   (Total: 3161 journals)

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Showing 1 - 200 of 3161 Journals sorted alphabetically
A Practical Logic of Cognitive Systems     Full-text available via subscription   (Followers: 9)
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 35, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 24, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 97, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 27, 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: 418, 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: 2)
Acta de Investigación Psicológica     Open Access   (Followers: 3)
Acta Ecologica Sinica     Open Access   (Followers: 10, SJR: 0.18, CiteScore: 1)
Acta Haematologica Polonica     Free   (Followers: 1, SJR: 0.128, CiteScore: 0)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 266, SJR: 3.263, CiteScore: 6)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, 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: 3, 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: 6, 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: 14, 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: 8, 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: 163, 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: 8, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 15, 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: 10, 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: 14, 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: 33, 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: 4)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 13)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 27, 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: 19, 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: 12)
Advances in Digestive Medicine     Open Access   (Followers: 9)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 7)
Advances in Drug Research     Full-text available via subscription   (Followers: 25)
Advances in Ecological Research     Full-text available via subscription   (Followers: 44, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 28, 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: 46, 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: 60, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Genetics     Full-text available via subscription   (Followers: 18, 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: 2, 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: 8, 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: 18, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 11, 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: 3)
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: 24, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 12)
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: 65)
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: 406, 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: 34, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 18)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 14)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 47, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 351, 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: 465, 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: 42, 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: 1, SJR: 0.604, CiteScore: 3)
Alexandria J. of Medicine     Open Access   (Followers: 1, SJR: 0.191, CiteScore: 1)
Algal Research     Partially Free   (Followers: 10, 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: 53, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 58, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 44, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 10)
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: 221, 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: 28, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 29, SJR: 2.164, CiteScore: 4)
American J. of Surgery     Hybrid Journal   (Followers: 38, 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: 18, 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: 42, SJR: 1.512, CiteScore: 5)
Analytical Biochemistry     Hybrid Journal   (Followers: 186, 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: 12)
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: 204, SJR: 1.58, CiteScore: 3)

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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  [3161 journals]
  • 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
    • 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
    • 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.
  • Treatment of pediatric restless leg syndrome
    • Abstract: Publication date: Available online 18 December 2018Source: Advances in PharmacologyAuthor(s): Lourdes DelRosso, Oliviero Bruni Restless legs syndrome (RLS) is not uncommon in children with an estimated prevalence of 2%. There is clear evidence that RLS affects quality of life, sleep, cognition and behavior in children and adults. Although the diagnosis of RLS can be challenging in young children, the International Restless Legs Study Group (IRLSSG) has published guidelines for diagnosis which include description of symptoms in the child's own words. Once the diagnosis is made, treatment options must be explored. It is commonly accepted that non-pharmacological interventions be recommended to all affected families. These include maintaining a consistent bedtime routine, establishing healthy eating habits and exercise, avoiding caffeine and other substances that can exacerbate RLS, and stretching before bedtime. Pharmacological interventions in children are challenged by the lack of solid data supporting effectiveness and long-term safety. Historically and based on pathophysiology, iron supplementation is the first line therapy in children. Recently intravenous iron supplementation has shown promising results, following studies in adults. Most studies in children on various pharmacological options follow a robust body of data previously published in adult patient with RLS, yet data in children remain scarce. This chapter will discuss both non-pharmacologic and pharmacologic treatment options for children with RLS.
  • Primary Hepatocytes and Their Cultures for the Testing of Drug-Induced
           Liver Injury
    • Abstract: Publication date: Available online 1 September 2018Source: Advances in PharmacologyAuthor(s): Vânia Vilas-Boas, Axelle Cooreman, Eva Gijbels, Raf Van Campenhout, Emma Gustafson, Steven Ballet, Pieter Annaert, Bruno Cogliati, Mathieu Vinken Drug-induced liver injury is a major reason for discontinuation of drug development and withdrawal of drugs from the market. Intensive efforts in the last decades have focused on the establishment and finetuning of liver-based in vitro models for reliable prediction of hepatotoxicity triggered by drug candidates. Of those, primary hepatocytes and their cultures still are considered the gold standard, as they provide an acceptable reflection of the hepatic in vivo situation. Nevertheless, these in vitro systems cope with gradual deterioration of the differentiated morphological and functional phenotype. The present paper gives an overview of traditional and more recently introduced strategies to counteract this dedifferentiation process in an attempt to set up culture models that can be used for long-term testing purposes. The relevance and applicability of such optimized cultures of primary hepatocytes for the testing of drug-induced cholestatic liver injury is demonstrated.
  • Chapter Fourteen - Pharmacogenetics of Antidiabetic Drugs
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 83Author(s): Shylaja Srinivasan, Sook Wah Yee, Kathleen M. Giacomini Pharmacogenetic studies of antidiabetic drugs have so far focused largely on response to metformin, which is the first-line therapy for treatment of type 2 diabetes (T2D). The first studies of metformin pharmacogenetics were focused on candidate genes that were implicated in metformin pharmacokinetics and transport. Since 2011, genome-wide association studies have been conducted in large cohorts of individuals with T2D identifying genes that are associated with glycemic response to metformin. There have been fewer pharmacogenetic studies of other antidiabetic drugs, and those have been largely limited to candidate gene studies with small sample sizes. Understanding the pharmacogenetics of antidiabetes medications is important for the integration of genetic screening into therapeutic decision making, and to achieve the goal of “precision medicine” for patients with T2D. In this chapter, we provide a review of the pharmacogenetics investigations of metformin and other antidiabetes medications. In addition, we highlight the importance of collaborative efforts with large sample size and representation from multiple ethnic groups in pharmacogenetics studies.
  • Chapter Thirteen - Pharmacogenetics in Cardiovascular Medicine
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 83Author(s): Peter E. Weeke Considerable interindividual variability in response to cardiovascular pharmacotherapy exists with drug responses varying from being efficacious to inadequate to induce severe adverse events. Fueled by advancements and multidisciplinary collaboration across disciplines such as genetics, bioinformatics, and basic research, the vision of personalized medicine, rather than a one-size-fits-all approach, may be within reach. Pharmacogenetics offers the potential to optimize the benefit–risk profile of drugs by tailoring diagnostic and treatment strategies according to the individual patient. To date, a multitude of studies has tried to delineate the effects of gene–drug interactions for drugs commonly used to treat cardiovascular-related disease. The focus of this review is on how genetic variability may modify drug responsiveness and patient outcomes following therapy with commonly used cardiovascular drugs including clopidogrel, warfarin, statins, and β-blockers. Also included are examples of how genetic studies can be used to guide drug discovery and examples of how genetic information may be deployed in clinical decision making.
  • Chapter Twelve - Pharmacogenetics in Psychiatry
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 83Author(s): Filippo Corponi, Chiara Fabbri, Alessandro Serretti Mental illness represents a major health issue both at the individual and at the socioeconomical level. This is partly due to the current suboptimal treatment options: existing psychotropic medications, including antidepressants, antipsychotics, and mood stabilizers, are effective only in a subset of patients or produce partial response and they are often associated with debilitating side effects that discourage adherence. Pharmacogenetics is the study of how genetic information impacts on drug response/side effects with the goal to provide tailored treatments, thereby maximizing efficacy and tolerability. The first pharmacogenetic studies focused on candidate genes, previously known to be relevant to the pharmacokinetics and pharmacodynamics of psychotropic drugs. Results were mainly inconclusive, but some replicated candidates were identified and included as pharmacogenetic biomarkers in drug labeling and in some commercial kits. With the advent of the genomic revolution, it became possible to study the genetic variation on an unprecedented scale, throughout the whole genome with no need of a priori hypothesis. This may lead to the personalized prescription of existing medications and potentially to the development of innovative ones, thanks to new insights into the genetics of mental illness. Promising findings were obtained, but methods for the generation and analysis of genome-wide and sequencing data are still in evolution. Future pharmacogenetic tests may consist of hundreds/thousands of polymorphisms throughout the genome or selected pathways in order to take into account the complex interactions across variants in a number of genes.
  • Chapter Eleven - The Pharmacogenetics of Immune-Modulating Therapy
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 83Author(s): Ingolf Cascorbi Immunosuppressive drugs are a prerequisite in organ transplantation to prevent rejection and are also widely used in inflammatory diseases such as inflammatory bowel disease (IBD) or also in some hematologic malignancies—depending on the mode of action. For thiopurine analogs the polymorphic thiopurine S-methyltransferase (TPMT) was early detected to be associated with thiopurine-induced leukopenia; recent studies identified also NUDT15 to be related to this severe side effect. For drugs like methotrexate and mycophenolate mofetil a number of ADME genes like UDP-glucuronosyltransferases (UGTs) and ABC efflux transporters were investigated, however, with partly contradicting results. For calcineurin inhibitors like cyclosporine and in particular tacrolimus however, cytochrome P450 3A4 and 3A5 variants were found to significantly affect the pharmacokinetics. Genetic variants in genes encoding relevant pharmacodynamic proteins, however, lacked compelling evidence to affect the clinical outcome.This chapter reviews the current evidence on the association of pharmacogenetic traits to dose finding and clinical outcome of small-molecule immunosuppressants. Moreover this chapter critically summarizes suitability to apply pharmacogenetics in clinical practice in order to optimize immunosuppressant therapy.
  • Chapter Ten - Pharmacogenetics in Pain Treatment
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 83Author(s): Ana M. Peiró Pain is an unpleasant feeling usually resulting from tissue damage that can persist along weeks, months, or even years after the injury, turning into pathological chronic pain, the leading cause of disability. Currently, pharmacology interventions are usually the first-line therapy but there is a highly variable analgesic drug response. Pharmacogenetics (PGx) offers a means to identify genetic biomarkers that can predict individual analgesic response opening doors to precision medicine. PGx analyze the way in which the presence of variations in the DNA sequence (single-nucleotide polymorphisms, SNPs) could be responsible for portions of the population reaching different levels of pain relief (phenotype) due to gene interference in the drug mechanism of action (pharmacodynamics) and/or its concentration at the place of action (pharmacokinetics). SNPs in the cytochrome P450 enzymes genes (CYP2D6) influence metabolism of codeine, tramadol, hydrocodone, oxycodone, and tricyclic antidepressants. Blood concentrations of some NSAIDs depend on CYP2C9 and/or CYP2C8 activity. Additional candidate genes encode for opioid receptors, transporters, and other molecules important for pharmacotherapy in pain management. However, PGx studies are often contradictory, slowing the uptake of this information. This is likely due, in large part, to a lack of robust evidence demonstrating clinical utility and to its polygenic response modulated by other exogenous or epigenetics factors. Novel therapies, including targeting of epigenetic changes and gene therapy-based approaches, broaden future options to improve understanding of pain and the treatment of people who suffer it.
  • Chapter Nine - Implementation of Pharmacogenomics in Everyday Clinical
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 83Author(s): Paul C.D. Bank, Jesse J. Swen, Henk-Jan Guchelaar Currently, germline pharmacogenomics (PGx) is successfully implemented within certain specialties in clinical care. With the integration of PGx in pharmacotherapy multiple stakeholders are involved, which are identified in this chapter. Clinically relevant pharmacogenes with their related PGx test are discussed, along with diagnostic test criteria to guide clinicians and policy makers in PGx test selection. The chapter further reviews the similarities and the differences between the guidelines of the Dutch Pharmacogenetics Working Group and the Clinical Pharmacogenetics Implementation Consortium which both support healthcare professionals in understanding PGx test results and help guiding pharmacotherapy by providing evidence-based dosing recommendations. Finally, clinical studies which provide scientific evidence and information on cost-effectiveness supporting clinical implementation of PGx in clinical care are discussed along with the remaining barriers for adoption of PGx testing by healthcare professionals.
  • Chapter Eight - Pharmacogenetics: Applications to Pediatric Patients
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 83Author(s): Tiphaine Adam de Beaumais, Evelyne Jacqz-Aigrain Individual genomic differences may affect drug disposition and effects of many drugs, and identification of biomarkers are crucial to personalize dosage and optimize response. In children, developmental changes associated with growth and maturation translate into different relationships between genotype and phenotype and different responses to treatment compared to adults. This review aims to summarize some developmental aspects of pharmacogenetics, based on practical examples.
  • Chapter Seven - Pharmacogenetics of Adverse Drug Reactions
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 83Author(s): Orod Osanlou, Munir Pirmohamed, Ann K. Daly Adverse drug reactions (ADRs) are an important cause of morbidity and mortality. Genetic factors predispose to many ADRs, affecting susceptibility to both type A and type B reactions. The overall contribution of genetics will vary according to drug and ADR, and should be considered when attempting to predict and prevent ADRs. Genetic risk factors are considered in detail for a number of type A ADRs, especially those relating to warfarin and thiopurines, and type B ADRs affecting skin, the liver, and the heart. As the availability of whole genome sequencing increases, it is likely that prospective genotype for particular ADRs prior to drug prescription will become more common in the future. Current examples of genetic testing to prevent ADRs which have already been implemented and future prospects for developments in the field are discussed in detail.
  • Chapter Six - Population Diversity in Pharmacogenetics: A Latin American
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 83Author(s): Guilherme Suarez-Kurtz, Esteban J. Parra Pharmacogenetics/pharmacogenomics (PGx) relies on human genetic diversity. In this review we initially examine the PGx implications of human demographic history and genetic diversity, and highlight results from recent studies on the worldwide distribution of common and rare variants in pharmacogenes. The abundance of rare variants implies that a substantial effort will be required to identify their putative functional effects and to develop reliable algorithms for PGx-guided prescription. Furthermore, variants in all pharmacogenes relevant to a drug treatment must be considered. This implies a shift of the current paradigm of PGx-informed prescription based on genotyping a few common variants in selected genes toward comprehensive sequencing approaches. The following sections deal with the impact of population admixture on PGx diversity focusing on Latin America, where a kaleidoscopic combination of individual proportions of Native American, European, and sub-Saharan African ancestries prevails. We illustrate this diversity by contrasting Brazil and Mexico, the two most populous countries in Latin America, and show that population average admixture proportions are not predictive of the corresponding proportions at the individual level. As a consequence of admixture, the genetic differentiation of common pharmacogenetic variants in Latin Americans is much attenuated in comparison to their most relevant ancestral populations. Finally, we review data for tacrolimus and warfarin to illustrate the opportunities and challenges presented by Latin American populations for PGx studies and clinical implementation.
  • Chapter Five - Pharmacoepidemiology in Pharmacogenetics
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 83Author(s): Thomas P. Ahern Epidemiologic methods provide rigorous means by which to study the interplay between genetic factors and drug response. In this chapter, we describe the differences between experimental and observational study designs, and illustrate how to implement the highly efficient case–control study design. We discuss analytic approaches to evaluating gene–drug interactions within typical study designs and review sources of bias that must be assessed and accounted for in epidemiologic analyses.
  • Chapter Four - Imaging in Pharmacogenetics
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 83Author(s): Mikkel H. Vendelbo, Lars C. Gormsen, Niels Jessen An increasing collection of imaging technologies makes it possible to differentiate treatment responders from nonresponders based on genetic variation. This chapter will review some of the imaging technologies currently available in nuclear medicine to visualize drug absorption, distribution, metabolism, and elimination. Some of the commonly used techniques to detect radiation-emitting compounds are the two-dimensional scintigraphy and the three-dimensional single-photon emission computed tomography (SPECT) which both detect photons using a gamma camera, and the three-dimensional positron emission tomography (PET), which detect the decay of positron-emitting radionuclides. Current examples include visualization of functional effects of genetic variants, and these provide proof of concept for imaging in pharmacogenetics as a tool to improve efficacy and safety of drugs.
  • Chapter Three - Tamoxifen and CYP2D6: A Controversy in Pharmacogenetics
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 83Author(s): Deirdre P. Cronin-Fenton, Per Damkier Tamoxifen reduces the rate of breast cancer recurrence by about one-half. It is converted to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6) and transported by ATP-binding cassette transporters. Genetic polymorphisms that confer reduced CYP2D6 activity or concurrent use of CYP2D6-inhibiting drugs may reduce the clinical efficacy of tamoxifen. The issue of the clinical utility of CYP2D6 genotype testing is subject to considerable and ongoing academic and clinical controversy. In this chapter, we outline tamoxifen's clinical pharmacology and give an overview of the research to date on the association between CYP2D6 inhibition and tamoxifen effectiveness. Based on the evidence to date, the impact of drug-induced and/or gene-induced inhibition of CYP2D6 activity is likely to be null or small, or at most moderate in subjects carrying two reduced function alleles. Future research should examine the effect of polymorphisms in genes encoding enzymes in tamoxifen's complete metabolic pathway, should comprehensively evaluate other biomarkers that affect tamoxifen effectiveness, such as the transport enzymes, and focus on subgroups of patients, such as premenopausal breast cancer patients, for whom tamoxifen is the only guideline approved endocrine therapy.
  • Chapter Two - Epigenetics and MicroRNAs in Pharmacogenetics
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 83Author(s): Ulrich M. Zanger, Kathrin Klein, Nicole Kugler, Tamara Petrikat, Chang S. Ryu Germline pharmacogenetics has so far mainly studied common variants in “pharmacogenes,” i.e., genes encoding drug metabolizing enzymes and transporters (DMET genes), certain auxiliary and regulatory genes, and drug target genes. Despite remarkable progress in understanding genetically determined differences in pharmacokinetics and pharmacodynamics of drugs, currently known common variants even in important pharmacogenes explain genetic variability only partially. This suggests “missing heritability” that may in part be due to rare variants in the classical pharmacogenes, but current evidence suggests that largely unexplored resources with potential for pharmacogenetics exist, both within already known pharmacogenes and in entirely new areas. In particular, recent studies suggest that epigenetic processes and noncoding RNAs, including mostly microRNAs (miRNAs), represent important and largely unexplored layers of DMET gene regulation that may fill some of the gaps in understanding interindividual variability and lead to new biomarkers. In this chapter we summarize recent advances in the understanding of genetic variability in epigenetic and miRNA-mediated processes with focus on their significance for DMET regulation and pharmacokinetic or pharmacological endpoints.
  • Chapter One - Cytochrome P450 in Pharmacogenetics: An Update
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 83Author(s): Aleksi Tornio, Janne T. Backman Interindividual variability in drug disposition is a major cause of lack of efficacy and adverse effects of drug therapies. The majority of hepatically cleared drugs are metabolized by cytochrome P450 (CYP) enzymes, mainly in families CYP1, CYP2, and CYP3. Genes encoding these enzymes are highly variable with allele distribution showing considerable differences between populations. Genetic variability of especially CYP2C9, CYP2C19, CYP2D6, and CYP3A5 is known to have clear clinical impact on drugs that are metabolized by these enzymes. CYP1A2, CYP2A6, CYP2B6, CYP2C8, and CYP3A4 all show variability that affects pharmacokinetics of drugs as well, but so far the evidence regarding their clinical implications is not as conclusive. In this review, we provide an up-to-date summary of the pharmacogenetics of the major human drug-metabolizing CYP enzymes, focusing on clinically significant examples.
  • d-Serine+Signaling&rft.title=Advances+in+Pharmacology&rft.issn=1054-3589&">Chapter Fourteen - The Neurobiology of        class="small-caps">d-Serine Signaling
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 82Author(s): Herman Wolosker d-Serine is a physiological coagonist of NMDA receptors involved in synaptic plasticity, neurodevelopment, and neurodegeneration. d-Serine is synthesized by the enzyme serine racemase, which converts l- to d-serine. Recent studies indicate that the supply of l-serine by astroglia fuels the neuronal synthesis of d-serine. This pathway, named the serine shuttle, highlights the importance of the glia–neuron metabolic crosstalk for regulating NMDA receptor activity. Dysfunction of different components of the serine shuttle pathway leads to neurodevelopmental defects, neurodegeneration, and may be involved in psychiatric diseases. Serine racemase and other components of the serine shuttle are therefore promising targets for neuroprotective drugs. Here we review several aspects of the neurobiology of d-serine focusing on mechanisms regulating d-serine signaling in health and disease.
  • Chapter Thirteen - Synaptotoxic Signaling by Amyloid Beta Oligomers in
           Alzheimer's Disease Through Prion Protein and mGluR5
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 82Author(s): A. Harrison Brody, Stephen M. Strittmatter Alzheimer's disease (AD) represents an impending global health crisis, yet the complexity of AD pathophysiology has so far precluded the development of any interventions to successfully slow or halt AD progression. It is clear that accumulation of Amyloid-beta (Aβ) peptide triggers progressive synapse loss to cause AD symptoms. Once initiated by Aβ, disease progression is complicated and accelerated by inflammation and by tau pathology. The recognition that Aβ peptide assumes multiple distinct states and that soluble oligomeric species (Aβo) are critical for synaptic damage is central to molecular understanding of AD. This knowledge has led to the identification of specific Aβo receptors, such as cellular prion protein (PrPC), mediating synaptic toxicity and neuronal dysfunction. The identification of PrPC as an Aβo receptor has illuminated an Aβo-induced signaling cascade involving mGluR5, Fyn, and Pyk2 that links Aβ and tau pathologies. This pathway provides novel potential therapeutic targets for disease-modifying AD therapy. Here, we discuss the methods by which several putative Aβo receptors were identified. We also offer an in-depth examination of the known molecular mechanisms believed to mediate Aβo-induced synaptic dysfunction, toxicity, and memory dysfunction.
  • Chapter Twelve - Mu Opioid Pharmacology: 40 Years to the Promised Land
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 82Author(s): Gavril W. Pasternak Opioids continue to play a major role in medicine, but not without problems. Side effects limit their utility medically, while the potential of addiction has had a major societal impact. Pharmacologists have been trying to develop opioids lacking side effects since the first derivative, heroin, was synthesized in the 1870s. The identification of opioid receptors about 40 years ago opened up new insights into our understanding of opioid action, fueled by the molecular biology revolution of the 1980s and 1990s. A major result of these studies was the discovery that the mu opioid receptor gene, Oprm1, undergoes extensive alternative splicing in mice, rats, and humans. This single gene generates three sets of proteins, each containing many variants. The object of this review is to describe these variants and how they can be targeted to generate safer, effective analgesic drugs. Mu opioid receptor multiplicity was first suggested over 35 years ago based upon a series of selective antagonists and detailed binding assays. The identification of the different classes of mu opioid receptor splice variants enabled us to target one of the classes of splice variants to obtain potent analgesics lacking respiratory depression, physical dependence, and reward behavior. They also displayed no cross tolerance to morphine analgesia and had diminished effects on gastrointestinal transit. Forty years after the identification of opioid-binding sites in brain the promised land of safer, nonaddictive analgesics is in sight.
  • Chapter Eleven - Anti-NMDA Receptor Encephalitis: Clinical Features and
           Basic Mechanisms
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 82Author(s): David R. Lynch, Amy Rattelle, Yi Na Dong, Kylie Roslin, Amy J. Gleichman, Jessica A. Panzer In slightly more than 10 years, anti-NMDA receptor (NMDAR) encephalitis has changed from a rare paraneoplastic syndrome to the most common cause of nonviral encephalitis. It presents fulminantly with progressive psychosis, seizures, and autonomic dysfunction, leading to death if untreated. However, rapid recognition and treatment can lead to survival and a return to baseline levels of functioning in many patients. While initially associated with ovarian teratomas, it is now associated with other tumors and can reflect a postviral event. The antibodies to the NMDAR made in this syndrome are pathogenic and are directed at the extracellular domain of the GluN1 subunit. Such antibodies lead to internalization of NMDARs in model systems, leading to a physiological state characterized by NMDAR hypofunction. Analogous disorders, characterized by antibodies to other synaptic receptors, present with neurological and psychiatric dysfunction and also appear to reflect antibody-induced internalization of receptors. However, this simple pathophysiology may be too simplistic to reflect the complexity of events in anti-NMDAR encephalitis. Future scientific investigations may allow a more complete understanding of this disorder and improve treatment of anti-NMDAR encephalitis.
  • Chapter Ten - Phosphorylation of the Amino Terminus of the Dopamine
           Transporter: Regulatory Mechanisms and Implications for Amphetamine Action
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 82Author(s): Caline S. Karam, Jonathan A. Javitch Amphetamines (AMPHs) are potent psychostimulants that are widely used and abused, with profound medical and societal impact. Their actions at dopaminergic neurons are thought to mediate their therapeutic efficacy as well as their liability for abuse and dependence. AMPHs target the dopamine transporter (DAT), the plasmalemmal membrane protein that mediates the inactivation of released dopamine (DA) through its reuptake. AMPHs act as substrates for DAT and are known to cause mobilization of dopamine (DA) to the cell exterior via DAT-mediated reverse transport (efflux). It has become increasingly evident that the mechanisms that regulate AMPH-induced DA efflux are distinct from those that regulate DA uptake. Central to these mechanisms is the phosphorylation of the DAT amino (N)-terminus, which has been repeatedly demonstrated to facilitate DAT-mediated DA efflux, without impacting other aspects of DAT physiology. This review aims to summarize the current status of knowledge regarding DAT N-terminal phosphorylation and its regulation by protein modulators and the membrane microenvironment. A better understanding of these mechanisms may lead to the identification of novel therapeutic approaches that interfere selectively with the pharmacological effects of AMPHs without altering the physiological function of DAT.
  • Chapter Nine - RNA-Based Fluorescent Biosensors for Detecting Metabolites
           in vitro and in Living Cells
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 82Author(s): Samie R. Jaffrey Genetically encoded sensors are important tools for measuring metabolites and other small molecules in vitro and in live cells. Until recently, genetically encoded sensors exclusively comprised fluorescent proteins that undergo changes in Förster resonance energy transfer upon binding a target analyte. However, recently a new class of fluorescent sensor has been developed composed of RNA. These RNA-based sensors rely on Spinach and other RNA mimics of green fluorescent protein. In each case, the RNA-based sensors contain an analyte-binding aptamer domain which transduces binding of the analyte into a conformational change in Spinach. Two types of sensors have been developed: allosteric Spinach sensors and Spinach riboswitches. Allosteric Spinach sensors exhibit metabolite-induced folding and subsequent fluorescence. Spinach riboswitches are naturally occurring riboswitches that have been modified to contain the Spinach aptamer. The resulting RNA is a fluorogenic riboswitch, and produces fluorescence upon binding its cognate analyte. We describe the development of this new technology, its uses, and future directions to facilitate the use of this assay technology in mammalian cells and in high-throughput applications.
  • Chapter Eight - Imaging Translocator Protein as a Biomarker of
           Neuroinflammation in Dementia
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 82Author(s): William C. Kreisl, Ioline D. Henter, Robert B. Innis Neuroinflammation has long been considered a potential contributor to neurodegenerative disorders that result in dementia. Accumulation of abnormal protein aggregates in Alzheimer's disease, frontotemporal dementia, and dementia with Lewy bodies is associated with the activation of microglia and astrocytes into proinflammatory states, and chronic low-level activation of glial cells likely contributes to the pathological changes observed in these and other neurodegenerative diseases. The 18 kDa translocator protein (TSPO) is a key biomarker for measuring inflammation in the brain via positron emission tomography (PET). Increased TSPO density has been observed in brain tissue from patients with neurodegenerative diseases and colocalizes to activated microglia and reactive astrocytes. Several radioligands have been developed to measure TSPO density in vivo with PET, and these have been used in clinical studies of different dementia syndromes. However, TSPO radioligands have limitations, including low specific-to-nonspecific signal and differential affinity to a polymorphism on the TSPO gene, which must be taken into consideration in designing and interpreting human PET studies. Nonetheless, most PET studies have shown that increased TSPO binding is associated with various dementias, suggesting that TSPO has potential as a biomarker to further explore the role of neuroinflammation in dementia pathogenesis and may prove useful in monitoring disease progression.
  • Chapter Seven - Unique Effects of Clozapine: A Pharmacological Perspective
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 82Author(s): Jibran Y. Khokhar, Angela M. Henricks, Emily D.K. Sullivan, Alan I. Green Schizophrenia is a heterogenous and severe neuropsychiatric disorder that affects nearly 1% of the population worldwide. Antipsychotic drugs are the mainstay of treatment, but not all patients with schizophrenia respond to treatment with these agents. Clozapine, the first atypical antipsychotic, is a highly effective medication for patients with schizophrenia who do not respond to other antipsychotics. Although clozapine tends not to produce extrapyramidal symptoms, other side effects of the drug (e.g., agranulocytosis, myocarditis, seizures) limit its widespread use. This chapter reviews clozapine's unique clinical effects and unusual pharmacological profile. In addition to its effects in treatment-resistant schizophrenia, clozapine has been shown to decrease suicidality, which occurs at an increased rate in patients with schizophrenia. Still preliminary, but consistent data, also suggest that clozapine limits substance use in these patients, an important effect since substance use disorders are common in patients with schizophrenia and are associated with a poor outcome, including an increased risk for suicide and poor response to treatment. We have suggested, from animal studies, that clozapine's apparent ability to limit substance use may occur through its actions as a weak dopamine D2 receptor antagonist, a potent norepinephrine α-2 receptor antagonist and a norepinephrine reuptake inhibitor. Using animal models, we have built combinations of agents toward creation of safer clozapine-like drugs to reduce substance use in these patients. Future research into the mechanisms of action of clozapine toward the development of safe clozapine-like agents is of great public health importance.
  • Chapter Six - Regulation of Mitochondrial, Cellular, and Organismal
           Functions by TSPO
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 82Author(s): Moshe Gavish, Leo Veenman In 1999, the enigma of the 18 kDa mitochondrial translocator protein (TSPO), also known as the peripheral-type benzodiazepine receptor, was the seeming disparity of the many functions attributed to TSPO, ranging from the potential of TSPO acting as a housekeeping gene at molecular biological levels to adaptations to stress, and even involvement in higher emotional and cognitive functioning, such as anxiety and depression. In the years since then, knowledge regarding the many functions modulated by TSPO has expanded, and understanding has deepened. In addition, new functions could be firmly associated with TSPO, such as regulation of programmed cell death and modulation of gene expression. Interestingly, control by the mitochondrial TSPO over both of these life and death functions appears to include Ca++ homeostasis, generation of reactive oxygen species (ROS), and ATP production. Other mitochondrial functions under TSPO control are considered to be steroidogenesis and tetrapyrrole metabolism. As TSPO effects on gene expression and on programmed cell death can be related to the wide range of functions that can be associated with TSPO, several of these five elements of Ca++, ROS, ATP, steroids, and tetrapyrroles may indeed form the basis of TSPO's capability to operate as a multifunctional housekeeping gene to maintain homeostasis of the cell and of the whole multicellular organism.
  • Chapter Five - Carboxypeptidase E and the Identification of Novel
           Neuropeptides as Potential Therapeutic Targets
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 82Author(s): Lloyd D. Fricker Peptides and small molecules that bind to peptide receptors are important classes of drugs that are used for a wide variety of different applications. The search for novel neuropeptides traditionally involved a time-consuming approach to purify each peptide to homogeneity and determine its amino acid sequence. The discovery in the 1980s of enkephalin convertase/carboxypeptidase E (CPE), and the observation that this enzyme was involved in the production of nearly every known neuropeptide led to the idea for a one-step affinity purification of CPE substrates. This approach was successfully used to isolate hundreds of known neuropeptides in mouse brain, as well as over a dozen novel peptides. Some of the novel peptides found using this approach are among the most abundant peptides present in brain, but had not been previously identified by traditional approaches. Recently, receptors for two of the novel peptides have been identified, confirming their role as neuropeptides that function in cell–cell signaling. Small molecules that bind to one of these receptors have been developed and found to significantly reduce food intake and anxiety-like behavior in an animal model. This review describes the entire project, from discovery of CPE to the novel peptides and their receptors.
  • Chapter Four - Nitric Oxide Signaling in Neurodegeneration and Cell Death
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 82Author(s): Ted M. Dawson, Valina L. Dawson In this tribute to Solomon H. Snyder (Sol) we discuss the mechanisms by which nitric oxide (NO) kills neurons. We provide a historical perspective regarding the discovery that glutamate excitotoxicity is mediated by NO. It also contains a discussion of the discovery that neuronal nitric oxide synthase (nNOS) catalytic activity accounts for NADPH diaphorase activity and its localization in the central nervous system. NADPH diaphorase/nNOS neurons are unique in that they are resistant to toxic effects of excess glutamate and that they are resistant to neurodegeneration in a variety of neurodegenerative diseases. NADPH diaphorase/nNOS neurons are resistant to neurotoxicity and neurodegeneration through the overexpression of manganese superoxide dismutase. The review also delves into the mechanisms by which NO kills neurons including NO's activation of the glyceraldehyde-3-phosphate dehydrogenase-dependent cell pathway. In addition, there is a review of parthanatos in which NO combines with the superoxide anion (O2⋅−) to form peroxynitrite (ONOO−) that damages DNA and activates poly (ADP-ribose) (PAR) polymerase (PARP). This ultimately leads to activation of the PARP-dependent apoptosis-inducing factor-associated nuclease, the final executioner in NO-dependent cell death. Finally, there is a discussion of potential targets that are under development that target the mechanisms by which NO kills neurons.
  • Chapter Three - The Role of Serine Racemase in the Pathophysiology of
           Brain Disorders
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 82Author(s): Joseph T. Coyle, Darrick T. Balu The N-methyl-d-aspartate receptor (NMDAR) is unique in requiring two agonists to bind simultaneously to open its cation channel: the neurotransmitter, glutamate, and the coagonists, glycine, or d-serine. The Snyder laboratory was the first to clone serine racemase (SR), the enzyme that synthesizes d-serine, and to localize it immunocytochemically. Our laboratory has focused on the role of d-serine in brain disorders. Silencing the expression of SR, a risk gene for schizophrenia (SCZ), in mice (SR −/−), results in a phenotype that closely resembles SCZ including: cortical atrophy, reduced dendritic spine density and complexity, downregulation of parvalbumin-positive cortical GABAergic neurons, and cognitive impairments. This pathology can be reversed by treatment of SR −/− mice with d-serine in adulthood. SR −/− mice also exhibit abnormal response toward abusable substances, such as stimulants. They show reduced behavioral sensitization to d-amphetamine, but fail to extinguish it. Place preference to cocaine is altered, and the hedonic response to it is profoundly impaired as assessed by intracranial self-stimulation. d-cycloserine, a partial agonist at the NMDAR glycine modulatory site, shows therapeutic benefit for treating pathologic anxiety in combination with behavioral therapies. Studies in vitro with cortical culture and in vivo with middle cerebral artery occlusion show that silencing SR provides substantial protection against ischemic neuronal death. Finally, the switch of SR expression from neurons to reactive astrocytes after closed head trauma accounts for the reduced in vivo neuroplasticity, electroencephalogram abnormalities, and cognitive impairments.
  • Chapter Two - Receptor Binding Assays and Drug Discovery
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 82Author(s): David B. Bylund, S.J. Enna Although Solomon Snyder authored hundreds of research reports and several books covering a broad range of topics in the neurosciences, he is best known by many as the person who developed neurotransmitter receptor radioligand binding assays. By demonstrating the utility of this approach for studying transmitter receptors in brain, Dr. Snyder provided the scientific community with a powerful new tool for identifying and characterizing these sites, for defining their relationship to neurological and psychiatric disorders, and their involvement in mediating the actions of psychotherapeutics. Although it was hoped the receptor binding technique could also be used as a primary screen to speed and simplify the identification of novel drug candidates, experience has taught that ligand binding is most useful for drug discovery when it is used in conjunction with functional, phenotypic assays. The incorporation of ligand binding assays into the drug discovery process played a significant role in altering the search for new therapeutics from solely an empirical undertaking to a mechanistic and hypothesis-driven enterprise. This illustrates the impact of Dr. Snyder's work, not only on neuroscience research but on the discovery, development, and characterization of drugs for treating a variety of medical conditions.
  • Chapter One - Multiple Pathways Mediate MicroRNA Degradation: Focus on the
           Translin/Trax RNase Complex
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 82Author(s): Jay M. Baraban, Aparna Shah, Xiuping Fu The discovery of the microRNA system has revolutionized our understanding of translational control. Furthermore, growing appreciation of the pivotal role that de novo translation plays in activity-dependent synaptic plasticity has fueled interest among neuroscientists in deciphering how the microRNA system impacts neuronal signaling and the pathophysiology of neuropsychiatric disorders. Although we have a general understanding of how the microRNA system operates, many key questions remain. In particular, the biosynthesis of microRNAs and their role in translational silencing are fairly well understood. However, much less is known about how microRNAs are degraded and silencing is reversed, crucial aspects of microRNA signaling. In contrast to microRNA synthesis which is mediated almost exclusively by a single pathway that culminates in Dicer, recent studies indicate that there are multiple pathways of microRNA degradation that target different subpopulations of microRNAs. While the Lin-28 pathway of microRNA degradation has been investigated extensively, the translin/trax RNase complex has emerged recently as another pathway mediating microRNA degradation. Accordingly, we summarize herein key features of the translin/trax RNase complex as well as important gaps in our understanding of its regulation and function that are the focus of ongoing studies.
  • Foreword
    • Abstract: Publication date: 2018Source: Advances in Pharmacology, Volume 82Author(s): Les Iversen
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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