GPCR drug discovery-moving beyond the orthosteric to the allosteric domain.
Abstract 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 t...
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Felder CC Tags: Adv Pharmacol Source Type: research

Nitric oxide: Antidepressant mechanisms and inflammation.
Abstract 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 i...
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Ghasemi M Tags: Adv Pharmacol Source Type: research

Selective allosteric modulation of muscarinic acetylcholine receptors for the treatment of schizophrenia and substance use disorders.
Abstract Muscarinic acetylcholine receptor (mAChRs) subtypes represent exciting new targets for the treatment of schizophrenia and substance use disorder (SUD). Recent advances in the development of subtype-selective allosteric modulators have revealed promising effects in preclinical models targeting the different symptoms observed in schizophrenia and SUD. M1 PAMs display potential for addressing the negative and cognitive symptoms of schizophrenia, while M4 PAMs exhibit promise in treating preclinical models predictive of antipsychotic-like activity. In SUD, there is increasing support for modulation of mesocor...
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Teal LB, Gould RW, Felts AS, Jones CK Tags: Adv Pharmacol Source Type: research

Medications development for food-based and drug use disorders.
Abstract 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...
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: de Moura FB, Kohut SJ, Bergman J Tags: Adv Pharmacol Source Type: research

Lipid rafts in psychiatry.
Abstract 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. PMID: 31378253 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Wray NH, Rasenick MM Tags: Adv Pharmacol Source Type: research

Obsessive compulsive disorder (OCD): Current treatments and a framework for neurotherapeutic research.
Abstract 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...
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Woody EZ, Hoffman KL, Szechtman H Tags: Adv Pharmacol Source Type: research

Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders.
Abstract The dopamine D1 receptor plays an important role in motor activity, reward, and cognition. Efforts to develop D1 agonists have been mixed due to poor drug-like properties, tachyphylaxis, and inverted U-shaped dose-response curves. Recently, positive allosteric modulators (PAMs) for the dopamine D1 receptor were discovered and initial pharmacological profiling has suggested that several of the above issues could be addressed with this mechanism. This paper presents an overview of key findings for DETQ (2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquino...
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Svensson KA, Hao J, Bruns RF Tags: Adv Pharmacol Source Type: research

Rapid-acting antidepressants.
Abstract 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 control...
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Witkin JM, Martin AE, Golani LK, Xu NZ, Smith JL Tags: Adv Pharmacol Source Type: research

mGlu2/3 receptor antagonists.
Abstract 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. I...
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Chaki S Tags: Adv Pharmacol Source Type: research

Preface.
PMID: 31378258 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Witkin JM Tags: Adv Pharmacol Source Type: research

Primary hepatocytes and their cultures for the testing of drug-induced liver injury.
Abstract 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. Th...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Vilas-Boas V, Cooreman A, Gijbels E, Van Campenhout R, Gustafson E, Ballet S, Annaert P, Cogliati B, Vinken M Tags: Adv Pharmacol Source Type: research

Role and mechanisms of autophagy in alcohol-induced liver injury.
Abstract 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 pathophysiologica...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Chao X, Ding WX Tags: Adv Pharmacol Source Type: research

Mechanisms of idiosyncratic drug-induced liver injury.
Abstract 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 tolera...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Uetrecht J Tags: Adv Pharmacol Source Type: research

Idiosyncratic drug-induced liver injury in patients: Detection, severity assessment, and regulatory implications.
Abstract 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 ...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Watkins PB Tags: Adv Pharmacol Source Type: research

Acetaminophen hepatotoxicity: A mitochondrial perspective.
Abstract 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, whi...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Ramachandran A, Jaeschke H Tags: Adv Pharmacol Source Type: research

Biomarkers of drug-induced liver injury.
Abstract 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 c...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: McGill MR, Jaeschke H Tags: Adv Pharmacol Source Type: research

Mechanisms and biomarkers of liver regeneration after drug-induced liver injury.
Abstract 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 diff...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Clemens MM, McGill MR, Apte U Tags: Adv Pharmacol Source Type: research

Evaluation and treatment of acetaminophen toxicity.
Abstract A review of the typical clinical course, diagnosis and treatment of acetaminophen toxicity is provided. For an acute overdose, most adults must ingest about 12g 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 48-96h after acute ingestion. It is possible for patients to present in liver ...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Fisher ES, Curry SC Tags: Adv Pharmacol Source Type: research

Cell death in drug-induced liver injury.
Abstract 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 DIL...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Iorga A, Dara L Tags: Adv Pharmacol Source Type: research

Drug-induced liver injury in obesity and nonalcoholic fatty liver disease.
Abstract 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 o...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Allard J, Le Guillou D, Begriche K, Fromenty B Tags: Adv Pharmacol Source Type: research

Preface.
PMID: 31307593 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Ramachandran A, Jaeschke H Tags: Adv Pharmacol Source Type: research

The neurophysiology of hyperarousal in restless legs syndrome: Hints for a role of glutamate/GABA.
Abstract 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 dysfunc...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Lanza G, Ferri R Tags: Adv Pharmacol Source Type: research

Iron uptake at the blood-brain barrier is influenced by sex and genotype.
Abstract 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 (associat...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Wade QW, Chiou B, Connor JR Tags: Adv Pharmacol Source Type: research

Caenorhabditis elegans and its applicability to studies on restless legs syndrome.
Abstract 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 c...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Chen P, Ijomone OM, Lee KH, Aschner M Tags: Adv Pharmacol Source Type: research

Role of MEIS1 in restless legs syndrome: From GWAS to functional studies in mice.
Abstract 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 gangli...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Salminen AV, Lam DD, Winkelmann J Tags: Adv Pharmacol Source Type: research

Non-dopaminergic vs. dopaminergic treatment options in restless legs syndrome.
ero D Abstract 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 symptom...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Wanner V, Garcia Malo C, Romero S, Cano-Pumarega I, García-Borreguero D Tags: Adv Pharmacol Source Type: research

Idiopathic restless legs syndrome treatment: Progress and pitfalls?
Abstract 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 ...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Ghorayeb I Tags: Adv Pharmacol Source Type: research

D3 receptor agonist efficacy in restless legs syndrome.
Abstract 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 ...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Casoni F, Galbiati A, Ferini-Strambi L Tags: Adv Pharmacol Source Type: research

Treatment of pediatric restless legs syndrome.
Abstract 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 m...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: DelRosso L, Bruni O Tags: Adv Pharmacol Source Type: research

Pharmacological treatments of augmentation in restless legs syndrome patients.
Abstract 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 r...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Trenkwalder C, Paulus W Tags: Adv Pharmacol Source Type: research

Adenosine mechanisms and hypersensitive corticostriatal terminals in restless legs syndrome. Rationale for the use of inhibitors of adenosine transport.
orreguero D Abstract 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...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Ferré S, Quiroz C, Rea W, Guitart X, García-Borreguero D Tags: Adv Pharmacol Source Type: research

The heterotetrameric structure of the adenosine A1-dopamine D1 receptor complex: Pharmacological implication for restless legs syndrome.
, Casadó V Abstract 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 superf...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Cortés A, Casadó-Anguera V, Moreno E, Casadó V Tags: Adv Pharmacol Source Type: research

D3 and D1 receptors: The Yin and Yang in the treatment of restless legs syndrome with dopaminergics.
Abstract 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 e...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Clemens S, Ghorayeb I Tags: Adv Pharmacol Source Type: research

Preface.
PMID: 31229179 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Clemens S, Ghorayeb I Tags: Adv Pharmacol Source Type: research

Pharmacoepidemiology in Pharmacogenetics.
Abstract 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. PMID: 29801572 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Ahern TP Tags: Adv Pharmacol Source Type: research

Population Diversity in Pharmacogenetics: A Latin American Perspective.
Abstract 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 th...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Suarez-Kurtz G, Parra EJ Tags: Adv Pharmacol Source Type: research

Pharmacogenetics of Adverse Drug Reactions.
Abstract 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...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Osanlou O, Pirmohamed M, Daly AK Tags: Adv Pharmacol Source Type: research

Pharmacogenetics: Applications to Pediatric Patients.
Abstract 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. PMID: 29801575 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Adam de Beaumais T, Jacqz-Aigrain E Tags: Adv Pharmacol Source Type: research

Implementation of Pharmacogenomics in Everyday Clinical Settings.
Abstract 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 bot...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Bank PCD, Swen JJ, Guchelaar HJ Tags: Adv Pharmacol Source Type: research

Pharmacogenetics in Pain Treatment.
e; AM Abstract 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...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Peiró AM Tags: Adv Pharmacol Source Type: research

The Pharmacogenetics of Immune-Modulating Therapy.
Abstract 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 eff...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Cascorbi I Tags: Adv Pharmacol Source Type: research

Pharmacogenetics in Psychiatry.
Abstract 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...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Corponi F, Fabbri C, Serretti A Tags: Adv Pharmacol Source Type: research

Cytochrome P450 in Pharmacogenetics: An Update.
Abstract 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 a...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Tornio A, Backman JT Tags: Adv Pharmacol Source Type: research

Epigenetics and MicroRNAs in Pharmacogenetics.
Abstract 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 ev...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Zanger UM, Klein K, Kugler N, Petrikat T, Ryu CS Tags: Adv Pharmacol Source Type: research

Pharmacogenetics in Cardiovascular Medicine.
Abstract 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 multitu...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Weeke PE Tags: Adv Pharmacol Source Type: research

Pharmacogenetics of Antidiabetic Drugs.
Abstract 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 ...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Srinivasan S, Yee SW, Giacomini KM Tags: Adv Pharmacol Source Type: research

Tamoxifen and CYP2D6: A Controversy in Pharmacogenetics.
Abstract 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 ov...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Cronin-Fenton DP, Damkier P Tags: Adv Pharmacol Source Type: research

Imaging in Pharmacogenetics.
Abstract 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 tomogra...
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Vendelbo MH, Gormsen LC, Jessen N Tags: Adv Pharmacol Source Type: research

Preface.
ier P PMID: 29801586 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Brøsen K, Damkier P Tags: Adv Pharmacol Source Type: research

Multiple Pathways Mediate MicroRNA Degradation: Focus on the Translin/Trax RNase Complex.
Abstract 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. Ho...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Baraban JM, Shah A, Fu X Tags: Adv Pharmacol Source Type: research