Fundamental and clinical neuropharmacology, a terra incognita with constantly expanding frontiers.

Neuropharmacology is the science that studies the effects of drugs on the central nervous system. Examining the recent history of neuropharmacology allows us to identify future challenges and to project into the future. The contemporary history of neuropharmacology begins with the empirical use of psychotropic alkaloids in barbiturate preparations. Then the discovery of neuroleptics in the 1950s truly opened up the field of pharmacological science, with psychopharmacological clinical exploration in psychiatry, complemented by the contributions of neurochemists and biochemists discovering and exploring neurotransmission. These studies also contributed to the development of dopaminergic and serotonergic drugs used in neurology. The more recent period brought the advent of neuropsychopharmacology, sharing therapeutic targets in neurology and psychiatry on the one hand, and a translational research approach on the other. Moreover, the pharmacology of brain drugs is still a growing discipline in 2020. Despite emerging pharmacological concepts (biased agonists, glial targeting, epigenetic therapeutics, etc.), entire areas of brain-based therapeutics need to be renewed, particularly in psychiatry, offering great challenges to a new generation of pharmacologists and clinicians.

Cannabinoids: Emerging developments in neuropsychopharmacology and biological psychiatry.

Cannabinoids from the cannabis plant were one of the earliest psychoactive phytochemicals harnessed by humanity for their medicinal properties and remain one of the most frequently used and misused classes of chemicals in the world. Despite our long-standing history with cannabinoids, much more is said than is known regarding how these molecules influence the brain and behavior. We are in a rapidly evolving discovery phase regarding the neuroscience of cannabinoids. This period of insight began in the mid-1990s when it was discovered that phytocannabinoids (e.g., delta-9-tetrahydrocannabinol) act on G protein-coupled receptors (i.e., CB1/CB2) in the brain to produce their psychoactive effects. Shortly thereafter, it was discovered that endogenous ligands (i.e., endocannabinoids) exist for these receptor targets and, that they are synthetized on demand under a variety of physiological conditions. Thus, we can now study how phytochemicals, endogenous ligands, and synthetic/metabolic enzymes of the endocannabinoid system influence the brain and behavior by activating known receptor targets. Our increased ability to study cannabinoid interactions with the brain and behavior coincides with an increase in international interest in utilizing cannabinoids as a medicine. At the same time, the potency of, and administration routes by which cannabinoids are used is rapidly changing. And, these trends in cannabinoid misuse are producing lasting neural adaptations that have implications for mental health. In this special edition, we will summarize our recent period of discovery regarding how: 1) phytocannabinoids, synthetic cannabinoids and endocannabinoids act on the brain to produce behavioral effects; 2) cannabinoids can be harnessed to produce pharmacotherapeutic utility in the field of medicine; and 3) use of increasingly more cannabinoid variants through unique routes of administration alter the brain and behavior, especially when used in critical developmental periods like pregnancy and adolescence.

Mitos y evidencias en el empleo de la toxina botulínica: neurofarmacología y distonías / Myths and evidence on the use of botulinum toxin: neuropharmacology and dystonia

Introducción. La toxina botulínica de tipo A (TBA) ha supuesto una verdadera revolución terapéutica en neurología, y en la actualidad es el tratamiento rutinario en las distonías focales y la espasticidad. Objetivo. Plantear, revisar y responder cuestiones controvertidas en relación con la neurofarmacología de a TBA y su uso en las distonías en la práctica clínica habitual. Desarrollo. Un grupo de expertos en trastornos del movimiento revisó una lista de temas controvertidos relacionados con la farmacología de la TBA y su uso en las distonías. Revisamos la bibliografía e incluimos artículos relevantes especialmente en inglés, pero también, si su importancia lo merece, en castellano y en francés, hasta junio de 2016. El documento se estructuró como un cuestionario que incluyó las preguntas que podrían generar mayor controversia o duda. El borrador inicial del documento fue revisado por los miembros del panel y se realizaron las modificaciones necesarias hasta alcanzar el mayor grado de consenso. Incluimos preguntas sobre diferentes aspectos de la neurofarmacología, especialmente el mecanismo de acción, la bioequivalencia de los diferentes preparados y la inmunogenicidad. En relación con el subapartado de las distonías, se incluyeron aspectos sobre la evaluación y el tratamiento de las distonías focales. Conclusiones. Esta revisión no pretende ser una guía, sino una herramienta práctica destinada a neurólogos y médicos internos residentes interesados en esta área, dentro de diferentes ámbitos específicos del manejo de la TBA (AU)

Introduction. Botulinum toxin type A (BTA) is a bacterial endotoxin, whose therapeutic use has had a dramatic impact on different neurological disorders, such as dystonia and spasticity. Aim. To analyze and summarize different questions about the use of BTA in our clinical practice. Development. A group of experts in neurology developed a list of topics related with the use of BTA. Two groups were considered: neuropharmacology and dystonia. A literature search at PubMed, mainly for English language articles published up to June 2016 was performed. The manuscript was structured as a questionnaire that includes those questions that, according to the panel opinion, could generate more controversy or doubt. The initial draft was reviewed by the expert panel members to allow modifications, and after subsequent revisions for achieving the highest degree of consensus, the final text was then validated. Different questions about diverse aspects of neuropharmacology, such as mechanism of action, bioequivalence of the different preparations, immunogenicity, etc. were included. Regarding dystonia, the document included questions about methods of evaluation, cervical dystonia, blepharospasm, etc. Conclusion. This review does not pretend to be a guide, but rather a tool for continuous training of residents and specialists in neurology, about different specific areas of the management of BTA (AU)

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

Three-dimensional patterning in biomedicine: Importance and applications in neuropharmacology.

Nature manufactures biological systems in three dimensions with precisely controlled spatiotemporal profiles on hierarchical length and time scales. In this article, we review 3D patterning of biological systems on synthetic platforms for neuropharmacological applications. We briefly describe 3D versus 2D chemical and topographical patterning methods and their limitations. Subsequently, an overview of introducing a third dimension in neuropharmacological research with delineation of chemical and topographical roles is presented. Finally, toward the end of this article, an explanation of how 3D patterning has played a pivotal role in relevant fields of neuropharmacology to understand neurophysiology during development, normal health, and disease conditions is described. The future prospects of organs-on-a--like devices to mimic patterned blood-brain barrier in the context of neurotherapeutic discovery and development for the prioritization of lead candidates, membrane potential, and toxicity testing are also described. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1369-1382, 2018.

Recent advances in the neurobiology and neuropharmacology of Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive deterioration of cognitive functions. The pathological hallmarks are extracellular deposits of amyloid plaques and intracellular neurofibrillary tangles of tau protein. The cognitive deficits seen are thought to be due to synaptic dysfunction and neurochemical deficiencies. Various neurochemical abnormalities have been observed during progressive ageing, and are linked to cognitive abnormalities as seen with the sporadic form of AD. Acetylcholinesterase inhibitors are one of the major therapeutic strategies used for the treatment of AD. During the last decade, various new therapeutic strategies have shown beneficial effects in preclinical studies and under clinical development for the treatment of AD. The present review is aimed at discussing the neurobiology of AD and association of neurochemical abnormalities associated with cognitive deterioration and new therapeutic strategies for the treatment of AD.

Neuroimmune Pharmacology, 2nd Edition - A Perspective.

It has been almost nine years since the 1st edition of Neuroimmune Pharmacology was published on May 23rd, 2008. The 2nd edition of Neuroimmune Pharmacology by Ikezu and Gendelman (Editors) with Przedborski, Masliah and Cosentino (Associate Editors) manages to fulfill two separate missions: to provide comprehensive, but highly topical access to a rapidly evolving field and to serve as a standalone reference for scientists and clinicians in need of guidance regarding questions pertinent to neuroimmune pharmacology. Doing a PubMed search on the terms neuroimmune and pharmacology yields 1090 publications, with a first publication by Dougherty and Dafny, published in the Journal of Neuroscience Research in 1988, entitled "Neuroimmune intercommunication, central opioids, and the immune response to bacterial endotoxin." Since 2000, there have been 979 publications using these search terms, with 137 published since the beginning of 2016. The obvious conclusion to be drawn is that this is a burgeoning field that represents the cusp between our understanding of relationships between the immune and nervous systems and how we might treat disease with pharmacologic approaches when normal homeostatic mechanisms go awry.

Neuropharmacology beyond reductionism - A likely prospect.

Neuropharmacology had several major past successes, but the last few decades did not witness any leap forward in the drug treatment of brain disorders. Moreover, current drugs used in neurology and psychiatry alleviate the symptoms, while hardly curing any cause of disease, basically because the etiology of most neuro-psychic syndromes is but poorly known. This review argues that this largely derives from the unbalanced prevalence in neuroscience of the analytic reductionist approach, focused on the cellular and molecular level, while the understanding of integrated brain activities remains flimsier. The decline of drug discovery output in the last decades, quite obvious in neuropharmacology, coincided with the advent of the single target-focused search of potent ligands selective for a well-defined protein, deemed critical in a given pathology. However, all the widespread neuro-psychic troubles are multi-mechanistic and polygenic, their complex etiology making unsuited the single-target drug discovery. An evolving approach, based on systems biology considers that a disease expresses a disturbance of the network of interactions underlying organismic functions, rather than alteration of single molecular components. Accordingly, systems pharmacology seeks to restore a disturbed network via multi-targeted drugs. This review notices that neuropharmacology in fact relies on drugs which are multi-target, this feature having occurred just because those drugs were selected by phenotypic screening in vivo, or emerged from serendipitous clinical observations. The novel systems pharmacology aims, however, to devise ab initio multi-target drugs that will appropriately act on multiple molecular entities. Though this is a task much more complex than the single-target strategy, major informatics resources and computational tools for the systemic approach of drug discovery are already set forth and their rapid progress forecasts promising outcomes for neuropharmacology.

Efectos de los inductores antiepilépticos en la neuropsicofarmacología: una cuestión ignorada. Parte II: cuestiones farmacológicas y comprensión adicional / The effects of antiepileptic inducers in neuropsychopharmacology, a neglected issue. Part II: pharmacological issues and further understanding

La literatura sobre los inductores en la epilepsia y el trastorno bipolar está contaminada por falsos negativos. Esta segunda parte de una revisión exhaustiva sobre los fármacos antiepilépticos (FAE) con propiedades inductoras aporta más material educativo a los clínicos acerca de la complejidad de interpretar sus interacciones farmacológicas. Se revisa la farmacología básica de la inducción incluyendo los citocromos P450 (CYP), las enzimas de glucuronización (UGT) y la glucoproteína P (P-gp). Los CYP2B6 y CYP3A4 son muy sensibles a la inducción. El CYP1A2 es moderadamente sensible. Los el CYP2C9 y el CYP2C19 son solo levemente sensibles. El CYP2D6 no puede ser inducida por los fármacos. La inducción de las enzimas metabólicas, los CYP o las UGT, y los transportadores como la P-gp, se debe a un incremento de la síntesis de estas proteínas mediado por los denominados receptores nucleares (receptores constitutivo de androstano, de los estrógenos, de los glucocorticoides y de pregnano X). Aunque la primera parte de este artículo describe los factores de corrección para los antiepilépticos inductores, la extrapolación de estos valores desde un paciente promedio a un individuo concreto está influenciada por la ruta de administración, la carencia de la enzima metabólica debida a razones genéticas, y la presencia de inhibidores, u otros inductores. También pueden ser importantes las interacciones farmacológicas de los FAE al nivel de los mecanismos farmacodinámicos. Se describen 6 pacientes con una sensibilidad extrema a los inductores antiepilépticos (AU)

The literature on inducers in epilepsy and bipolar disorder is seriously contaminated by false negative findings. Part II of this comprehensive review on antiepileptic drug (AED) inducers provides clinicians with further educational material about the complexity of interpreting AED drug-drug interactions. The basic pharmacology of induction is reviewed including the cytochrome P450 (CYP) isoenzymes, the Uridine Diphosphate Glucuronosyltransferases (UGTs), and P-glycoprotein (P-gp). CYP2B6 and CYP3A4 are very sensitive to induction. CYP1A2 is moderately sensitive while CYP2C9 and CYP2C19 are only mildly sensitive. CYP2D6 cannot be induced by medications. Induction of UGT and P-gp are poorly understood. The induction of metabolic enzymes such as CYPs and UGTs, and transporters such as P-gp, implies that the amount of these proteins increases when they are induced; this is almost always explained by increasing synthesis mediated by the so-called nuclear receptors (constitutive androstane, estrogen, glucocorticoid receptors and pregnane X receptors). Although part i provides correction factors for AEDs, extrapolation from an average to an individual patient may be influenced by administration route, absence of metabolic enzyme for genetic reasons, and presence of inhibitors or other inducers. AED pharmacodynamic DDIs may also be important. Six patients with extreme sensitivity to AED inductive effects are described (AU)

Smart drugs and synthetic androgens for cognitive and physical enhancement: revolving doors of cosmetic neurology.

Cognitive enhancement can be defined as the use of drugs and/or other means with the aim to improve the cognitive functions of healthy subjects in particular memory, attention, creativity and intelligence in the absence of any medical indication. Currently, it represents one of the most debated topics in the neuroscience community. Human beings always wanted to use substances to improve their cognitive functions, from the use of hallucinogens in ancient civilizations in an attempt to allow them to better communicate with their gods, to the widespread use of caffeine under various forms (energy drinks, tablets, etc.), to the more recent development of drugs such as stimulants and glutamate activators. In the last ten years, increasing attention has been given to the use of cognitive enhancers, but up to now there is still only a limited amount of information concerning the use, effect and functioning of cognitive enhancement in daily life on healthy subjects. The first aim of this paper was to review current trends in the misuse of smart drugs (also known as Nootropics) presently available on the market focusing in detail on methylphenidate, trying to evaluate the potential risk in healthy individuals, especially teenagers and young adults. Moreover, the authors have explored the issue of cognitive enhancement compared to the use of Anabolic Androgenic Steroids (AAS) in sports. Finally, a brief overview of the ethical considerations surrounding human enhancement has been examined.

The 20th scientific conference of the Society on NeuroImmune Pharmacology.

The 20th conference of the Society on NeuroImmune Pharmacology will be held March 26-29, 2014. It features the latest in research examining the intersection of neuroscience, immunology and pharmacology, relevant for human health and disease. Particular emphases are placed on HIV and other infectious diseases, and abused substances, including illicit drugs and alcohol.

Why is neuroimmunopharmacology crucial for the future of addiction research?

A major development in drug addiction research in recent years has been the discovery that immune signaling within the central nervous system contributes significantly to mesolimbic dopamine reward signaling induced by drugs of abuse, and hence is involved in the presentation of reward behaviors. Additionally, in the case of opioids, these hypotheses have advanced through to the discovery of the novel site of opioid action at the innate immune pattern recognition receptor Toll-like receptor 4 as the necessary triggering event that engages this reward facilitating central immune signaling. Thus, the hypothesis of major proinflammatory contributions to drug abuse was born. This review will examine these key discoveries, but also address several key lingering questions of how central immune signaling is able to contribute in this fashion to the pharmacodynamics of drugs of abuse. It is hoped that by combining the collective wisdom of neuroscience, immunology and pharmacology, into Neuroimmunopharmacology, we may more fully understanding the neuronal and immune complexities of how drugs of abuse, such as opioids, create their rewarding and addiction states. Such discoveries will point us in the direction such that one day soon we might successfully intervene to successfully treat drug addiction. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

Pharmacotherapy of traumatic brain injury: state of the science and the road forward: report of the Department of Defense Neurotrauma Pharmacology Workgroup.

Despite substantial investments by government, philanthropic, and commercial sources over the past several decades, traumatic brain injury (TBI) remains an unmet medical need and a major source of disability and mortality in both developed and developing societies. The U.S. Department of Defense neurotrauma research portfolio contains more than 500 research projects funded at more than $700 million and is aimed at developing interventions that mitigate the effects of trauma to the nervous system and lead to improved quality of life outcomes. A key area of this portfolio focuses on the need for effective pharmacological approaches for treating patients with TBI and its associated symptoms. The Neurotrauma Pharmacology Workgroup was established by the U.S. Army Medical Research and Materiel Command (USAMRMC) with the overarching goal of providing a strategic research plan for developing pharmacological treatments that improve clinical outcomes after TBI. To inform this plan, the Workgroup (a) assessed the current state of the science and ongoing research and (b) identified research gaps to inform future development of research priorities for the neurotrauma research portfolio. The Workgroup identified the six most critical research priority areas in the field of pharmacological treatment for persons with TBI. The priority areas represent parallel efforts needed to advance clinical care; each requires independent effort and sufficient investment. These priority areas will help the USAMRMC and other funding agencies strategically guide their research portfolios to ensure the development of effective pharmacological approaches for treating patients with TBI.