, underlined.

This essay takes its point of departure from Mark Solms' contention that Freud's neurological thinking informs his work throughout, and that the RSE renders this more thoroughly than the SE. Starting from this contention I examine and compare the RSE and the SE on the question Freud's theorization of difference from his neurological writings onward. I pay special attention to the subtle distinction in the original German of Freud's uses of (difference between) and Differenz (difference).

Oxetane Promise Delivered: Discovery of Long-Acting IDO1 Inhibitors Suitable for Q3W Oral or Parenteral Dosing.

3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3 weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identification system (ALIS).

A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors.

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. Starting from second-generation lead structures such as , we were able to refine these structures to obtain extremely potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules such as demonstrated sufficient oral bioavailability to maintain therapeutic levels in rats and cynomolgus monkeys after dosing with an enabled formulation.

Murderous Racism as Normal Psychosis: The Case of Dylann Roof.

Dylann Roof killed nine people in a Black church in 2015 in order to start a "war" between the white and Black races. This case is used here to develop a psychoanalytic theory of murderous racism, and even genocide. Major concepts from Freud (self-preservation, hatred, narcissism, life and death drives, delusion), Klein (projective identification), and Bion (psychotic and nonpsychotic parts of the personality) are employed.

Characterization of indoleamine-2,3-dioxygenase 1, tryptophan-2,3-dioxygenase, and Ido1/Tdo2 knockout mice.

Indoleamine-2,3-dioxygenase 1 (IDO1) and tryptophan-2,3-dioxygenase 2 (TDO2) degrade tryptophan (Trp) to kynurenine (Kyn), and these enzymes have promise as therapeutic targets. A comprehensive characterization of potential safety liabilities of IDO1 and TDO2 inhibitors using knockout (KO) mice has not been assessed, nor has the dual Ido1/Tdo2 KO been reported. Here we characterized male and female mice with KOs for Ido1, Tdo2, and Ido1/Tdo2 and compared findings to the wild type (WT) mouse strain, evaluated for 14 days, using metabolomics, transcriptional profiling, behavioral analysis, spleen immunophenotyping, comprehensive histopathological analysis, and serum clinical chemistry.

Is there a role for the no observed adverse effect level in safety pharmacology?

In nonclinical toxicology the highest dose or exposure without test article-related adverse effects, known as the No Observed Adverse Effect Level (NOAEL), is a variable that may be determined. In safety pharmacology the vast majority of the endpoints measured are quantitative numeric functional endpoints such as changes in heart rate, blood pressure or respiratory frequency, endpoints that are usually not assessed using a defined framework of adversity. Therefore, we asked the question: is there a role for the NOAEL in safety pharmacology? To help answer this question, we conducted a survey via the Safety Pharmacology Society.

Time for a Fully Integrated Nonclinical-Clinical Risk Assessment to Streamline QT Prolongation Liability Determinations: A Pharma Industry Perspective.

Defining an appropriate and efficient assessment of drug-induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc-prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation.

Discovery and optimization of heteroaryl piperazines as potent and selective PI3Kδ inhibitors.

A high-throughput screening (HTS) campaign identified a class of heteroaryl piperazines with excellent baseline affinity and selectivity for phosphoinositide 3-kinase δ (PI3Kδ) over closely related isoforms. Rapid evaluation and optimization of structure-activity relationships (SAR) for this class, leveraging the modular nature of this scaffold, facilitated development of this hit class into a series of potent and selective inhibitors of PI3Kδ. This effort culminated in the identification of 29, which displayed excellent potency in enzyme and cell-based assays, as well as favorable pharmacokinetic and off-target profiles.

Response of safety pharmacologists to challenges arising from the rapidly evolving changes in the pharmaceutical industry.

This commentary highlights and expands upon the thoughts conveyed in the lecture by Dr. Alan S. Bass, recipient of the 2017 Distinguished Service Award from the Safety Pharmacology Society, given on 27 September 2017 in Berlin, Germany.

Structure Overhaul Affords a Potent Purine PI3Kδ Inhibitor with Improved Tolerability.

PI3Kδ catalytic activity is required for immune cell activation, and has been implicated in inflammatory diseases as well as hematological malignancies in which the AKT pathway is overactive. A purine PI3Kδ inhibitor bearing a benzimidazolone-piperidine motif was found to be poorly tolerated in dog, which was attributed to diffuse vascular injury. Several strategies were implemented to mitigate this finding, including reconstruction of the benzimidazolone-piperidine selectivity motif.

Characterizing Pharmacokinetic-Pharmacodynamic Relationships and Efficacy of PI3K Inhibitors in Respiratory Models of TH2 and TH1 Inflammation.

We leveraged a clinical pharmacokinetic (PK)/pharmacodynamics (PD)/efficacy relationship established with an oral phosphatidylinositol 3-kinase (PI3K) inhibitor (Idelalisib) in a nasal allergen challenge study to determine whether a comparable PK/PD/efficacy relationship with PI3K inhibitors was observed in preclinical respiratory models of type 2 T helper cell (TH2) and type 1 T helper cell (TH1) inflammation. Results from an in vitro rat blood basophil (CD63) activation assay were used as a PD biomarker. IC values for PI3K inhibitors, MSD-496486311, MSD-126796721, Idelalisib, and Duvelisib, were 1.

A Historical View and Vision into the Future of the Field of Safety Pharmacology.

Professor Gerhard Zbinden recognized in the 1970s that the standards of the day for testing new candidate drugs in preclinical toxicity studies failed to identify acute pharmacodynamic adverse events that had the potential to harm participants in clinical trials. From his vision emerged the field of safety pharmacology, formally defined in the International Conference on Harmonization (ICH) S7A guidelines as "those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above." Initially, evaluations of small-molecule pharmacodynamic safety utilized efficacy models and were an ancillary responsibility of discovery scientists.

Evaluation of drug-induced QT interval prolongation in animal and human studies: a literature review of concordance.

Evaluating whether a new medication prolongs QT intervals is a critical safety activity that is conducted in a sensitive animal model during non-clinical drug development. The importance of QT liability detection has been reinforced by non-clinical [International Conference on Harmonization (ICH) S7B] and clinical (ICH E14) regulatory guidance from the International Conference on Harmonization. A key challenge for the cardiovascular safety community is to understand how the finding from a non-clinical in vivo QT assay in animals predicts the outcomes of a clinical QT evaluation in humans.

Overcoming mutagenicity and ion channel activity: optimization of selective spleen tyrosine kinase inhibitors.

Development of a series of highly kinome-selective spleen tyrosine kinase (Syk) inhibitors with favorable druglike properties is described. Early leads were discovered through X-ray crystallographic analysis, and a systematic survey of cores within a selected chemical space focused on ligand binding efficiency. Attenuation of hERG ion channel activity inherent within the initial chemotype was guided through modulation of physicochemical properties including log D, PSA, and pKa.

Discovery of liver-targeted inhibitors of stearoyl-CoA desaturase (SCD1).

Inhibitors based on a benzo-fused spirocyclic oxazepine scaffold were discovered for stearoyl-coenzyme A (CoA) desaturase 1 (SCD1) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model. Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties. After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles.

Safety pharmacology in 2010 and beyond: survey of significant events of the past 10 years and a roadmap to the immediate-, intermediate- and long-term future in recognition of the tenth anniversary of the Safety Pharmacology Society.

In recognition of the tenth anniversary of the Safety Pharmacology Society (SPS), this review summarizes the significant events of the past 10years that have led to the birth, growth and evolution the SPS and presents a roadmap to the immediate-, intermediate- and long-term future of the SPS. The review discusses (i) the rationale for an optimal non-clinical Safety Pharmacology testing, (ii) the evolution of Safety Pharmacology over the last decade, (iii) its impact on drug discovery and development, (iv) the merits of adopting an integrated risk assessment approach, (v) the translation of non-clinical findings to humans and finally (vi) the future challenges and opportunities facing this discipline. Such challenges include the emergence of new molecular targets and new approaches to treat diseases, the rapid development of science and technologies, the growing regulatory concerns and associated number of guidance documents, and the need to train and educate the next generation of safety pharmacologist.

Measuring the risk of torsades de pointes: electrocardiographic evaluation of PNU-142093 in conscious cynomolgus non-human primates using restraint and non-restraint procedures.

Objective: Drug-induced torsades de pointes (TdP) arrhythmia is a serious public health concern that has significantly slowed the advancement of promising new therapeutic agents to the marketplace. Modeling for the potential to produce TdP has relied in part on the surrogate biomarker QT interval prolongation, measured in vivo in animals and in the clinic in man. This study was a comparison of the effects of PNU-142093, a selective 5HT1D-serotonin receptor agonist, on QT interval prolongation under restraint and non-restraint conditions in conscious cynomolgus non-human primates.

Exploratory drug safety: a discovery strategy to reduce attrition in development.

Identification of novel new molecules which hold the greatest promise of safe and effective therapies remains a continuous challenge to the pharmaceutical industry. This has led the industry to implement strategies for identification of the most promising candidates during the discovery phase and for their safe and expeditious advancement through development. Testing for potential liable properties in the discovery phase has included the evaluation of major areas of pharmaceutics that have led to failure such as its physical and pharmaceutical properties, drug metabolism and pharmacokinetic characteristics, various safety endpoints including pre-development safety pharmacology, general toxicology and genetic toxicology and interrogation of counter-screen data to identify off-target affinities (i.

Benchmarking safety pharmacology regulatory packages and best practice.

Introduction: The objectives of this survey were to obtain a global information update regarding current industry perspectives that describe Safety Pharmacology programs as they relate to the ICH S7A and S7B regulatory guidelines but also to obtain a broader perspective of other practises practices in the field currently used by companies. Preliminary findings were presented at the 7th Annual Meeting of the Safety Pharmacology Society (SPS) (Edinburgh, Scotland, Sept 19-21, 2007).

Methods: The survey was distributed by the SPS to 125 pharmaceutical companies.

Scientific review and recommendations on preclinical cardiovascular safety evaluation of biologics.

Biological therapeutic agents (biologicals), such as monoclonal antibodies (mAbs), are increasingly important in the treatment of human disease, and many types of biologicals are in clinical development. During preclinical drug development, cardiovascular safety pharmacology studies are performed to assess cardiac safety in accord with the ICH S7A and S7B regulations that guide these studies. The question arises, however, whether or not it is appropriate to apply these guidelines, which were devised primarily to standardize small molecule drug testing, to the cardiovascular evaluation of biologicals.

Points to consider emerging from a mini-workshop on cardiac safety: assessing torsades de pointes liability.

A mini-workshop on cardiac safety focusing on assessing drug-induced Torsades de Pointes (TdP) liability was convened as part of the 6th Annual Meeting of the Safety Pharmacology Society. The purpose of this brief publication is to disseminate the salient points emanating from this workshop as a means of engaging the scientific community in the appropriate discussions needed to advance this important field of human safety. The recommendations in this publication extend those of the workshop on "Moving Towards Better Predictors of Drug-Induced Torsades de Pointes" held in November 2005 under the auspice of the International Life Sciences Institute, Health and Environmental Sciences Institute; they fall into four key areas: molecular and cellular biology underlying TdP, dynamics of periodicity, models of TdP proarrhythmia and key considerations for demonstrating utility of non-clinical models.

ILSI-HESI cardiovascular safety subcommittee dataset: an analysis of the statistical properties of QT interval and rate-corrected QT interval (QTc).

Introduction: The Health and Environmental Sciences Institute of the International Life Sciences Institute (ILSI/HESI) Cardiovascular Safety Subcommittee outlined a set of in vivo telemetry studies to determine how well this preclinical model identified compounds known to cause torsades de pointes (TdP) and prolong QT interval in humans. In the original analysis of these data, QT, QTcB (Bazett model), QTcF (Fridericia model), and QTcQ (animal-specific model) were evaluated. We further evaluate the statistical properties of these measurements, using a method that can properly account for the sources of variability in the dataset.

ILSI-HESI cardiovascular safety subcommittee initiative: evaluation of three non-clinical models of QT prolongation.

Introduction: Drugs that delay cardiac repolarization pose potential safety risks to patients and cause serious regulatory concern because of the link between QT interval prolongation and the potentially fatal arrhythmia torsades de pointes (TdP). Predicting which drugs will cause TdP is an inexact and difficult science. The utility of non-clinical assays was not well understood due in part to variability in methods, species, and consistency in the assays reported in the literature.

Validation of a motor activity system by a robotically controlled vehicle and using standard reference compounds.

Introduction: A series of experiments were undertaken to evaluate the accuracy, precision, specificity, and sensitivity of an automated, infrared photo beam-based open field motor activity system, the MotorMonitor v. 4.01, Hamilton-Kinder, LLC, for use in a good laboratory practices (GLP) Safety Pharmacology laboratory.

Non-clinical evaluation of ventricular repolarization (ICH S7B): results of an interim survey of international pharmaceutical companies.

Introduction: The propensity of drugs to cause a potentially fatal arrhythmia, torsades des pointes (TdP), is a significant public health issue. The draft International Conference on Harmonization (ICH) S7B guidelines describe a battery of non-clinical studies to evaluate a drug's potential to prolong ventricular repolarization (VR); an accepted surrogate/risk factor for TdP. A worldwide survey of pharmaceutical industry practices, related to ICH S7B was conducted.