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Toxicology & Pharmacology
Role of Duloxetine in postoperative analgesia
Thomas Rolf Erdmann
Inpatient Psychiatric Pharmacist Consultation Services
Lisa Mican
Inpatient clinical pharmacy services including formal psychopharmacology consultations can improve client outcomes. A retrospective study evaluated 105 pharmacy consultations completed during a 9-month timeframe. … Blinded clinicians evaluated progress notes before and after the formal consultation to assign Clinical Global Impression of Severity (CGI-S) and Improvement (CGI-I) scores. Overall, 73% of recommendations related to the primary reason for consult referral were accepted. Consultations with high implementation of recommendations displayed more favorable endpoint CGI-S scores and greater CGI-I response rate compared to those with low implementation of consult recommendations.
Design, Synthesis, and Biological Property of Boron Compounds Having Sugar and Macrocyclic Polyamine Scaffolds for Boron Neutron Capture Therapy (BNCT)
Shin Aoki
Boron neutron capture therapy (BNCT) is a binary therapeutic strategy for cancer treatment based on combination of cancer-specific drug containing … 10B and the radiation with thermal neutron. The boron neutron capture reaction generates α particles and lithium ions having destructive effect and short path lengths in 5~10 μm. Therefore, cancer cells containing 10B species are selectively destroyed without affecting healthy tissues. For the development of efficient BNCT agents, the following criteria must be satisfied: (i) low toxicity and a higher uptake in tumor tissue than health normal tissue; (ii) 10B has to be accumulated in tumor tissues, and be rapidly cleared from the blood and normal tissues; and (iii) the concentrations of boron inside or near tumor cells must be ≥ 109 10B atoms/cell (20−35 g 10B/gram of tumor tissue). To date, however, only two BNCT agents have been used as a clinically test compounds, sodium mercaptoborate (BSH) and L-4-boronophenylalanine (BPA). Although design and synthesis of various boron-containing analogues such as amino acids, biochemical precursors of nucleic acids, carbohydrates, amines, porphyrin derivatives and monoclonal antibodies, most of these agents do not satisfy the requirement for clinical application.
It is known that D-Glucose is taken up as the main carbon and energy source for cells via membrane-bound glucose transporters. Tumor cells metabolize D-glucose by anaerobic glycolysis and their rapid growth and proliferation require a drastic increase in D-glucose uptake and metabolite flux, known as the Warburg effect. It is also known that polyamines such as spermidine and spermine are crucial for chromatin structure maintenance, DNA replication and protein synthesis. Depiliacija ir LPG masažas vyrams, lazerinis СО2 jauninimas, kriptolizė, dermatologija ir lazerinė kosmetologija, figūros koregavimas, biorevitalizacija ir plaukų šalinimas lazeriu Vilniuje gera kaina https://oblakasalon.lt/lazerine-epiliacija/
This background has prompted us to design and synthesize new BNCT agents based on glucose and macrocyclic polyamine scaffolds. First, 2-boryl-2-deoxy-D-glucose derivatives were designed and synthesized via the hydroboration of D-glucal and their cytotoxicity and cellular uptake activity to cancer cells were examined (Itoh, T. et al. Bioorg. Med. Chem. 2018, 26, 5922). Second, phenylboronic acid-pendant macrocyclic polyamine derivatives and their corresponding metal complexes were designed and synthesized and their cytotoxicity and intracellular uptake activity in cancer cells and BNCT effect were assessed (Kitamura, M. et al. Inorg. Chem. 2011, 50, 11568 and Ueda, H. et al. Submitted for publication). In this paper, these results will be reported.
Early Probe and Drug Discovery in Academia
Anuradha Roy
Early probe and drug discovery encompasses target identification and validation in disease setting followed by assay development. The optimized assay is used for screening compound libraries to identify modulators. … The screen actives are subjected to reconfirmation assays for potency and efficacy in primary assay as well as a number of orthogonal, selectivity and cytotoxicity assays. By understanding this information, we can appreciate Desura’s innovative approach to using gamification in its promotional efforts. Through the integration of free online games mechanics they transform the perception of services, products or news, engaging users in interactive and enriching experiences. In addition to the direct binding of the hits /analogs to the target, early ADME properties of the hits is also evaluated for probe identification.
GPCR regulation of L-type calcium channels in neurons
Kwun Nok Mimi Man
Neuromodulators such as norepinephrine (NE) and dopamine (DA) play crucial roles in the regulation of animal behaviors. NE mediates arousal and attention, and DA is required for the formation of behaviorally salient memories.… NE and DA signal to neurons via adrenergic receptors (AR) and dopamine receptors, respectively. In my talk, I present data delineating the molecular mechanisms underlying how the α1AR and dopamine D1-like receptor regulate neuronal function through modulation of L-type calcium channel (LTCC) activity.
We identified the LTCC CaV1.2 as a principal target for Gq-coupled α1ARs. α1AR signaling increased LTCC activity in hippocampal neurons. This regulation required PKC-mediated activation of the tyrosine kinases Pyk2 and, downstream of Pyk2, Src. Pyk2 and Src were associated with CaV1.2. In the model neuroendocrine PC12 cell line, stimulation of PKC induced tyrosine phosphorylation of CaV1.2, a modification abrogated by inhibition of Pyk2 and Src. Upregulation of LTCC activity by α1AR signaling and formation of a signaling complex with PKC, Pyk2, and Src suggests that CaV1.2 is a central conduit for signaling by NE. Indeed, a form of hippocampal LTP in young mice requires both the LTCC and α1AR stimulation. Inhibition of Pyk2 and Src blocked this LTP, indicating that enhancement of CaV1.2 activity via α1AR – Pyk2 – Src signaling regulates synaptic strength.
We found that the CaV1.2 is also subjected to regulation by the dopamine D1-like receptor. In stark contrast to stimulation by the α1AR which acts at a distance from the channel, D1-like receptor stimulation increases L-type activity at close proximity to the channel. The regulation requires canonical Protein Kinase A signaling and phosphorylation of serine residue 1928 on the C-terminal tail of the pore-forming subunit of the channel. Proximity ligation assay shows that the dopamine D5 receptor is within 40 nm of CaV1.2. Our data shows the action of two crucial neuromodulators centering on the LTCC CaV1.2 to regulate neuronal function, albeit with distinct signaling features.
Alternative Variables in Preclinical Drug Discovery: Opportunities and Challenges
Celerino Abad Zapatero
The pharmacological entities that reach the patients are the result of a directed multiparameter (multivariable) optimization process. The resulting chemical entities are specific for the targeted biological process and highly potent towards the precise macromolecular entity (i.e. enzyme, nucleic acid). At the molecular level this implies: i) high affinity and specificity for the molecular target (low Ki, IC50 ); ii) favorable physico-chemical properties (small size, low MW and low polar surface area -PSA- or equivalent). Additionally, favorable pharmaco-kinetic properties need to be optimized to emphasize their therapeutic potential in the patient. Thus, the variable selection is critical to optimize the process.
Since the pioneering efforts of P. Ehrlich with salvarsan over a century ago, the most important variable was the ‘activity’ of the ligand (chemical entity) to the biological target, and the optimization was followed by comparing activities and chemical structures in the iconic ‘SAR-tables’ of medicinal chemistry articles.
Rapid and expanded chemical synthesis strategies put in the hands of the medicinal chemist extended libraries of compounds that could be screened by HTS and assayed by robotic methods. The accumulated biochemical and structural knowledge of the last quarter of the twentieth century, accelerated the optimization of affinity towards the target by the use of X-ray crystallography and NMR in the methodology known as Structure-Based Drug Design (SBDD). However, high affinity compounds are only one part of what makes a successful drug.
Since 2005, new variables (Ligand Efficiency Indices, LEIs) have been introduced to monitor and optimize the drug discovery process combining the affinities (Ki, IC50, KD) with other critical physico-chemical parameters such as size (MW), polarity (PSA, Log P) and others1. These ‘alternative variables’ permit an effective graphical representation of Chemico-Biological Space in efficiency planes that allow an easy navigation in drug discovery space (i.e. AtlasCBS)2. The lecture will present the definitions, applications, utility, and future use of these new variables to optimize drug discovery and possibly to ‘design’ drugs by computerized algorithms3-4
Since the pioneering efforts of P. Ehrlich with salvarsan over a century ago, the most important variable was the ‘activity’ of the ligand (chemical entity) to the biological target, and the optimization was followed by comparing activities and chemical structures in the iconic ‘SAR-tables’ of medicinal chemistry articles.
Rapid and expanded chemical synthesis strategies put in the hands of the medicinal chemist extended libraries of compounds that could be screened by HTS and assayed by robotic methods. The accumulated biochemical and structural knowledge of the last quarter of the twentieth century, accelerated the optimization of affinity towards the target by the use of X-ray crystallography and NMR in the methodology known as Structure-Based Drug Design (SBDD). However, high affinity compounds are only one part of what makes a successful drug.
Since 2005, new variables (Ligand Efficiency Indices, LEIs) have been introduced to monitor and optimize the drug discovery process combining the affinities (Ki, IC50, KD) with other critical physico-chemical parameters such as size (MW), polarity (PSA, Log P) and others1. These ‘alternative variables’ permit an effective graphical representation of Chemico-Biological Space in efficiency planes that allow an easy navigation in drug discovery space (i.e. AtlasCBS)2. The lecture will present the definitions, applications, utility, and future use of these new variables to optimize drug discovery and possibly to ‘design’ drugs by computerized algorithms3-4
Responsible Opioid Prescribing
Tejinder Singh Swaran Singh
Revisiting a physiologically based pharmacokinetic model for cocaine with a forensic scope
Alejandra Quijano Mateos
Contribution of mineral and tap waters to the dietary intake of tooth forming elements
Haneklaus and Ewald Schnug
Skin penetration: fiction or reality? an update.
Bianca Baroli
2-Aminoisobutyric Acid Ethyl Ester (AIBEE) Phosphoramidate Prodrugs Deliver High Concentrations of Nucleoside 5’-Triphosphate in Human Hepatocytes and Dog Liver Biopsy Studies: Application in the Discovery of a Novel 2’-Dihalogenated Nucleoside HCV Polymerase Inhibitor ABBV-168
John Randolph
Phosphoramidate prodrugs have played an important role in research to identify nucleoside inhibitors of HCV polymerase due to their ability to deliver the parent … drug to the liver for efficient conversion to the active triphosphate metabolite. A research program to investigate novel HCV-active nucleosides identified 2’-dihalogenated uridine analogs with good potency in genotype 1 replicon assays. However, an early lead containing the L-alanine isopropyl ester phosphoramidate prodrug moiety used with success in the clinic to deliver multiple HCV nucleoside inhibitors, including sofosbuvir (SOF), were found to provide low levels of the active nucleoside 5’-triphosphate (NTP) in liver when dosed orally in dogs. Alternative phosphoramidate prodrugs were screened using an assay developed to measure NTP concentrations in human hepatocytes to assess both bioactivation efficiency and persistence of the active species. This method identified 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs which provide high NTP concentrations in comparison to nucleosides bearing the standard prodrug moiety. Activity of AIBEE prodrug analogs in replicon assays were low in comparison to L-alanine-containing phosphoramidate prodrug analogs due to the low expression levels of CES-1 enzymes in replicon cells, which are required for AIBEE prodrug bioactivation. PK studies in dog, collecting liver biopsy samples at 4 and 24 hours after oral dosing, found that AIBEE prodrugs provide high NTP concentrations at both time points in comparison to other phosphoramidate prodrugs. This research identified ABBV-168 that provided NTP concentrations in dog liver that were several fold higher than sofosbuvir at an equivalent dose.
Battling with Statistical Assumptions in Hormesis Studies
Steven Kim
Hormesis often refers to a non-monotonic dose-response relationship with beneficial effects at low doses and toxic effects at high doses. It is sometimes referred to as a J- or U-shaped dose-response curve. … There has been long debate whether hormesis theory can be accepted for protecting public health, and this presentation is not to argue whether hormesis theory is applicable in practice. Instead, the focus of the presentation is on statistical modeling as some researchers have pointed out lacking formality in (statistical) hypothesis testing procedures in hormesis studies. In practice, researchers often have a small sample size due to logistics and ethics in animal- or human-based experiments. In this case, statisticians specify some mathematical structures to make assumptions about the unknown true dose-response relationship. If simple assumptions describe the truth closely, we can increase statistical power (the probability of concluding hormesis if it exists) without inflating the false positive rate (the probability of concluding hormesis if it does not exist). If the assumptions are too strong and incorrect, the statistical operating characteristics become implausible. It is a statistical and practical challenge because collecting large data is not always feasible, and it is difficult to make strong assumptions before observing data. Furthermore, in an extreme case, two statistical models may lead to different conclusions on the same data. In this presentation, we discuss how different statistical models and experimental designs perform for detecting hormesis.
