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Rational drug design is an area of science that evolves continuously in order to answer contemporary demands for a decrease in novel drug discovery turnover time. Multiple drug design modalities exist which may be exploited in response to the parameters of specific drug design projects. Bioisosteric modification of existing molecules and de novo design are two such approaches, both of which were employed in parallel in this study which aimed to compare their scope and efficiency using Tricyclic Antidepressants (TCAs) and Selective Serotonin Reuptake Inhibiting (SSRIs) molecules as case studies. Results indicated that bioisosterically modified structures did not have a higher affinity for their cognate receptor when compared to the template structure while the de novo design yielded molecules that were markedly different to the template from a structural perspective, and which also bound to the cognate receptor with an affinity superior to that of the template. This study showed therefore that bioisosteric modification is of utility when minor structural variations are considered sufficiently relative to a template molecule, and could consequently be of utility in the acquisition of new patents, in the reduction of toxicity, or in the attainment of improved biological profiles. It indicated furthermore, the role of the de novo approach in the successful exploration of novel pharmacophoric space and in the generation of molecular structures with an affinity significantly greater than that of lead molecules for a target receptor. [ABSTRACT FROM AUTHOR]

Management of castration resistant prostate cancer is limited by androgen receptor reactivation resulting in loss of remission. A recent study indicated that abiraterone exhibits antagonist activity towards the androgen receptor in addition to CYP17A1 inhibition. Metribolone has demonstrable in vitro and in vivo high affinity for the A R thus it was established as a benchmark against which the affinity of abiraterone and de novo designed non-steroidal molecules could be compared. Binding affinities of abiraterone manually superimposed onto the steroid scaffold of metribolone (pKd 7.16) and abiraterone that was allowed limited rotation (pKd 7.23)were comparable to metribolone (pKd 7.44).The de novo study generated an 8 analogue molecular series with affinities ranging between 5.26 and 7.23. This study yielded sufficient analogues that may be proposed for further molecular optimisation to yield innovative non-steroidal high affinity molecules with superior side-effect profiles for the management of prostate cancer. [ABSTRACT FROM AUTHOR]

Case Summary: A castrated male domestic shorthair cat from a wooded area in Missouri had recovered from typical severe cytauxzoonosis at 4 years of age, after intensive in-hospital supportive care and administration of atovaquone and azithromycin. At 11 years of age, the same cat again experienced an acute febrile illness compatible with cytauxzoonosis. Intraerythrocytic piroplasms typical of Cytauxzoon felis were identified by cytology. The owners opted for euthanasia but allowed collection of splenic and hepatic tissue for histopathologic examination. Schizont-laden macrophages were identified in both tissue specimens, confirming active cytauxzoonosis at the time of the cat's death., Relevance and Novel Information: Although cats that have recovered from cytauxzoonosis can harbor red blood cell piroplasms for many years without apparent clinical illness, repeat illness owing to either disease recrudescence or repeat infection has never been documented. In fact, recovered cats have been thought to be resistant to reinfection and subsequent illness. This report describes a cat that had recovered from documented cytauxzoonosis 7 years previously and then developed a subsequent clinical illness typical of cytauxzoonosis, which was accompanied not only by intraerythrocytic piroplasms, but also by schizont-laden tissue macrophages pathognomonic of clinical cytauxzoonosis., Competing Interests: Conflict of interest: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: Measuring expression profiles of inflammatory biomarkers is important in monitoring the polarization of immune responses; therefore, results should be independent of quantitation methods if they are to be accepted as validated clinical pathology biomarkers. To evaluate effects of differing quantitation methods, the seven major circulating Th1/Th2/Th17 cytokines interleukin 2 (IL-2), interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), IL-4, IL-6, IL-10 and IL-17A were quantified in plasma of lipopolysaccharide (LPS)-treated mice with two different multiplex platforms., Methods: Female C57BL6 mice were treated orally with vehicle or dexamethasone, followed by LPS intravenously. Plasma samples were analyzed 0.5, 1, 2, 4, and 6 h post-LPS challenge with assays at Myriad-RBM and compared to assays performed on a BD Accuri C6 flow cytometer., Results: IL-17A response to LPS was limited but sustained, and the response for the remaining cytokines were early and transient; dexamethasone reduced expression of all 7 cytokines. TNF-α and IL-6 levels were similar across both assays, and IL-4 levels were generally very low. Plasma levels of remaining cytokines were variably lower with BD assays than Myriad-RBM assays., Conclusions: The present findings demonstrate that quantitation of circulating biomarkers of inflammation can be achieved using multiplexed flow cytometry, but careful consideration must be taken for assay validation when cross-referencing with another multiplexed assay., Competing Interests: All study procedures were reviewed and approved by Sinclair Research Center’s Institutional Animal Care and Use Committee.Not applicable.The authors are employees of Sinclair Research Center, a private research organization. The Sinclair Research Center did not have any influence on the outcome the study or the interpretation of the data.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Multiple Sclerosis (MS) is a chronic autoimmune disorder affecting the Central Nervous System (CNS) through inflammation, demyelination and neurodegeneration. Sphingosine-1-phosphate receptor (S1PR1) modulators have been approved for the management of MS. Phosphorylated fingolimod mimics endogenous sphingosine-1-phosphate (S1P), a bioactive lipid that regulates remyelination and cell injury. Amiselimod was developed as a successor of fingolimod, with more specificity for S1PR1, and showed promising results until phase 2 clinical trials. This study utilized the fingolimod and amiselimod scaffolds, together with their critical binding interactions for the S1PR1 Ligand Binding Pocket, as templates for the in silico de novo design of high efficiency binding Lipinski rule-compliant molecules. A rigorous selection process identified two molecules, Molecules 003 and 019, deriving from fingolimod and amiselimod, respectively, which were deemed most suitable for further optimization.

A functional observational battery (FOB) is recommended as the first-tier neurotoxicity screening in the preclinical safety pharmacology testing guidelines. Minipigs have increasingly been used in regulatory toxicology studies; however, no current FOB protocol is available for neurotoxicity testing in these species. Hence, a minipig FOB instrument was developed. A complete crossover study with Sinclair minipigs was performed to evaluate physiologic, neurologic, and behavioral effects of amphetamine, ketamine, and diazepam. The treated minipigs were first observed in their home cage, were video-recorded for 10 minutes in an open field, and then went through a complete neurologic examination. Both ketamine and diazepam were shown to reduce the freezing and behavior shifts of treated minipigs, while increasing their exploratory behaviors. Both drugs also caused muscular and gait impairment. The effects of ketamine and diazepam were consistent with their roles as central nervous system (CNS) suppressants. Unique effects were also observed with ketamine and diazepam treatments, which may reflect their unique mechanisms of action. Consistent with its role as a CNS stimulant, amphetamine caused the treated minipigs to be hyperactive and to display increased freezing and behavior shifts and reduced exploring activities. These effects of amphetamine were opposite to those observed with ketamine and diazepam. Amphetamine also increased locomotion in the treated minipigs. The present effects of amphetamine, ketamine, and diazepam are in agreement with observations by others. In conclusion, the minipig is a suitable species for FOB evaluation of pharmaceuticals in preclinical safety pharmacology testing.

Formulation of nonclinical evaluations is a challenge, with the fundamental need to achieve multiples of the clinical exposure complicated by differences in species and routes of administration-specific tolerances, depending on concentrations, volumes, dosing regimen, duration of each administration, and study duration. Current practice to approach these differences is based on individual experience and scattered literature with no comprehensive data source (the most notable exception being our 2006 publication on this same subject). Lack of formulation tolerance data results in excessive animal use, unplanned delays in the evaluation and development of drugs, and vehicle-dependent results. A consulting firm, a chemical company, and 4 contract research organizations conducted a rigorous data mining operation of vehicle data from studies dating from 1991 to 2015, enhancing the data from this author's 2006 publication (3 of the six 2015 contributors were also 2006 contributors). Additional data were found in the published literature. The results identified 108 single-component vehicles (and 305 combination formulations) used in more than 1,040 studies across multiple species (dog, primate, rat, mouse, rabbit, guinea pig, minipig, pig, chick embryo, and cat) by multiple routes for a wide range of study durations. The tabulated data include maximum tolerated use levels by species, route, duration of study, dose-limiting toxicity where reported, review of the available literature on each vehicle, guidance on syringe selection, volume and pH limits by route with basic guidance on nonclinical formulation development, and guidance on factors to be considered in nonclinical route selection., (© The Author(s) 2016.)