Maximizing insights from nonclinical safety studies in the context of rising costs and changing regulations.

The traditional paradigm of non-rodent safety assessment studies, primarily reliant on non-human primates (NHPs) and dogs, is undergoing a transformation. During the 2023 Safety Pharmacology Society Annual Meeting, scientists from leading nonclinical contract organizations discussed how traditional IND-enabling studies can benefit from employing underutilized alternative non-rodent models, such as the swine. Swine offer a cost-effective approach to drug development and share many anatomical and physiological similarities with humans. The inclusion of non-traditional species in safety assessments, coupled with advanced measurement techniques, aids in de-risking compounds early on and adapting projects to the evolving cost landscape.

A Randomized Trial Comparing Freely Moving and Zonal Instruction of Veterinary Surgical Skills Using Ovariohysterectomy Models.

Timely, specific feedback is the most important feature of simulation-based training, but providing adequate instructor supervision is challenging. Students' (n = 76) surgical skills were assessed after training using either the traditional (T) method of large-group teaching by multiple instructors or the alternative method of one instructor assigned (A) to a defined group of students. Instructors rotated to a different group of students for each laboratory session. The instructor-to-student ratio and environment remained identical. No differences were found in raw assessment scores or the number of students requiring remediation, suggesting that students learned in this environment whether they received feedback from one instructor or multiple. Students had no preference between the methods, though 88% of the instructors preferred the assigned method, because they perceived an increased ability to teach and observe individual students. There was no difference in the number of students identified as at-risk of remediation between groups. When both groups were considered together, students identified as at-risk were more likely (40% vs. 10%) to require post-assessment remediation. However, only 22% of students requiring remediation had been identified as at-risk, and A-group instructors were more accurate than T-group instructors at identifying at-risk students. These results suggest that students accept either instructional method, but most instructors prefer to be assigned to a small group of students. Surgical skills were learned similarly well by students in both groups, although assigned instructors were more accurate at identifying at-risk students, which could prove beneficial if early intervention measures can be offered.

The shifting landscape of safety pharmacology in 2015.

The relative importance of the discipline of safety pharmacology (which integrates physiology, pharmacologyand toxicology) has evolved since the incorporation of the Safety Pharmacology Society (SPS) as an entity on August 10, 2000. Safety pharmacology (SP), as a synthesis of these other fields of knowledge, is concerned with characterizing the safety profile (or potential undesirable pharmacodynamic effects) of new chemical entities (NCEs) and biologicals. Initially focused on the issue of drug-induced QT prolongation it has developed into an important discipline over the past 15years with expertise beyond its initial focus on torsades de pointes (TdP). It has become a repository for interrogation of models for drug safety studies and innovative non-clinical model development, validation and implementation. Thus, while safety pharmacology consists of the triumvirate obligatory cardiovascular, central nervous system (CNS) and respiratory system core battery studies it also involves assessing drug effects on numerous other physiological systems (e.g., ocular, auditory, renal, gastrointestinal, blood, immune) leveraging emerging new technologies in a wide range of non-clinical drug safety testing models. As with previous editorials that preface the themed issue on safety pharmacology methods published in the Journal of Pharmacological and Toxicological Methods (JPTM), we highlight here the content derived from the most recent (2014) SPS meeting held in Washington, DC. The dynamics of the discipline remain fervent and method development, extension and refinement are reflected in the content. This issue of the JPTM continues the tradition of providing a publication summary of articles (reviews, commentaries and methods) with impact on the discipline of safety pharmacology.

Overview of Respiratory Studies to Support ICH S7A.

Tests of pulmonary function are useful tools for evaluating the potential for compounds to produce toxicity affecting the pulmonary system. Insults to the pulmonary system (i.e., due to drugs, biologics, toxins) can cause detectable dysfunction through multiple mechanisms. Manifestation of the response to insults will depend on the component(s) involved and the compensatory mechanism(s) initiated. The purpose of this chapter is to introduce the concepts of pulmonary testing as it is applied to the preclinical evaluation of pharmaceutical test articles. The topics will include the techniques and methods that have been developed for use in nonclinical (animal) subjects and the parameters that are routinely measured.

Efficacy of hydroxocobalamin for the treatment of acute cyanide poisoning in adult beagle dogs.

INTRODUCTION: The efficacy of hydroxocobalamin for acute cyanide poisoning was compared with that of saline vehicle in dogs. METHODS: Anesthetized adult beagle dogs were administered potassium cyanide (0.4 mg/kg/min, IV) until 3 min after the onset of apnea. Hydroxocobalamin (75 mg/kg [n = 19] or 150 mg/kg [n = 18], IV) or saline vehicle [n = 17] was then infused over 7.5 min while animals were ventilated with 100% oxygen, which was stopped after 15 min. RESULTS: In vehicle-treated animals cyanide produced deterioration that culminated in a moribund state requiring euthanasia within 4 h in 10 of 17 animals and in neurological deficits necessitating euthanasia within 2-4 d in an additional 4 animals (mortality rate 82%). Survival through 14 d was observed in 15 of 19 animals administered hydroxocobalamin 75 mg/kg (mortality rate 21%), and 18 of 18 administered hydroxocobalamin 150 mg/kg (mortality rate 0%). CONCLUSION: Hydroxocobalamin reversed cyanide toxicity and reduced mortality in a canine model.