Safety Pharmacology: Achieving a quarter century milestone as a scientific discipline.

This editorial prefaces the annual themed issue on those methods with application to safety pharmacology (SP) in the Journal of Pharmacological and Toxicological Methods (JPTM). Highlighted content is derived from the 2024 Safety Pharmacology Society (SPS) meeting held in San Diego, CA, USA. The meeting showcased 122 posters, many of which are reproduced as abstracts published in JPTM.

Current practices on the measurement of electrocardiogram and hemodynamic parameters in non-rodent species in regulatory safety assessment studies.

Introduction: Cardiovascular (CV) parameters such as blood pressure (BP), electrocardiogram (ECG), and heart rate (HR) are recorded in non-rodent non-clinical safety studies to support drug development. However, measurement quality varies depending on the methodology used, including restraint-based or telemetry (implanted or jacketed) techniques. Measurement quality, in this context, refers to the sensitivity and reliability of CV measurements in affecting baseline values of measured CV parameters and in detecting pharmacological effects.

Surgical instrumentation of cardiovascular telemetry device has minimal impact on the general toxicology data interpretation in Cynomolgus monkeys.

Increasing numbers of general toxicology studies with integrated implanted cardiovascular (CV) telemetry are being conducted due to the constrained supply of nonhuman primates and demands for higher method sensitivities as per ICH S7B Q&A. However, limited information is available for the potential impact of surgical instrumentation on the toxicology data. In this study, we reviewed the reports of implanted CV telemetry studies conducted in cynomolgus monkeys from 2017 to 2022 at our facility.

Reference intervals and method sensitivity for electrocardiology, hemodynamics, and body temperature parameters in healthy cynomolgus monkeys.

In nonclinical studies, electrocardiograms (ECG) of cynomolgus monkey are recorded intermittently by external leads in manually restrained animals (snapshot recording) or continuously by jacketed external telemetry (JET) or implanted radiotelemetry transmitter in freely moving animals. With the implanted device, blood pressure and core body temperature can be monitored simultaneously. Despite the frequent use of cynomolgus monkeys in nonclinical safety pharmacology testing, few reference data are available for this species, comparisons of the ECG recording methods are limited, and power analyses are seldom conducted.

Telemetric assessment of social and single housing: Evaluation of electrocardiographic intervals in jacketed cynomolgus monkeys.

Introduction: Proactive efforts to socially house laboratory animals are a contemporary, important focus for enhancing animal welfare. Jacketing cynomolgus monkeys has been traditionally considered an exclusionary criterion for social housing based on unsubstantiated concerns that study conduct or telemetry equipment might be compromised. Our objective was to evaluate the effects of jacketing naïve, adolescent cynomolgus monkeys in different single and social housing types based on parallel comparisons of heart rate.

Agonist-specific compartmentation of cGMP action in myometrium.

Nitric oxide relaxes myometrium in a cGMP-independent manner. Although cGMP activates its cognate kinase, this is not required for the inhibitory effect of nitric oxide. Thus, nitric oxide-mediated cGMP elevation does not enjoy the same set of substrates as it does in other smooth muscles.

Dissociation of cGMP accumulation and relaxation in myometrial smooth muscle: effects of S-nitroso-N-acetylpenicillamine and 3-morpholinosyndonimine.

In guinea pig, primate and man, nitric oxide (NO)-induced regulation of myometrial smooth muscle contraction is distinct from other smooth muscles because cyclic guanosine 3',5'-cyclic monophosphate (cGMP) accumulation is neither necessary nor sufficient to relax the tissue. To further our understanding of the mechanism of action of NO in myometrium, we employed the NO donors, S-nitroso-N-acetylpenicillamine (SNAP), and 3-morpholinosyndonimine (SIN-1) proposed to relax airway smooth muscle by disparate mechanisms involving elevation in intracellular calcium ([Ca(2+)](i)) or cGMP accumulation, respectively. Treatment of guinea pig myometrial smooth muscle with either NO donor at concentrations thought to produce maximal relaxation of smooth muscles resulted in significant elevations in cGMP that were accompanied by phosphorylation of the cGMP-dependent protein kinase substrate vasodilator-stimulated phosphoprotein (VASP), shown here for the first time to be present and phosphorylated in myometrium.

Excitatory motor innervation in the canine rectoanal region: role of changing receptor populations.

1. Motor innervation in the canine rectoanal region was examined in isolated strips of the circular muscle layer. Contractile responses to electrical field stimulation began at lower frequencies and were more persistent in the internal anal sphincter (IAS) than in the rectum.