Seizures are complex electrophysiological disturbances affecting one or more populations of brain neurons. Seizures following test article (TA) exposure pose significant challenges in drug development. This paper considers the diverse neurological manifestations, mechanisms, and functional and structural assessments needed to investigate TA-related seizure liabilities, with a particular focus on nonclinical species.
View Article and Find Full Text PDFTest article (TA)-induced seizures represent a major safety concern in drug development. Seizures (altered brain wave [electrophysiological] patterns) present clinically as abnormal consciousness with or without tonic/clonic convulsions (where "tonic" = stiffening and "clonic" = involuntary rhythmical movements). Neuropathological findings following seizures may be detected using many methods.
View Article and Find Full Text PDFPsychopharmacology (Berl)
January 2025
Rationale: There is increasing interest in establishing psychedelic research programs at academic medical centers. However, psychedelics are intensely psychoactive, carry considerable sociopolitical baggage, and most are Schedule I drugs, creating significant potential impediments to implementation. There is little formal guidance for investigators on navigating the complex on-the-ground obstacles associated with establishing psychedelic research programs.
View Article and Find Full Text PDFJ Pharmacol Toxicol Methods
May 2017
The Safety Pharmacology Society (SPS) conducted an industry survey in 2015 to identify industry practices as they relate to central, peripheral and autonomic nervous system ('CNS') drug safety testing. One hundred fifty-eight (158) participants from Asia (16%), Europe (20%) and North America (56%) responded to the survey. 52% of participants were from pharmaceutical companies (>1000 employees).
View Article and Find Full Text PDFJ Pharmacol Toxicol Methods
May 2017
Electroencephalogram (EEG) data in nonclinical species can play a critical role in the successful evaluation of a compound during drug development, particularly in the evaluation of seizure potential and for monitoring changes in sleep. Yet, while non-invasive electrocardiogram (ECG) monitoring is commonly included in preclinical safety studies, pre-dose or post-dose EEG assessments are not. Industry practices as they relate to preclinical seizure liability and sleep assessments are not well characterized and the extent of preclinical EEG testing varies between organizations.
View Article and Find Full Text PDFCannabinoid receptor 1 (CB(1)) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications.
View Article and Find Full Text PDFDespite the knowledge that gamma-aminobutyric acid(A) modulators can affect learning and memory, their capacity for disrupting each of these complex processes is rarely compared, and often mistakenly assumed to occur with identical potency. For these reasons, the effects of flunitrazepam (0.056-3.
View Article and Find Full Text PDFThe CB1 inverse agonist/antagonist SR141716A recently has been introduced for the management of obesity (rimonabant; Acomplia) and appears to have beneficial effects. However, its utility may be hampered in some individuals by adverse effects including nausea or emesis or by mood depression. The recent development of biochemically 'neutral' antagonists such as AM4113 (Sink et al.
View Article and Find Full Text PDFRationale: Clinical studies have suggested that marijuana and nabilone have anxiolytic effects in humans, yet studies of anxiolytic-like effects of cannabinoid agonists in mice and rats have yielded mixed results.
Objective: The purpose of the present study was to compare the effects of cannabinoid agonists and clinically used anxiolytic drugs in monkeys using punished responding and midazolam discrimination procedures.
Methods: Monkeys were trained to discriminate an i.
Exp Clin Psychopharmacol
November 2002
The nonserotonergic benzodiazepine, triazolam, was compared with two 5-HT1A receptor agonists, 8-OH-DPAT and buspirone, in squirrel monkeys responding under a repeated-acquisition procedure. In each session, subjects acquired a 4-response sequence by responding sequentially on 3 keys in the presence of 4 discriminative stimuli (colors). Response sequences for each session were maintained by food presentation under a second-order fixed-ratio schedule.
View Article and Find Full Text PDFRationale: Establishing functional deficits as a result of neurotoxic dosing regimens of MDMA has been difficult. However, moderate success has been achieved when sensitive animal models and drug challenge have been used together.
Objective: The present study used a repeated-acquisition technique and dose-effect determinations before, during and after neurotoxic MDMA exposure to characterize the effects of serotonergic drugs on learning, and to determine if MDMA-induced serotonin (5-HT) neurotoxicity is associated with learning deficits as measured by changes in response rate or the percentage of errors.
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