Arrhythmias Seen in Baseline 24-Hour Holter ECG Recordings in Healthy Normal Volunteers During Phase 1 Clinical Trials

Hingorani, Pooja; Karnad, Dilip R.; Rohekar, Prashant; Kerkar, Vaibhav; Lokhandwala, Yash; Kothari, Snehal

doi:10.1002/jcph.679

Cited by 57 publications

(52 citation statements)

References 16 publications

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“…Another difficulty with NHP HR arises from the normal resting cardiac activity of a typical adolescent rhesus macaque (e.g., 5 to 9 kg in weight). In addition to the faster HRs typical for macaques relative to adult humans, our recordings show far more frequent transient arrhythmias (e.g., premature ventricular contractions, PVCs) than reported for healthy human subjects (87). The higher HR reduces the electrically quiet time between beats.…”

Section: Measuring Affective Influences On Heart Ratementioning

confidence: 52%

Using pupil size and heart rate to infer affective states during behavioral neurophysiology and neuropsychology experiments

Mitz

Chacko

Putnam

et al. 2017

Journal of Neuroscience Methods

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Background Nonhuman primates (NHPs) are a valuable research model because of their behavioral, physiological and neuroanatomical similarities to humans. In the absence of language, autonomic activity can provide crucial information about cognitive and affective states during single-unit recording, inactivation and lesion studies. Methods standardized for use in humans are not easily adapted to NHPs and detailed guidance has been lacking. New Method We provide guidance for monitoring heart rate and pupil size in the behavioral neurophysiology setting by addressing the methodological issues, pitfalls and solutions for NHP studies. The methods are based on comparative physiology to establish a rationale for each solution. We include examples from both electrophysiological and lesion studies. Results Single-unit recording, pupil responses and heart rate changes represent a range of decreasing temporal resolution, a characteristic that impacts experimental design and analysis. We demonstrate the unexpected result that autonomic measures acquired before and after amygdala lesions are comparable despite disruption of normal autonomic function. Comparison with Existing Methods Species and study design differences can render standard techniques used in human studies inappropriate for NHP studies. We show how to manage data from small groups typical of NHP studies, data from the short behavioral trials typical of neurophysiological studies, issues associated with longitudinal studies, and differences in anatomy and physiology. Conclusions Autonomic measurement to infer cognitive and affective states in NHP is neither off-the-shelf nor onerous. Familiarity with the issues and solutions will broaden the use of autonomic signals in NHP single unit and lesion studies.

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Section: Measuring Affective Influences On Heart Ratementioning

confidence: 52%

Using pupil size and heart rate to infer affective states during behavioral neurophysiology and neuropsychology experiments

Mitz

Chacko

Putnam

et al. 2017

Journal of Neuroscience Methods

View full text Add to dashboard Cite

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“…PVBs are a common ECG finding in the general population and are recorded in up to 75% of healthy individuals undergoing 24-hour ambulatory ECG monitoring, with a prevalence that increases with ageing 9–12. Whether PVBs are more frequently observed in athletes than in their sedentary counterparts is unclear.…”

Section: Is There a Greater Prevalence Of Pvbs In Athletes?mentioning

confidence: 99%

How to evaluate premature ventricular beats in the athlete: critical review and proposal of a diagnostic algorithm

et al. 2019

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Although premature ventricular beats (PVBs) in young people and athletes are usually benign, they may rarely mark underlying heart disease and risk of sudden cardiac death during sport. This review addresses the prevalence, clinical meaning and diagnostic/prognostic assessment of PVBs in the athlete. The article focuses on the characteristics of PVBs, such as the morphological pattern of the ectopic QRS and the response to exercise, which accurately stratify risk. We propose an algorithm to help the sport and exercise physician manage the athlete with PVBs. We also address (1) which athletes need more indepth investigation, including cardiac MRI to exclude an underlying pathological myocardial substrate, and (2) which athletes can remain eligible to competitive sports and who needs to be excluded.

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“…Each event was of short duration, asymptomatic, and not associated with haemodynamic instability. SVT is more common in those aged >45 years compared with those <45 years (13.9% vs. 1.1%, respectively; Hingorani, Karnad, Rohekar, Lokhandwala, & Kothari, ). There was no association between the time of onset and concentration of GSK294 or miridesap.…”

Section: Discussionmentioning

confidence: 99%

Identification, preclinical profile, and clinical proof of concept of an orally bioavailable pro‐drug of miridesap

Richards

Bamford

Liefaard

et al. 2020

British J Pharmacology

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Background and Purpose Miridesap, a depleter of serum amyloid P component (SAP), forms an essential component of a novel approach to remove systemic amyloid deposits; low oral bioavailability necessitates that it is given parenterally. We sought to identify and clinically characterise a pro‐drug that preserves the pharmacological properties of miridesap while having adequate oral bioavailability and physical stability. Experimental Approach We utilised a preclinical screening cascade focused on appropriate physicochemical properties, physical and gut stability, and conversion to miridesap in liver microsomes and blood. GSK3039294 (GSK294) had the desired in vitro profile and progressed to preclinical in vivo pharmacokinetic and safety assessments. Based on a favourable profile, it was tested in healthy participants after single and repeat dosing. Key Results GSK294 was highly soluble and stable in simulated gastric and intestinal fluids, stable in intestinal microsomes, and permeable in Madine Darby Canine Kidney type II cells. GSK294 was rapidly hydrolysed to miridesap and its mono pro‐drug ester in blood and liver microsomes. GSK294 showed good oral bioavailability of miridesap in rats and dogs. Following administration of GSK294 600 mg QD for 7 days in humans, pharmacodynamically active concentrations of miridesap were achieved with substantial and sustained depletion of plasma SAP. The study was terminated due to observations of arrhythmia, the relation of which to GSK294 remains unclear. Conclusion and Implications Using a preclinical screening cascade, we identified a pro‐drug for a palindromic molecule with unique pharmacology (miridesap). The pro‐drug depleted circulating SAP with a time course and extent similar to that of parenterally administered miridesap.

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Arrhythmias Seen in Baseline 24-Hour Holter ECG Recordings in Healthy Normal Volunteers During Phase 1 Clinical Trials

Cited by 57 publications

References 16 publications

Using pupil size and heart rate to infer affective states during behavioral neurophysiology and neuropsychology experiments

Using pupil size and heart rate to infer affective states during behavioral neurophysiology and neuropsychology experiments

How to evaluate premature ventricular beats in the athlete: critical review and proposal of a diagnostic algorithm

Identification, preclinical profile, and clinical proof of concept of an orally bioavailable pro‐drug of miridesap

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