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S Palethorpe

Publications and source records attributed to S Palethorpe.

4 recordsLinked to original sources
PubMed2003

Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development.

OBJECTIVE: To attempt to determine the relative value of preclinical cardiac electrophysiology data (in vitro and in vivo) for predicting risk of torsade de pointes (TdP) in clinical use. METHODS: Published data on hERG (or I(Kr)) activity, cardiac action potential duration (at 90% repolarisation; APD(90)), and QT prolongation in dogs were compared against QT effects and reports of TdP in humans for 100 drugs. These data were set against the free plasma concentrations attained during clinical use (effective therapeutic plasma concentrations; ETPC(unbound)). The drugs were divided into five categories: (1) Class Ia and III antiarrhythmics; (2) Withdrawn from market due to TdP; (3) Measurable incidence/numerous reports of TdP in humans; (4) Isolated reports of TdP in humans; (5) No reports of TdP in humans. RESULTS: Data from hERG (or I(Kr)) assays in addition to ETPC(unbound) data were available for 52 drugs. For Category 1 drugs, data for hERG/I(Kr) IC(50), APD(90), QTc in animals and QTc in humans were generally close to or superimposed on the ETPC(unbound) values. This relationship was uncoupled in the other categories, with more complex relationships between the data. In Category 1 (except amiodarone), the ratios between hERG/I(Kr) IC(50) and ETPC(unbound) (max) ranged from 0.1- to 31-fold. Similar ranges were obtained for drugs in Category 2 (0.31- to 13-fold) and Category 3 (0.03- to 35-fold). A large spread was found for Category 4 drugs (0.13- to 35700-fold); this category embraced an assortment of mechanisms ranging from drugs which may well be affecting I(Kr) currents in clinical use (e.g. sparfloxacin) to others such as nifedipine (35700-fold) where channel block is not involved. Finally, for the majority of Category 5 drugs there was a >30-fold separation between hERG/I(Kr) activity and ETPC(unbound) values, with the notable exception of verapamil (1.7-fold), which is free from QT prolongation in man; this is probably explained by its multiple interactions with cardiac ion channels. CONCLUSIONS: The dataset confirms the widely-held belief that most drugs associated with TdP in humans are also associated with hERG K(+) channel block at concentrations close to or superimposed upon the free plasma concentrations found in clinical use. A 30-fold margin between C(max) and hERG IC(50) may suffice for drugs currently undergoing clinical evaluation, but for future drug discovery programmes, pharmaceutical companies should consider increasing this margin, particularly for drugs aimed at non-debilitating diseases. However, interactions with multiple cardiac ion channels can either mitigate or exacerbate the prolongation of APD and QT that would ensue from block of I(Kr) currents alone, and delay of repolarisation per se is not necessarily torsadogenic. Clearly, an integrated assessment of in vitro and in vivo data is required in order to predict the torsadogenic risk of a new candidate drug in humans.

Animals↗
PubMed2000

Reading aloud begins when the computation of phonology is complete.

Naming latency experiments in which monosyllabic items are read aloud are based on the assumption that the vocal response is not initiated until the phonology of the entire syllable has been computed. Recently, this assumption has been challenged by A. H. Kawamoto, C. T. Kello, R. Jones, and K. Bame (1998), who argued instead that the reading-aloud response begins as soon as the initial phoneme is computed. This view would be refuted by evidence of anticipatory coarticulation effects on the initial phoneme due to the nature of the following vowel in the speeded reading-aloud task. The authors provide such evidence.

Humans↗
PubMed1996

Vowel classification in children.

Research into the developing vowel system has assumed greater importance in recent years with growing evidence for a more important theoretical role for vowels in child phonology. One limitation of acoustic studies in child speech has been the practical difficulties associated with formant-based analysis and the experiments reported in this paper compare the reliability of critical bands and formant frequencies as acoustic correlates of vowel identity in children. Gaussian classification of vowels in/CVd/Australian English words was carried out using data collected from 4-year-old children and male and female adults. The results show that the use of critical bands for the classification of vowels in children is a robust technique which requires less experimenter intervention in the analysis procedure than the use of formant frequencies, while achieving similar results. The ability to utilize an automatic methodology such as critical band analysis can provide a very powerful tool for large-scale studies in this area.

Child, Preschool↗