Comparisons between electromagnetic and X-beam transit-time flow measurements for evaluating drug actions on cardiac output in the conscious dog.

INTRODUCTION: Cardiac output remains an important preclinical measurement for evaluating the cardiovascular effects of drugs. We evaluated the performance of the Triton Active Redirection Transit-Time, ART(2), which represents a new class of X-beam flow systems and compared it in vivo and in vitro to an electromagnetic flow (EMF) system for measuring large vessel flow. METHODS: In vivo, simultaneous aortic flow measurements were obtained during alpha- and beta-adrenergic receptor stimulation in 5 conscious dogs instrumented with both ART(2) and EMF probes on their ascending aortas. In vitro, simultaneous measurements of volume flow using the ART(2), EMF, and timed-volume collection were made using a novel benchtop flow apparatus that ensured probe alignment and precise timed-volume flow measurements. Accuracy and sensitivity of both systems were assessed by recording flow measurements while varying rates, temperature and hematocrit. RESULTS: In vivo aortic flow measurements between ART(2) and EMF were closely correlated (linear regression r(2) values ranged from 0.84 to 0.99), with the ART(2) system recording lower flow values than the EMF. In vitro ART(2) flow rates were in excellent agreement with timed-volume flow, while EMF flow rates were lower (p<0.05) and exhibited more variation and dependency upon temperature or hematocrit than the ART(2). Saline flows measured by ART(2) and EMF averaged 97+/-2% and 91+/-5% accuracy, respectively, over the temperature range 32 degrees C to 42 degrees C. For blood hematocrit values between 35% and 45%, ART(2) accuracy averaged 98+/-2%, compared to 89+/-5% accuracy with the EMF. DISCUSSION: The ART(2) flow measurements in conscious dogs correlated closely to concurrent measurements obtained with the EMF over a wide range of flow rates, even though the absolute aortic flow values differed. Since it accurately measured flow in vitro, the ART(2) system is an appropriate alternative for evaluating cardiovascular effects of disease progression or drug administration in experimental animals.

Topical drug classification.

Current definitions of lotions, gels, creams and ointments vary depending on literature source, market history or traditional use. This often leads to confusion when deciding which dosage form to prescribe and/or purchase. The existing classification of topical dosage forms needs to be re-examined to ensure that definitions for different dosage forms are based on consistent scientific principles and that dosage forms can be distinguished from one another. The purpose of this study is to obtain a scientifically based, systematic classification of dosage forms for topical drugs. A variety of prescription and over-the-counter topical products currently marketed as lotions, gels, creams, and ointments are evaluated using different techniques including rheology (viscosity and shear rate versus shear stress), loss on drying (LOD), specific gravity, surface tension, thermogravimetric analysis (TGA), water absorption, dilution properties, microscopic evaluation, transmittance of visible light, appearance and composition. Rheology is the most discriminating property separating creams and lotions. Water plus volatiles (as measured by LOD) and composition separate ointments and creams. Composition and thermal behavior separate gels from the other dosage forms. Based on these findings, new definitions and a decision tree are presented to assist in the determination of the appropriate nomenclature for a topical dosage form.

Differential effect of HERG blocking agents on cardiac electrical alternans in the guinea pig.

Beat-to-beat alternations of the cardiac monophasic action potential, known as electrical alternans, were studied at drug concentrations that have known arrhythmogenic outcomes. Electrical alternans were elicited from the heart of anesthetized guinea pigs, both in the absence and presence of drugs that inhibit the delayed rectifier K(+) channel encoded by the human ether a-go-go related-gene (HERG), and are associated with the fatal arrhythmia, Torsade de Pointes. Two other HERG inhibiting drugs not associated with Torsade de Pointes were also studied. At concentrations known to be proarrhythmic, E-4031 and bepridil increased mean alternans 10 and 40 ms at pacing frequencies

Analyses of dynamic beat-to-beat QT-TQ interval (ECG restitution) changes in humans under normal sinus rhythm and prior to an event of torsades de pointes during QT prolongation caused by sotalol.

BACKGROUND: Restitution through intracardiac pacing has been used to assess arrhythmia vulnerability. We examined whether analyses of sequential beat-to-beat QT and TQ interval measures can be used to quantify ECG restitution changes under normal sinus rhythm. METHODS: The QT, R-R and TQ intervals were examined 22.5 hour Holter monitoring before and after oral sotalol in normal male and female volunteers. Additionally, comparisons were made to those observed in the time-matched dataset prior to torsades de pointes in a heart diseased patient that received a single dose of sotalol. RESULTS: Sotalol increased QT, R-R and TQ intervals 71, 101, and 125 ms after 160 mg (n = 38) and 194, 235, and 135 ms after 320 mg (n = 19) during maximum plasma concentrations, respectively. The percentage of beats with a QT/TQ ratio >1 was reduced 25% over the entire 22.5 hours after sotalol and the lower TQ interval boundary (5th quantile) was increased 22-30%. In contrast, 99% of the beats prior to torsades de pointes had a QT/TQ ratio > 1 and the median TQ interval was below the lower 98% confidence bounds of normals before and after sotalol. CONCLUSIONS: ECG restitution changes are quantifiable under varying states (nocturnally, beta-adrenergic blockade, QT prolongation) in healthy subjects.

Dynamic beat-to-beat modeling of the QT-RR interval relationship: analysis of QT prolongation during alterations of autonomic state versus human ether a-go-go-related gene inhibition.

Methods to correct the QT interval for heart rate are often in disagreement and may be further confounded by changes in autonomic state. This can be problematic when trying to distinguish the changes in QT interval by either drug-induced delayed repolarization or from autonomic-mediated physiological responses. Assessment of the canine dynamic QT-RR interval relationship was visualized by novel programming of the dynamic beat-to-beat confluence of data or "clouds". To represent the nonuniformity of the clouds, a bootstrap sampling method that computes the mathematical center of the uncorrected beat-to-beat QT value (QTbtb) with upper 95% confidence bounds was adopted and compared with corrected QT (QTc) using standard correction factors. Nitroprusside-induced reflex tachycardia reduced QTbtb by 43 ms, whereas an increase of 55 and 16 ms was obtained using the Bazett (QTcB) and Fridericia (QTcF) formulae, respectively. Phenylephrine-induced reflex bradycardia increased QTbtb by 3 ms but decreased QTcB by 20 ms and QTcF by 12 ms. Delayed repolarization with E-4031 (1-[2-(6-methyl-2-pyridyl)ethyl]-4-methylsulfonylaminobenzoyl)-piperidine), an inhibitor of rectifier potassium current, increased QTbtb by 26 ms but QT prolongation calculations using QTcF and QTcB were between 12 and 52% less, respectively, when small decreases in heart rate (5-8 beats per minute) were apparent. Dynamic assessment of beat-to-beat data, using the bootstrap method, allows quantification of QT interval changes under varying conditions of heart rate, autonomic tone, and direct repolarization that may not be distinguishable with use of standard correction factors.