Biomedical subjects

Robert L Hamlin

Publications and source records attributed to Robert L Hamlin.

24 records · Page 2Linked to original sources

PubMed2002

Amiodarone-induced keratopathy in healthy dogs.

Amiodarone has a broad spectrum as an antiarrhythmic agent and is indicated for patients with atrial and ventricular arrhythmias. Amiodarone-induced corneal deposits are the most common reversible side effect (70-100%) in humans. Additional ocular effects in humans include deposits in the lens, retina and optic nerve. This study was conducted to determine ocular effects of chronic oral amiodarone in healthy dogs. Six chronically amiodarone-treated dogs and four controls were used for this study. Ophthalmic examination was performed using biomicroscopy and indirect ophthalmoscopy at the end of 4th, 7th and 11th weeks when dogs received amiodarone. Corneal microdeposits were observed at the end of the 7th week in one eye and at end of the 11th week in the other eye of one dog. Immediately following euthanasia, corneas and optic nerves were harvested for light and electron microscopic analysis. Light microscopic analysis showed corneal deposits in the basal epithelial cells of the cornea of the clinically affected dog. In addition, a significant increase in basal cell turnover as indicated by mitotic index was observed in the affected dog compared to both nondeposit amiodarone and control groups. All remaining animals were normal. One out of six dogs treated with amiodarone demonstrated corneal deposits (16%). This prevalence is low compared to humans. Explanations for this may include species variations particularly in volume of lacrimal secretion, or the need for longer administration. In addition, sunlight is believed to exacerbate the corneal deposits in humans and all dogs in this study were housed indoors.

Administration, Oral↗

PubMed2002

Changes in concentrations of neuroendocrine hormones and catecholamines in dogs with myocardial failure induced by rapid ventricular pacing.

OBJECTIVE: To describe neuroendocrine responses that develop in dogs subjected to prolonged periods of ventricular pacing. ANIMALS: 14 adult male hound-type dogs. PROCEDURE: Samples were obtained and neuroendocrine responses measured before (baseline) and after 3 periods of ventricular pacing. A pacemaker was used to induce heart rates of 180, 200, and 220 beats/min (BPM). Each heart rate was maintained for 3 weeks before increasing to the next rate. Atrial natriuretic peptide, antidiuretic hormone, aldosterone, norepinephrine, epinephrine, and dopamine concentrations and plasma renin activity were measured. Severity of left ventricular compromise was estimated. RESULTS: Shortening fraction decreased significantly with increasing heart rates (mean +/- SE, 35.5 +/- 1.4, 25.0 +/- 1.4, 19.5 +/- 1.9, and 12.2 +/- 2.3 for baseline, 180 BPM, 200 BPM, and 220 BPM, respectively). Atrial natriuretic peptide concentrations increased significantly at 180 BPM (44.1 +/- 3.0 pg/mL) and 200 BPM (54.8 +/- 5.5 pg/mL), compared with baseline concentration (36.8 +/- 2.6 pg/mL). Dopamine concentration increased significantly at 200 BPM (70.4 +/- 10.4 pg/mL), compared with baseline concentration (44.2 73 pg/mL). Norepinephrine concentrations increased significantly from baseline concentration (451 +/- 46.2 pg/mL) to 678 +/- 69.8, 856 +/- 99.6, and 1,003 +/- 2676 pg/mL at 180, 200, and 220 BPM, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Dogs subjected to ventricular pacing for 9 weeks developed neuroendocrine responses similar to those that develop in humans with more chronic heart failure and, except for epinephrine concentrations, similar to those for dogs subjected to ventricular pacing for < 6 weeks.

Aldosterone↗

PubMedDate not supplied

How many cardiac cycles must be measured to permit accurate RR, QT, and QTc estimates in conscious dogs?

INTRODUCTION: Electrocardiography is an essential tool to assess the liability of test articles to produce torsade de pointes. The number of cardiac cycles that must be measured from a dog to accurately characterize the relationship between RR and QT intervals, and thus assess this liability, is unknown. METHODS: In this study, electrocardiograms (ECGs) were obtained from 12 conscious dogs with sinus rhythm. In each dog, RR and QT intervals were measured for 12 cardiac cycles. Measurements for each were then averaged over all 12 cycles, and those results compared to the average of both the initial 6 and 3 cycles, as well as to the middle cycle alone, for 12, 6, and 4 of the dogs. QTc was calculated by dividing each QT by the cube root of the preceding RR interval. RESULTS: We found no significant differences in the results of measurements of RR, QT, or QTc obtained from 12, 6, 3, or 1 cycle, whether from 12, 6, or 4 dogs. Intraobserver variability of ECG measurements was tested by having a single observer measure 10 copies of 12 different ECGs. The greatest coefficient of variation (S.D./mean) for the measurement of any ECG parameter was less than 2.5%. DISCUSSION: We conclude that measurements of RR and QT intervals made by a trained observer from 1 cardiac cycle accurately reflect those that are averaged from 3, 6, or 12 cycles whether the number of dogs per group is 12, 6, or 4.

Animals↗

PubMedDate not supplied

Relationship between prolongation of QTc and prolongation of the peak of T (Tp) to the end of T (Te).

INTRODUCTION: Lengthening of ventricular repolarization is known to be a risk factor for development of torsade de pointes, a form of ventricular tachycardia thought to be initiated by an early after depolarization and to be sustained by a novel reentrant mechanism precipitated, putatively, by heterogeneity of repolarization among ventricular myocytes. While prolongation of QT and QTc are good predictors of torsdogenic potential, the duration from the peak to the end of the T wave (Tp-Te) is thought to be a more accurate reflection of heterogeneity of ventricular repolarization. This study, conducted on Langendorff guinea pig hearts, was designed to compare lengthening of QTc with lengthening of Tp-Te for 16 test articles known to be and 7 known not to be torsadogenic. METHODS: Bipolar, transventricular electrograms, recorded from 83 guinea pig hearts perfused according to methods of Langendorff, were exposed to escalating concentrations of test articles. RR, QT, QTc and Tp-Te were measured. QTc was calculated by the method of Fridericia. Data was analyzed using a mixed model ANOVA where least squared means (t-test) was used for comparing males vs. females and for concentration levels for each parameter studied. RESULTS: QTc lengthened in 16 of 16 test articles known to be torsadogenic and did not lengthen in 7 of 7 test articles known not to be torsadogenic--sensitivity and specificity of 1.0. In 9 out of 16 torsadogenic test compounds, the Tp-Te interval increased parallel with QTc. In 7 test compounds known not to be torsadogenic, two test compounds increased Tp-Te. DISCUSSION: It is clear that QTc prolongation is a more robust predictor of torsadogenicity than Tp-Te in the male guinea pig heart.

Animals↗

PubMedDate not supplied

Non-drug-related electrocardiographic features in animal models in safety pharmacology.

No study of a test article is complete without attempting to determine its risk for production of toxicity to all important components of cardiovascular function (e.g., electrophysiological, mechanical, biochemical, baroreceptor). Electrocardiography is extremely useful for interrogating important electrophysiological properties: chronotropy (heart rate), dromotropy (conduction through the atria and ventricles, and through atrioventricular conduction), and predilection to produce arrhythmia, in particular, torsade de pointes. However, there are many factors that make electrocardiography less than optimal for detecting potential toxicological effects in studies of safety pharmacology. This paper will present examples of common difficulties in recording or in interpreting electrocardiograms, specifically due to artifacts in ECGs produced by the methods of electrocardiography, and by the "unusual" electrophysiology of the species/subject. One of the most contentious issues in electrocardiology is correction of QT for heart rate (Mark, M. (2001) Problems of heart rate correction in assessment of drug-induced QT interval prolongation. Journal of Cardiovascular Electrophysiology, 12, 411-420). This will not be discussed.

Animals↗

PubMedDate not supplied

Effects of chronic oral amiodarone on left ventricular function, ECGs, serum chemistries, and exercise tolerance in healthy dogs.

Amiodarone, a class III antiarrhythmic with beta-adrenergic blocking and antimuscarinic properties, has a wide spectrum of clinical use in humans. This study was conducted to establish the effects of a 25 mg/kg q12h loading dose and a 30 mg/kg q24h maintenance dose of amiodarone, each given PO for 3.5 weeks, on systemic arterial pressure, echocardiographic (ECHO) indices of left ventricular function, ECGs, exercise tolerance, and serum biochemistries in adult, clinically normal dogs. Means were calculated and were compared by analysis of variance with repeated measures. When a significant F statistic was identified, specific means were compared by Bonferroni's post hoc test. Body weight and heart rate (HR) decreased, and PQ, QT, and corrected QT (QTc) increased significantly (P < .05) for the weeks that the dogs received the loading dose, but all parameters returned to values the same as those in the pretest for the weeks when dogs received the maintenance dose. Serum activity of hepatic enzyme activities and cholesterol concentrations increased, and serum concentrations of thyroid hormones (triiodothyronine [T3] and thyroxine [T4]), phosphorous, and total carbon dioxide decreased. The changes in PQ, QT, and QTc are similar to those obtained previously, but the detailed ECG and ECHO observations have not been reported. A dose of 25 mg/kg q12h, but not 30 mg/kg q24h, is an appetite suppressant, and the lower dose produces neither ECG nor ECHO changes of clinical or toxicological significance in normal dogs.

Administration, Oral↗