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Biomedical subjects

R Kannan

Publications and source records attributed to R Kannan.

At least 91 records · Page 5Linked to original sources
PubMed1987

Amiodarone efficacy in a young population: relationship to serum amiodarone and desethylamiodarone levels.

Serum amiodarone and desethylamiodarone levels were measured in children and young adults receiving chronic amiodarone therapy. The study population consisted of 34 children and young adults with ventricular tachycardia (36%), atrial flutter (36%), and recurrent supraventricular tachycardia (27%). The mean age was 12.9 +/- 8.6 years (range 4 months to 23 years) and the mean daily dose of amiodarone was 6.6 +/- 3.7 mg/kg/day (range 2.5 to 25 mg). Serum amiodarone and desethylamiodarone levels after 10.1 months (range 1 to 40 months) were 0.85 +/- 0.63 microgram/ml and 0.67 +/- 0.42 microgram/ml, respectively. In three patients for whom amiodarone therapy was unsuccessful, serum amiodarone levels were 0.27, 0.85, and 1.18 micrograms/ml. There was no significant correlation between serum amiodarone or desethylamiodarone levels and dosage of amiodarone. Four patients, all 13 years or older, developed toxicity (skin rash [one patient], keratopathy [two patients], and hyperthyroidism [one patient]). There was no correlation between serum amiodarone and desethylamiodarone levels and toxicity; although there was a trend toward elevated reverse serum triiodothyronine levels in patients who developed toxicity, the values fell within the range of those patients without toxic side effects. Serum amiodarone levels do not appear to be of great value in predicting efficacy and toxicity of amiodarone in children and young adults receiving chronic drug therapy.

Adolescent↗
PubMed1986

Electrophysiologic effects of the levo- and dextrorotatory isomers of sotalol in isolated cardiac muscle and their in vivo pharmacokinetics.

Dl-sotalol is a specific beta-adrenergic blocking agent that markedly lengthens cardiac action potential duration. To determine whether d-sotalol, with little or no beta-blocking effect, also lengthens repolarization, standard microelectrode studies were used to determine the electrophysiologic properties of dl-sotalol and its stereoisomers in isolated rabbit and canine myocardial fibers. D- and l-sotalol produced concentration-dependent increases in action potential duration to 50% (APD50) and 90% (APD90) repolarization, respectively, and in the effective refractory period without changes in the maximal rate of rise of action potential. In rabbit sinoatrial node, d- and l-sotalol produced concentration-dependent increases in spontaneous sinus cycle length (29 and 35%, respectively) by lengthening the action potential duration (by 58 and 55%) without effect on phase 4 depolarization. At the highest concentration (27.2 micrograms/ml), d- and l-sotalol prolonged APD90 (by 38 and 54%, respectively, in Purkinje fibers and by 32 and 34% in ventricular muscle) and effective refractory period (by 49 and 49% in Purkinje fibers and 29 and 40% in ventricular muscle). The effects of the two isomers were not significantly different. At the middle concentration (2.7 micrograms/ml), d-sotalol, unlike l-sotalol, had no beta-adrenergic blocking effect, but the electrophysiologic effects of dl-, d- and l-sotalol were indistinguishable. The data indicate that d-sotalol is equipotent with l-sotalol in lengthening the action potential duration and effective refractory period in cardiac muscle, an action unrelated to adrenergic antagonism or pharmacokinetic differences between the stereoisomers.

Action Potentials↗
PubMed1986

Heinz bodies induce clustering of band 3, glycophorin, and ankyrin in sickle cell erythrocytes.

In earlier model studies we demonstrated that artificially denatured hemoglobin binds to and clusters the protein, band 3, in the plane of the erythrocyte membrane. To determine whether denatured hemoglobin also clusters band 3 in vivo, we have compared the locations of denatured hemoglobin aggregates (Heinz bodies) with band 3 in sickle cells using phase contrast and immunofluorescence microscopy. We report that where Heinz bodies are found associated with the cytoplasmic surface of the membrane, clusters of band 3 are usually colocalized within the membrane. In contrast, normal erythrocyte membranes and regions of sickle cell membranes devoid of Heinz bodies display an uninterrupted staining of band 3. Similarly, ankyrin and glycophorin are periodically seen to aggregate at Heinz body sites, but the degree of colocalization is lower than for band 3. These data demonstrate that the binding of denatured hemoglobin to the membrane forces a redistribution of several major membrane components.

Anemia, Sickle Cell↗
PubMed1985

Tissue-serum correlates of digoxin-amiodarone pharmacokinetic interaction in rats: evidence for selective tissue accumulation and reduced tissue binding.

The pharmacokinetic interaction between digoxin (1) and amiodarone (2) has drawn increasing attention during recent years, but the tissue correlates of such an interaction are not known. This issue was therefore investigated in three groups of Sprague-Dawley rats. When 1 alone was given (250 micrograms/d), the serum concentration of 1 was 0.88 +/- 0.36 ng/mL; when 1 was combined with 2 (66 mg/kg/d), the level of 1 was 2.62 +/- 1.23 ng/mL (p less than 0.05) and was 5.49 +/- 1.07 ng/mL (p less than 0.05) when the dose of 2 was 132 mg/kg/d. These increases correlated with the serum levels of 2 and the deethyl metabolite 3. The myocardial level of 1 was 29.40 +/- 1.34 ng/g without 2; after a low dose of 2, it was 35.80 +/- 7.52 ng/g (nonsignificant) and, after a high dose, it was 42.80 +/- 7.20 (p less than 0.05). In skeletal muscle, the level of 1 was 22.50 +/- 14.7 ng/g without 2, 41.00 +/- 2.45 ng/g (p less than 0.05) after a low dose, and 77.60 +/- 17.45 ng/g (p less than 0.05) after a high dose. The corresponding values for the brain were 32.20 +/- 5.60 ng/g, 48.20 +/- 7.60 ng/g (p less than 0.05), and 60.90 +/- 11.00 ng/g (p less than 0.05). The tissue-serum ratios for 1 in all three tissues were reduced by 2, suggesting a decrease in the tissue binding of the glycoside. There was less uptake of 1 in the myocardium compared with uptake in the skeletal muscle and brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone↗
PubMed1984

Serum and myocardial kinetics of amiodarone and its deethyl metabolite after intravenous administration in rabbits.

The serum kinetics of amiodarone and its major metabolite the deethyl analogue were studied in rabbits after intravenous administration. The elimination of the drug and the metabolite from serum occurred as a biexponential function. Both compounds exhibited a rapid distribution phase (6.5 and 4.4 min, respectively) and had elimination half-lives of 136 and 235 min, respectively. There was a rapid uptake of both drugs by the myocardium, with maximal concentrations at 5 and 15 min. The myocardial concentrations were higher than the respective serum concentrations and declined with time. There was a wide scatter in myocardium-serum ratios, which ranged from 1 to 11 for amiodarone and 12 to 29 for the metabolite. Neither the drug nor the metabolite produced significant changes in the surface electrocardiogram after intravenous administration. These data suggest that accumulation of the metabolite does not account for the slow onset of action of amiodarone.

Amiodarone↗
PubMed1984

Electrophysiologic effects of amiodarone: experimental and clinical observation relative to serum and tissue drug concentrations.

Oral amiodarone is a potent antiarrhythmic agent with a slow onset of action. Its electrophysiologic properties following chronic administration are well known, but its acute electrophysiologic actions are poorly defined. The objectives of the present study were to correlate the electrophysiologic actions of intravenous amiodarone in humans with the acute and chronic effects of the drug relative to plasma and tissue concentrations of the drug. In humans (n = 10), 5 mg/kg intravenous amiodarone (serum concentration 6.50 +/- 3.34 micrograms/ml at 10 minutes; 2.13 +/- 0.71 micrograms/ml at 20 minutes, n = 7) increased the AH interval by 16.4% (p less than 0.005), the antegrade effective refractory period (ERP) of the atrioventricular (AV) node by 14.4% (p less than 0.025), and the functional refractory period (FRP) of the AV node by 15.5% (p less than 0.005). The ERP or FRP of the atrium of the right ventricle was not significantly changed; there was no effect on the HV interval or the QT and R-R intervals of the ECG. In rabbits (n = 11) given 10 mg/kg intravenous amiodarone (mean +/- SD serum concentration 0.49 +/- 0.17 micrograms/ml; mean myocardial concentration 7.0 +/- 1.9 micrograms/gm, n = 3), there were no significant effects on the ECG intervals. In isolated rabbit sinoatrial (SA) node, atria, and AV node (three preparations) superfused with 5 X 10(-6)M amiodarone (3.41 micrograms/ml), there was no effect on the action potential duration (APD) or other parameters of the transmembrane potential.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1984

Amiodarone-digoxin interaction: clinical significance, time course of development, potential pharmacokinetic mechanisms and therapeutic implications.

Administration of amiodarone (600 to 1,600 mg/day) to 28 patients during long-term digoxin therapy (0.25 +/- 0.05 mg/day) increased serum digoxin level from 0.97 +/- 0.45 to 1.98 +/- 0.84 ng/ml (p less than 0.001). Gastrointestinal side effects occurred in nine patients, central nervous system reactions occurred in five and cardiovascular reactions occurred in four. Pharmacokinetic studies in six patients with a 1 mg intravenous digoxin dose before and during amiodarone therapy increased serum digoxin level at 30 minutes from 8.59 +/- 1.68 to 10.07 +/- 1.70 ng/ml (p less than 0.05). Amiodarone caused a 31% prolongation of digoxin elimination half-life from 49.5 +/- 8.8 to 65.0 +/- 28.8 hours, but the increase in half-life was not statistically significant. Total body clearance was reduced significantly (29%, p less than 0.05) from 2.05 +/- 0.76 to 1.46 +/- 0.64 ml/min per kg. Nonrenal clearance also showed a significant decrease (33%, p less than 0.05) from 1.20 +/- 0.46 to 0.80 +/- 0.30 ml/min per kg. The renal clearance decreased by 22% and the volume of distribution decreased by 11% after amiodarone therapy, but these changes were not significant. The data show that the mechanism of digoxin-amiodarone interaction is multifactorial and emphasize the need for close monitoring of serum digoxin levels and clinical features during concurrent digoxin-amiodarone therapy.

Adult↗
PubMed1984

The clinical results of amiodarone in cardiac arrhythmias: optimal dosing.

Amiodarone hydrochloride is a relatively new antiarrhythmic agent, the properties of which differ in a significant manner electrophysiologically, pharmacokinetically and structurally from those of conventional as well as other investigational antidysrhythmic compounds. It is also pharmacologically unique in so far as its fundamental action on cardiac muscle following chronic therapy differs markedly from that found during the intravenous administration; its I.V. action is dominated by the lengthening of intranodal (AV) conduction time and the effective refractory period of the AV node, the electrophysiologic basis for which is unclear but accounts for the slowing of the ventricular response in atrial flutter and fibrillation and the variable conversion rate of narrow QRS reentrant paroxysmal supraventricular tachycardia. Intravenous amiodarone is ineffective in most other arrhythmias; it does not lengthen repolarization, nor does it prolong the effective refractory period of atria, ventricle, His-Purkinje system or the accessory pathways of the heart in the WPW syndrome. In contrast, chronically administered amiodarone lengthens repolarization and the effective refractory period of all cardiac tissues as a function of dose and duration of therapy consistent with its wide spectrum of antiarrhythmic activity in the prophylactic control of supraventricular and ventricular tachyarrhythmias. The nature of the slow onset of action of the oral drug is not well-understood; it may be due to the slow formation of active metabolites or the gradual and selective inhibition of T3 action on the myocardium since the effects of amiodarone on cardiac repolarization are identical to those of hypothyroidism and are negated by the concomitant administration of thyroxine. Serum reverse T3 levels increase as a function of dose and duration of amiodarone therapy and tentative data indicate that serial measurements of rT3 levels may provide a reliable index for gauging efficacy and toxicity of amiodarone during chronic therapy. The role of serum drug and metabolite levels appears less reliable in this regard. The exceedingly long and variable elimination half-life of amiodarone necessitates individualized loading and maintenance dosage regimens, and the latency of onset of antiarrhythmic action during oral therapy is not shortened by intravenous bolus injections or sustained infusions. However, the judicious choice of oral dosage as discussed herein permits the development of an effective prophylactic regimen for most patients with supraventricular and ventricular tachyarrhythmias; when the lowest dosage regimen to control a particular arrhythmia is identified, limiting side

Amiodarone↗
PubMed1984

Liver and adipose tissue contributions to newly formed fatty acids in an ascites tumor.

We determined the contribution from host hepatic and extrahepatic tissues to newly synthesized fatty acids (FA) in the Ehrlich ascites tumor (EAT). We administered 3H2O (subcutaneously) and [14C]glucose (in a test meal) and measured the appearance of radioactivity in plasma triglyceride fatty acids (TGFA) and free fatty acids (FFA) and in tumor total lipid fatty acids (TLFA). Using [14 C]FFA, we selectively labeled epididymal fat TGFA to estimate the FA transport rate from intraperitoneal adipose tissue directly to the tumor. Contributions of four major pathways to newly synthesized FA in EAT were determined by multicompartmental analysis. De novo FA synthesis by EAT accounted for more than 93% of the TLFA radioactivity found in the tumor. Contributions from liver TGFA via plasma TGFA (less than 0.5%), adipose tissue TGFA via plasma FFA (less than 6%), and adipose tissue TGFA via direct intraperitoneal transport of FFA (less than 1%) accounted for less than 7% of all TLFA radioactivity measured in the EAT. Thus the present study establishes that practically all labeled esterified FA in the EAT is derived from de novo synthesis by tumor cells.

Adipose Tissue↗
PubMed1984

Effects of chronic administration of amiodarone on kinetics of metabolism of iodothyronines.

Treatment with amiodarone, an iodinated anti-arrhythmic drug, is associated with increases in serum rT3 and serum L-T4 with a mild variable decrease in T3. We have examined the metabolic basis for these changes by studying the kinetics of metabolism of 125I-labeled iodothyronines in rabbits given amiodarone (20 mg/kg BW) for 3 weeks. The mean +/- SE MCR of rT3 was significantly (P less than 0.05) lower in amiodarone-treated rabbits (1.88 +/- 0.14 liters/day) than that in the control animals (2.72 +/- 0.25 liters/day), with no appreciable changes in the MCR of T3. The mean MCR of T4 was also significantly lower in amiodarone-treated animals than in controls (0.23 +/- 0.03 vs. 0.37 +/- 0.04 liters/day; P less than 0.05). Amiodarone had no significant effect on daily production rates (PRs) of rT3 or T3, but the PR of T4 showed an increase which was significant (P less than 0.05) when expressed per unit BW. The mean +/- SE molar ratio of daily PRs of T3 and T4 was reduced significantly (P less than 0.05) from 0.75 +/- 0.12 in controls to 0.35 +/- 0.06 in drug-treated rabbits. Amiodarone treatment was also associated with a moderate reduction in the ratio of the PRs of rT3 and T4, but the change was not statistically significant. The overall data suggest that amiodarone administration is associated with a reduction in the MCRs of rT3 and T4 and a reduction in monodeiodination of T4 in the outer ring; monodeiodination of T4 in the inner ring either remains unaffected or decreases moderately.

Amiodarone↗
PubMed1982

Elevation of serum lipids after chronic administration of amiodarone in rabbits.

Amiodarone hydrochloride is a potent, iodine-containing antiarrhythmic compound with a long elimination half-life, whose cardiac action appears to be mediated through an interference with thyroxine-dependent pathways in the heart. Whether it has any effect on lipid metabolism is not known. Its effect (20 mg/kg per day intraperitoneally) after 3 and 6 weeks of treatment on changes in serum lipoproteins were studied in male New Zealand white rabbits. Serum amiodarone levels reached a steady state (approximately 0.05 microgram/ml) after 3 weeks, and serum reverse T3 (an index of drug dose and duration of treatment) increased 3-4 fold by 3 and 6 weeks. In two discrete sets of studies, serum triglyceride (TG) and total cholesterol (CHOL) increased significantly (P less than 0.01) after 3 and 6 weeks on amiodarone when compared to the values in a control series of animals. Phospholipid (PL) levels were not changed. Very low density lipoproteins (VLDL) in the drug-treated groups showed a significant increase in triglyceride (P less than 0.01) and in apoprotein B (P less than 0.05). There was no change in low density lipoprotein-apoprotein B levels. Whether the abnormalities observed in serum lipids induced by amiodarone are mediated through changes in thyroid hormones or occur as a result of a direct effect on lipid metabolism is unknown, but the problem merits further investigation.

Amiodarone↗
PubMed1982

Amiodarone kinetics after oral doses.

Amiodarone serum kinetics after single oral doses and after long-term therapy were investigated in patients with ventricular tachyarrhythmias. When amiodarone was given as a single oral dose (1400 to 1800 mg, n = 6), serum levels of amiodarone and its metabolite, measured by high-performance liquid chromatography, correlated (r = 0.69, P less than 0.01). Peak concentrations (amiodarone, 3 to 14 microgram/ml; metabolite, 0.7 microgram/ml) were attained in 4.9 +/- 1.2 hr. Using computer fits to the data, amiodarone mean elimination rate constant and half-life (t 1/2 e) were 0.128 +/- 0.063 hr-1 and 7.2 +/- 5.0 hr. In 12 patients given a mean dose of 1327 +/- 338 mg/day of amiodarone for 4.1 +/- 2.3 wk, mean serum amiodarone level was 3.84 +/- 2.92 microgram/ml (range 0.92 to 11.99); in three patients simultaneous determination of concentrations of amiodarone and its metabolite revealed that concentration of the latter was about 50% of that of the parent drug during long-term therapy. In four patients on maintenance therapy (400 to 800 mg/day, serum level 1.08 +/- 1.3 microgram/ml) drug was discontinued and serum amiodarone levels were determined serially. Serum drug disappearance followed a single exponential function with an elimination rate constant of 0.030 +/- 0.012 day-1 and t 1/2 e of 29 +/- 19 days. Our kinetic data are consistent with the long therapeutic amiodarone t 1/2 noted in the treatment of cardiac arrhythmias.

Administration, Oral↗
PubMed1981

Hepatic contribution to newly made fatty acids in adipose tissue in rats and inhibition of hepatic and extrahepatic lipogenesis from glucose by dietary corn oil.

We have reexamined an earlier rat study in which the authors concluded that 60 min after [U-14C]-glucose injection half of labeled fatty acids found in adipose tissue had been made in liver and then transported to the adipose tissue. We have shown that even under conditions in which the lipogenic role of the liver is optimized (fed-refed rats on a fat-free, high-carbohydrate diet), almost none of the labeled fatty acids found in adipose tissue of rats 60 min after they were fed a labeled glucose test meal was derived from the liver. This conclusion was based experimentally on (a) the use of the blocking agent Triton WR 1339 to measure the total labeled triglyceride fatty acids (TGFA) synthesized and secreted by the liver in 60 min and (b) comparison of plasma TGFA-14C data with radioactivity found in liver and in adipose tissue in 60 min. Without using Triton WR 1339, mathematical, analysis of plasma TFGA-14C following the glucose test-meal leads one to the same conclusion: 97% of 14C-labeled fatty acids found in adipose tissue at 60 min was made in situ. Additional studies in rats established that the source of error in the earlier studies was an incorrect assumption that dietary corn oil could inhibit hepatic lipogenesis from glucose C without inhibiting fatty acid synthesis in adipose tissue. In our studies, 10% corn oil inhibited equally both hepatic and adipose tissue fatty acid synthesis from glucose C under conditions that precluded any significant transport of labeled TGFA-14C from liver to adipose tissue.

Adipose Tissue↗