Vasant Ranade

Effect of angiotensin-converting enzyme therapy on QT interval dispersion.

Patients with chronic heart failure (CHF) have an increased risk for sudden death. This increased risk has been associated with increased QT dispersion (QTd), a reflection of the heterogeneity in ventricular repolarization. Angiotensin-converting enzyme (ACE) inhibitors have been reported to decrease heart size as well as decreasing morbidity and mortality in moderate-to-severe CHF. The aim of this study was to determine if ACE therapy is associated with a decrease in QTd, a marker for increased electrical instability. Ninety-seven patients were evaluated. The normalized QTd after 2 months of ACE therapy decreased from 16 +/- 4 to 12 +/- 3, a 25% reduction in dispersions. QTd also decreased from 61 +/- 14 to 47 +/- 12 (P < .001) and QTc dispersions decreased from 71 +/- 18 to 52 +/- 14 (P < .001). After 2 months of ACE inhibitor therapy, heart rate slowed significantly (RR intervals 765 +/- 198 before and 838 +/- 186 after ACE). There was a negative correlation between ejection fraction and QTd (r = -0.8; P < .001). The study also found no correlation between ACE level, percent converting enzyme inhibition, and QTd. The effects of ACE therapy appear early on in terms of repolarization changes. The reduction in QTd may explain the reduced sudden death mortality in patients with heart failure who are treated with ACE inhibitor therapy.

Microarrays and microneedle arrays for delivery of peptides, proteins, vaccines and other applications

Introduction: Peptide and protein microarray and microneedle array technology provides direct information on protein function and potential drug targets in drug discovery and delivery. Because of this unique ability, these arrays are well suited for protein profiling, drug target identification/validation and studies of protein interaction, biochemical activity, immune responses, clinical prognosis and diagnosis and for gene, protein and drug delivery. Areas covered: The aim of this review is to describe and summarize past and recent developments of microarrays in their construction, characterization and production and applications of microneedles in drug delivery. The scope and limitations of various technologies in this respect are discussed. Expert opinion: This article offers a review of microarray/microneedle technologies and possible future directions in targeting and in the delivery of pharmacologically active compounds for unmet needs in biopharmaceutical research. A better understanding of the production and use of microarrays and microneedles for delivery of peptides, proteins and vaccines is needed.

QT prolongation and serum sotalol concentration are highly correlated following intravenous and oral sotalol.

Objectives: The aim of this study was to evaluate the correlation between QT interval (QT) and serum sotalol concentration following a single low dose of oral and intravenous sotalol. Methods: Fifteen healthy volunteers received 75 mg intravenous sotalol over 2.5 h and 80 mg oral sotalol in a random order. Serum sotalol concentrations and 12-lead electrocardiograms were obtained simultaneously at baseline and 7 times following dosings. Rate-corrected QT (QTc) was calculated by the Bazett, Fridericia and Framingham formulas. Linear regression analysis was performed between sotalol concentrations and QT measurements. Results: Significant QT prolongation was seen at very low sotalol doses and serum concentrations. QTc intervals calculated by the Framingham and Fridericia formulas showed the strongest and virtually identical correlations with serum sotalol concentration (r ≧ 0.97, p < 0.001) following oral and intravenous administrations. The equation QTc = 0.0342 (sotalol concentration) + 398 closely predicted actual QTc at any sotalol concentration. Conclusions: A strong correlation was observed between serum sotalol concentration and QTc prolongation across the entire concentration range. Low-dose sotalol caused significant QT prolongation. At similar concentrations, intravenous and oral sotalol caused similar QT and QTc effects. Knowing the QT effect can be used to guide further dose increase.

Comparative Effects of Rapid Bolus Administration of Aqueous Amiodarone Versus 10-Minute Cordarone I.V. Infusion on Mean Arterial Blood Pressure in Conscious Dogs

Objective: This study was designed to test the hypothesis that rapid bolus administration of an aqueous formulation of intravenous amiodarone causes less hypotension than a 10-minute infusion of the standard formulation, Cordarone IV. Hypotension was the most common adverse event reported with Cordarone IV. The hypotension was not dose related, but related to the rate of infusion. Therefore, product labeling calls Cordarone and its generic formulations to be administered over 10 minutes. Cordarone IV contains polysorbate 80 and benzyl alcohol, each causes hypotension. A new aqueous formulation of amiodarone (Amio-Aqueous) does not contain these agents and therefore may cause less hypotension.Methods: Six conscious beagle dogs were instrumented with a telemetric device for blood pressure monitoring. The study was conducted on 5 days. On the first 2 days, a 10-min infusion or a bolus of D5W was administered (placebo). Over the following 3 days, the dogs received (in randomized order, one per day) a 10-min infusion of 2.5 mg/kg Cordarone IV and boluses of 2.5 mg/kg and 5.0 mg/kg Amio-Aqueous injected over 2 to 5 sec. The dogs were monitored for 2 hrs after dosing.Results: Compared to placebo, boluses of aqueous amiodarone produced no significant changes in the mean arterial blood pressure (MABP). In contrast, Cordarone infusion produced significant decreases in MABP that lasted for at least 2 hrs (p < 0.001).Conclusion: Amio-Aqueous had significantly better hemodynamic profile permitting rapid intravenous administration. This is a significant advantage over the standard formulation, because Cordarone cannot be administered by rapid bolus due to excipient-related hypotension.

Gender Differences in Cardiac Repolarization Following Intravenous Sotalol Administration

Background: Females are more susceptible to drug-induced torsade de pointes (TdP), which is associated with excessive prolongation of the heart rate-corrected QT interval (QTc). Sotalol prolongs the cardiac action potential that can be observed as QT prolongation and can induce TdP. The aim of this study was to assess gender differences in sotalol-induced QTc prolongation. Methods: A total of 15 healthy volunteers, 9 female and 6 male (age: 32 ± 8 years) received 75 mg intravenous sotalol over 2.5 hours at a constant infusion rate. A 12-lead electrocardiograph (ECG) was recorded at baseline, 0.5, 1, 2, 3, 4, and 5 hours following the start of the infusion, and blood samples were collected simultaneously. QTc was calculated by the Fridericia and Framingham formulas. The 2 formulas resulted in virtually identical QTc intervals. The data analysis included repeated measures of analysis of variance (ANOVA), univariate analysis, and linear regression analysis. Results: The longest average QTc intervals were observed at 2 hours of sotalol infusion in both genders. Compared to baseline, the increase was very significant in females (411 ± 13 vs 438 ± 13 ms, P < .001), while it was less significant in males (395 ± 23 vs 413 ± 27 ms, P < .05). The magnitude of individual changes from baseline were greater in females than in males (34 ± 8 vs 21 ± 12 ms, P < .05). In each gender, QTc and serum sotalol concentration strongly correlated (r = .93, P < .001). An upward shift of the regression line in females indicates a longer QTc at any concentration level. Males had greater body weight and body surface area than females (P < .05) but neither correlated with QTc or predicted QTc prolongation. The univariate analysis indicated that the single predictor for the greater QTc prolongation was female gender. Conclusion: Females had greater QTc prolongation than males following sotalol administration. This enhanced response to drug action may explain the higher incidence of drug-induced TdP seen in females.

Pharmacology and toxicology of a new aqueous formulation of intravenous amiodarone (Amio-Aqueous) compared with Cordarone IV.

Hypotension is the most frequent adverse event reported with intravenous amiodarone (Cordarone IV). The hypotension has been attributed to the vasoactive solvents of the formulation, polysorbate 80 and benzyl alcohol, both known to exhibit negative inotropy and hypotensive effect. A new aqueous formulation of intravenous amiodarone (Amio-Aqueous) does not contain vasoactive excipients and may be less toxic and cause less hypotension than Cordarone IV. This hypothesis was tested in a series of animal studies with direct comparison of Amio-Aqueous and Cordarone IV. All studies were performed on Sprague-Dawley rats. The acute toxicology study showed that both LD50 and LD100 were 30% greater for Amio-Aqueous than for Cordarone. At the dose at which all animals expired on Cordarone, 50% of animals were still alive on Amio-Aqueous. The study on myocardial contractility showed that Amio-Aqueous was a far less negative inotropic than Cordarone IV (P < 0.001). Amio Aqueous did not have an effect on contractility at 5- and 10-mg/kg dose levels while Cordarone resulted in a 25% (P < 0.01) and 29% (P < 0.002) decrease, respectively. The study on arterial blood pressure showed that Cordarone caused a significant decrease in blood pressure at each of the 3, 5, 10, and 20 mg/kg doses (P < 0.05 to P < 0.001) while Amio-Aqueous did not. The study on the antiarrhythmic effects showed comparable efficacy for both formulations. In conclusion, Cordarone IV was more toxic and caused significant hypotension and negative inotropy while Amio-Aqueous lacked the hypotensive and cardiotoxic properties of Cordarone. Therefore, Amio-Aqueous is a safer alternative than the standard formulation.

The Additive Effects of the Active Component of Grapefruit Juice (Naringenin) and Antiarrhythmic Drugs on HERG Inhibition

Background: Grapefruit juice causes significant QT prolongation in healthy volunteers and naringenin has been identified as the most potent human ether-a-go-go-related gene (HERG) channel blocker among several dietary flavonoids. The interaction between naringenin and IKr-blocking antiarrhythmic drugs has not been studied. We evaluated the effect of combining naringenin with IKr-inhibiting antiarrhythmic drugs on cardiac IKr. Methods and Results:IKr current was studied by using HERG expressed in Xenopus oocytes, and the two-electrode voltage clamp technique was employed. Antiarrhythmic drugs (azimilide, amiodarone, dofetilide and quinidine) were tested. Experiments were performed at room temperature. Naringenin blocked HERG current dose dependently with an IC50 of 173.3 ± 3.1 µM. Naringenin 100 µM alone inhibited HERG current by 31 ± 6%, and this inhibitory effect was increased with coadministration of 1 or 10 µM antiarrhythmic drugs. When 100 µM naringenin was added to antiarrhythmic drugs, greater HERG inhibition was demonstrated, compared to the current inhibition caused by antiarrhythmic drugs alone. Addition of naringenin significantly increased current inhibition (p < 0.05). Conclusions: There is an additive inhibitory effect on HERG current when naringenin is combined with IKr-blocking antiarrhythmic drugs. This additive HERG inhibition could pose an increased risk of arrhythmias by increasing repolarization delay and possible repolarization heterogeneity.

Hypercalcemia, arrhythmia, and mood stabilizers

Recent findings in a bipolar patient receiving maintenance lithium therapy who developed hypercalcemia and severe bradyarrhythmia prompted the authors to conduct a retrospective study of bipolar patients with lithium-associated hypercalcemia. A printout of all cases of hypercalcemia that presented during a 1-year period was generated. After eliminating spurious hypercalcemias or those associated with intravenous fluids, the authors identified 18 non-lithium-treated patients with hypercalcemias related to malignancies and other medical conditions (group A) and 12 patients with lithium-associated hypercalcemia (group B). Patients in group B were not comparable to those in group A, as the latter were medically compromised and were receiving multiple pharmacotherapies. Thus, two control groups were generated: group C1, which included age- and sex-comparable lithium-treated bipolar normocalcemic patients, and group C2, which included bipolar normocalcemic patients treated with anticonvulsant mood stabilizers. The electrocardiographic (ECG) findings for patients in group B were compared with those of patients in groups C1 and C2. It was found that these groups did not differ in their overall frequency of ECG abnormalities; however, there were significant differences in the frequency of conduction defects. Patients with hypercalcemia resulting from medical diseases and bipolar patients with lithium-associated hypercalcemia had significantly higher frequencies of conduction defects. Patients in group A had significant mortality at 2-year follow-up (28%), in contrast to zero mortality in the other three groups. The clinical implications of these findings are discussed.

Chiral cardiovascular drugs : An overview

Stereochemistry in drug molecules is rapidly becoming an important aspect in drug research, design, and development. Recently, individual stereoisomers of drug molecules with asymmetric centers such as fexofenadine, cetirizine, verapamil, fluoxetine, levalbutarol, and amphetamine, for example, have been separated and developed as individual drugs. These stereoisomers have different therapeutic activity, and each isomer has contributed differently with respect to its formulations pharmacologic activity, side effects, and toxicity. The present overview discusses chirality among a select group of cardiovascular drugs, their stereochemical synthesis/preparation, isolation techniques using chiral chromatography, methods for confirmation of their enantiomeric purity, pharmacodynamics, and pharmacokinetics. Chirality has been visualized as an important factor in cardiovascular research. It is also becoming evident in other areas of therapeutics.

Developing a Safe Intravenous Sotalol Dosing Regimen

Recently, an intravenous formulation of sotalol has been approved by the food and drug administration for substitution for oral therapy in patients who are unable to take oral sotalol. The purpose of this randomized, 2-treatment, 2-period, crossover study was to develop a safe dosing regimen for intravenous sotalol that provides similar blood levels and therefore similar efficacy and safety to orally administered sotalol. Fifteen healthy subjects received 75 mg intravenous sotalol infusion administered over 2.5 hours and 80 mg oral sotalol. Standard pharmacokinetic methods were used to obtain maximum serum concentrations (Cmax) and areas under the concentration-time curves (AUC). Individual pharmacokinetic parameters were used in simulation studies to determine the optimal intravenous administration regimen. Intravenous sotalol administered over 2.5 hours resulted in a significantly greater Cmax than oral administration (830 ± 391 vs. 601 ± 289 ng/mL, P < 0.001). With increasing the length of infusions to 3, 4, and 5 hours, simulation studies showed that the Cmax decreased to 128%, 113%, and 102% of the oral Cmax. The length of infusion did not affect AUC. Based on these studies, a safe intravenous regimen for the replacement of 80-mg oral therapy requires 75 mg intravenous sotalol administered as a 5-hour infusion. Because the pharmacokinetics of sotalol are linear and dose proportional, 150 mg intravenous sotalol administered over 5 hours will provide similar Cmax and AUC as 160 mg oral sotalol. The food and drug administration-approved dosing regimen is 75 mg intravenous sotalol to replace 80 mg oral sotalol and 150 mg intravenous sotalol to replace 160 mg oral sotalol, both administered over 5 hours.