Atenolol blunts blood pressure increase during dynamic resistance exercise in hypertensives

AIMS

This study was conducted to determine whether atenolol was able to decrease BP level and mitigate BP increase during dynamic resistance exercise performed at three different intensities in hypertensives.

METHODS

Ten essential hypertensives (systolic/diastolic BP between 140/90 and 160/105 mmHg) were blindly studied after 6 weeks of placebo and atenolol. In each phase, volunteers executed, in a random order, three protocols of knee-extension exercises to fatigue: (i) one set at 100% of 1 RM; (ii) three sets at 80% of 1 RM; and (iii) three sets at 40% of 1 RM. Intra-arterial radial blood pressure was measured throughout the protocols.

RESULTS

Atenolol decreased systolic BP maximum values achieved during the three exercise protocols (100% = 186 ± 4 vs. 215 ± 7, 80% = 224 ± 7 vs. 247 ± 9 and 40% = 223 ± 7 vs. 252 ± 16 mmHg, P < 0.05). Atenolol also mitigated an increase in systolic BP in the first set of exercises (100% =+38 ± 5 vs.+54 ± 9; 80% =+68 ± 11 vs. +84 ± 13 and 40% =+69 ± 7 vs.+84 ± 14, mmHg, P < 0.05). Atenolol decreased diastolic BP values and mitigated its increase during exercise performed at 100% of 1 RM (126 ± 6 vs. 145 ± 6 and +41 ± 6 vs.+52 ± 6, mmHg, P < 0.05), but not at the other exercise intensities.

CONCLUSIONS

Atenolol was effective in both reducing systolic BP maximum values and mitigating BP increase during resistance exercise performed at different intensities in hypertensive subjects.     

Effects of amiodarone in a swine model of nortryptiline toxicity

Objectives

Antiarrhythmics can have devastating effects in cardiotoxic poisonings. Amiodarone is recommended for treatment of wide complex tachycardia, but its hemodynamic effects in wide complex tachycardia induced by tricyclic antidepressant poisoning are unknown. The objective of this study was to compare the effects of sodium bicarbonate, amiodarone, and normal saline in treating wide complex tachycardia secondary to nortriptyline poisoning.

Methods

This unblended randomized controlled animal study involved 18 anesthetized, intubated pigs with arterial and venous lines. Nortriptyline (2 mg/mL) was infused at 20 mg/min until the onset of toxicity, defined as a systolic blood pressure ≤50 mmHg or QRS ≥120 ms. At that point, the pigs were randomized into three groups of six. Group I received 0.9% normal saline, 10 ml/kg. Group II received hypertonic sodium bicarbonate, 1 mEq/kg. Group III received amiodarone, 15 mg/kg. The pigs were observed until death or survival at 60 minutes.

Results

After treatment, the changes in QRS were as follows: Group I, −2.0 ms; Group II, −33.0 ms; Group III, −21.7 ms. ANOVA demonstrated no significant difference between the groups (p = 0.28). Mean arterial pressures 10 minutes after treatment were as follows: Group I, 19.4 mmHg; Group II, 23.7 mmHg; Group III, 12.5 mmHg. Based on ANOVA, there was no significant difference between any of the groups (p = 0.50).

Conclusions

In this model of nortriptyline poisoning, the administration of amiodarone to correct wide complex tachycardia did not have a harmful effect.     

Time-dependent interactions of the hypotensive effects of sildenafil citrate and sublingual glyceryl trinitrate

AIM

To investigate the time course of the hypotensive interaction between sildenafil and glyceryl trinitrate (GTN).

METHODS

Two double-blind, placebo-controlled, randomized, crossover studies were performed. Subjects were challenged with sublingual GTN 400 µg at different times after oral sildenafil 100 mg. After each GTN challenge frequent measures of blood pressure (BP) were made. In the first study GTN was given 1–48 h after sildenafil/placebo to 33 healthy men. In the second study GTN was given 1–8 h after sildenafil/placebo to 20 men with stable angina.

RESULTS

In healthy men there was a greater mean maximum reduction in BP with sildenafil/GTN than with placebo/GTN only at 1 h. In angina patients, there was a greater mean maximum reduction in BP with sildenafil/GTN than with placebo/GTN for up to 8 h. The mean (95% confidence interval) differences in maximum systolic BP reduction (mmHg) at 1, 4, 6 and 8 h were −16 (−12, −21), −12 (−4, −20), −6 (1, −12) and −9 (−3, −15), all P < 0.05 except at 6 h (NS). At 6 and 8 h the interaction was not more than additive, and hypotensive symptoms did not occur.

CONCLUSIONS

In men with angina there is an interaction on BP reduction between sildenafil and GTN for ≥ 8 h after sildenafil administration, but this is no more than additive from 6 h. These data may be helpful to clinicians who are considering the use of GTN in patients presenting with angina who have received sildenafil within 24 h.     

Clinically relevant QTc prolongation due to overridden drug–drug interaction alerts: a retrospective cohort study

AIMS

To investigate whether, in patients in whom drug–drug interaction (DDI) alerts on QTc prolongation were overridden, the physician had requested an electrocardiogram (ECG), and if these ECGs showed clinically relevant QTc prolongation.

METHODS

For all patients with overridden DDI alerts on QTc prolongation during 6 months, data on risk factors for QT prolongation, drug class and ECGs were collected from the medical record. Patients with ventricular pacemakers, patients treated on an outpatient basis, and patients using the low-risk combination of cotrimoxazole and tacrolimus were excluded. The magnitude of the effect on the QTc interval was calculated if ECGs before and after overriding were available. Changes of the QTc interval in these cases were compared with those of a control group using one QTc-prolonging drug.

RESULTS

In 33% of all patients with overridden QTc alerts an ECG was recorded within 1 month. ECGs were more often recorded in patients with more risk factors for QTc prolongation and with more QTc overrides. ECGs before and after the QTc override were available in 29% of patients. Thirty-one percent of patients in this group showed clinically relevant QTc prolongation with increased risk of torsades de pointes or ventricular arrhythmias. The average change in QTc interval was +31 ms for cases and −4 ms for controls.

CONCLUSIONS

Overriding the high-level DDI alerts on QTc prolongation rarely resulted in the preferred approach to subsequently record an ECG. If ECGs were recorded before and after QTc overrides, clinically relevant QTc prolongation was found in one-third of cases. ECG recording after overriding QTc alerts should be encouraged to prevent adverse events.     

Assessment of the cardiac safety of prucalopride in healthy volunteers: a randomized, double-blind, placebo- and positive-controlled thorough QT study

AIMS

To assess steady-state effects of therapeutic and supra-therapeutic doses of prucalopride on the QT interval using a novel design involving a parallel placebo group with nested crossover for positive control.

METHODS

A double-blind, double-dummy, placebo- and active-controlled study was conducted in 120 healthy male and female volunteers ({"type":"clinical-trial","attrs":{"text":"NCT00903747","term_id":"NCT00903747"}}NCT00903747). Volunteers were randomized to receive prucalopride 2–10 mg once daily (therapeutic and supratherapeutic doses, respectively) (group 1), placebo with 400 mg moxifloxacin on day 1 (group 2a), or placebo with moxifloxacin on day 15 (group 2b). Twelve-lead 24 h Holter ECGs recorded at various time-points were evaluated blind and centrally.

RESULTS

Estimated mean difference in study specific corrected QT interval (QT_cSS) time-matched change from baseline between prucalopride (2 and 10 mg) and placebo was <5 ms at all time points (maximum mean difference: 3.83 ms at 3.5 h post dose on day 5 with 2 mg [90% Cl −0.33, 6.38 ms]). Upper limits of the two-sided 90% CI for QT_cSS were all <10 ms. There were no outlying QT_cSS values >450 ms and no subjects had an increase >60 ms following prucalopride. Moxifloxacin produced the expected significant changes in QT_cSS (>5 ms, maximum of +12.7 ms at 5 h post dose) at all time-points except 1 h post dose. Prucalopride resulted in small increases in heart rate (maximum of 5.8 beats min^–1), which were similar for 2 and 10 mg. Prucalopride was well tolerated after first day of treatment.

CONCLUSION

Prucalopride at both therapeutic and supra therapeutic doses has no clinically significant effects on cardiac repolarisation in healthy volunteers.     

Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjects

AIM

To characterize the effects of lamotrigine on QT interval in healthy subjects.

METHODS

Healthy subjects received a single oral dose of moxifloxacin (400 mg) or placebo in crossover design, followed by a dose-escalating regimen of lamotrigine (n = 76) over a 77-day period, or matched placebo (n = 76). Blood samples were taken for determination of moxifloxacin and lamotrigine concentrations and digital 12-lead ECGs were recorded. The relationships between individual QT values and respective individual moxifloxacin or lamotrigine concentrations were explored using population pharmacokinetic–pharmacodynamic (PK–PD) modelling.

RESULTS

Moxifloxacin was associated with a maximum mean increase from baseline in QTcF of 14.81 ms [90% confidence interval (CI) 13.50, 16.11] 2.5 h after dosing. Steady-state exposure to lamotrigine (50, 150 or 200 mg b.d.) was not associated with an increase in QTc interval. Small reductions in QTcF (maximum mean difference from placebo −7.48 ms, 90% CI −10.49, −4.46) and small increases in heart rate (maximum mean difference from placebo 5.94 bpm, 90% CI 3.81, 8.06) were observed with lamotrigine 200 mg b.d. vs. placebo. No effect of lamotrigine on QRS duration or blood pressure was observed. No outliers with QTcF > 450 ms, or with an increase from baseline of >60 ms were observed in the lamotrigine group. PK–PD modelling indicated statistically significant decreases in individually corrected QT intervals for lamotrigine and statistically significant increases in individually corrected QT intervals for moxifloxacin over the concentration ranges studied.

CONCLUSIONS

Therapeutic doses of lamotrigine (50–200 mg b.d.) were not associated with QT prolongation in healthy subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Drugs that inhibit the human cardiac delayed rectifier potassium current may lead to prolongation of the cardiac QT interval and are associated with a fatal, polymorphic, ventricular tachycardia known as torsades de pointes.
• Lamotrigine is indicated in the treatment of epilepsy and the prevention of mood episodes in patients with bipolar disorder.
• Lamotrigine inhibits the human cardiac delayed rectifier potassium current in vitro, and it has been hypothesized that QT prolongation may contribute to the risk of sudden unexpected death in epilepsy patients.

WHAT THIS STUDY ADDS

• This is the first reported thorough QT/QTc study with lamotrigine conducted to International Conference on Harmonization guidelines.
• The mean QTc interval was not prolonged by lamotrigine in healthy subjects, as assessed by the standard heart rate correction methods (Fridericia''s and Bazett''s).
• The in vitro inhibition of the delayed rectifier potassium current does not translate into an effect on QT in man.

     

High dose droperidol and QT prolongation: analysis of continuous 12-lead recordings

Aims

To investigate the QT interval after high dose droperidol using continuous 12-lead Holter recordings.

Methods

This was a prospective study of patients given droperidol with a continuous Holter recording. Patients were recruited from the DORM II study which included patients with aggression presenting to the emergency department. Patients initially received 10 mg droperidol as part of a standardized sedation protocol. An additional 10 mg dose was given after 15 min if required and further doses at the clinical toxicologist''s discretion. Continuous 12-lead Holter recordings were obtained for 2–24 h utilizing high resolution digital recordings with automated QT interval measurement. Electrocardiograms were extracted hourly from Holter recordings. The QT interval was plotted against heart rate (HR) on the QT nomogram to determine if it was abnormal. QT_cF (Fridericia''s HR correction) was calculated and >500 ms was defined as abnormal.

Results

Forty-six patients had Holter recordings after 10–40 mg droperidol and 316 QT–HR pairs were included. There were 32 abnormal QT measurements in four patients, three given 10 mg and one 20 mg. In three of the four patients QT_cF >500 ms but only in one taking methadone was the timing of QT_cF >500 ms consistent with droperidol dosing. Of the three other patients, one took amphetamines, one still had QT prolongation 24 h after droperidol and one took a lamotrigine overdose. No patient given >30 mg had a prolonged QT. There were no arrhythmias.

Conclusion

QT prolongation was observed with high dose droperidol. However, there was little evidence supporting droperidol being the cause and QT prolongation was more likely due to pre-existing conditions or other drugs.     

Investigation of mechanism of drug-induced cardiac injury and torsades de pointes in cynomolgus monkeys

BACKGROUND AND PURPOSE

Drug candidates must be thoroughly investigated for their potential cardiac side effects. During the course of routine toxicological assessment, the compound RO5657, a CCR5 antagonist, was discovered to have the rare liability of inducing torsades de pointes (polymorphic ventricular arrhythmia) in normal, healthy animals. Studies were conducted to determine the molecular mechanism of this arrhythmia.

EXPERIMENTAL APPROACH

Toxicological effects of repeat dosing were assessed in naïve monkeys. Cardiovascular effects were determined in conscious telemetry-implanted monkeys (repeat dosing) and anaesthetized instrumented dogs (single doses). Mechanistic studies were performed in guinea-pig isolated hearts and in cells recombinantly expressing human cardiac channels.

KEY RESULTS

In cynomolgus monkeys, RO5657 caused a low incidence of myocardial degeneration and a greater incidence of ECG abnormalities including prolonged QT/QTc intervals, QRS complex widening and supraventricular tachycardia. In telemetry-implanted monkeys, RO5657 induced arrhythmias, including torsades de pointes and in one instance, degeneration to fatal ventricular fibrillation. RO5657 also depressed both heart rate (HR) and blood pressure (BP), with no histological evidence of myocardial degeneration. In the anaesthetized dog and guinea-pig isolated heart studies, RO5657 induced similar cardiovascular effects. RO5657 also inhibited Kv11.1 and sodium channel currents.

CONCLUSIONS AND IMPLICATIONS

The molecular mechanism of RO5657 is hypothesized to be due to inhibition of cardiac sodium and Kv11.1 potassium channels. These results indicate that RO5657 is arrhythymogenic due to decreased haemodynamic function (HR/BP), decreased conduction and inhibition of multiple cardiac channels, which precede and are probably the causative factors in the observed myocardial degeneration.     

The effects of sitaxentan on sildenafil pharmacokinetics and pharmacodynamics in healthy subjects

AIMS

This study evaluated the effects of sitaxentan on the pharmacodynamic [systemic blood pressure (BP)] and pharmacokinetic (PK) parameters of sildenafil in healthy volunteers.

METHODS

Healthy subjects (18–60 years, n= 24) were randomized into two sequence groups. Group 1 received sitaxentan sodium 100 mg daily (7 days), followed by placebo (7 days). Group 2 received placebo (7 days), followed by sitaxentan sodium 100 mg (7 days). On day 7 of each treatment period, participants received sildenafil 100 mg. PK parameters and BP were analysed on day 7 in each treatment period.

RESULTS

Sildenafil exposure was slightly higher [AUC_∞ geometric mean ratio (GMR), 128%] when co-administered with sitaxentan 100 mg vs. placebo, demonstrating a weak, but statistically significant interaction (90% confidence interval 115.5%, 141.2%). The mean maximum positive (E_max+) and maximum negative (E_max–) changes from baseline in both systolic and diastolic BP were comparable for sitaxentan and placebo (range 4.8–7.3 mmHg) with three of four geometric mean ratios falling within the equivalence window, suggesting that the drug interaction was not clinically significant. Adverse events were similar between sitaxentan 100 mg (39%) and placebo (30%). No deaths or serious adverse events occurred during the study.

CONCLUSION

The dose of sildenafil does not need to be adjusted when co-administered with sitaxentan.     

The Electro-Mechanical window: a risk marker for Torsade de Pointes in a canine model of drug induced arrhythmias

BACKGROUND AND PURPOSE

In cardiovascular pharmacology, electrical and mechanical events can be distinguished, and the phrase ‘electro-mechanical window’ (EMw) describes the temporal difference between these events. We studied whether changes in EMw have potential predictive value for the occurrence of arrhythmias in fentanyl/etomidate-anaesthetized beagle (FEAB) dogs.

EXPERIMENTAL APPROACH

The EMw was calculated as differences between the QT interval and QLVP_end in FEAB dogs during atrial pacing, treatment with isoprenaline or atropine, body temperature changes and induction of Torsade de Pointes (TdP) in an LQT1 model.

KEY RESULTS

The electrical systole (QT interval) was shorter than the duration of the mechanical event (QLVP_end), providing a positive EMw. Atrial pacing, atropine or body temperature changes had no major effects on EMw, despite large changes in QT duration. However, β-adrenoceptor stimulation (with isoprenaline) decreased the EMw (from 90 to 5 ms) and in combination with HMR1556, a blocker of the slowly activating potassium current (I_Ks), induced a large negative EMw (−109 ms) and TdP. Prevention of TdP by atenolol or verapamil was associated with a less negative EMw (−23 to −16 ms). Mexiletine, a poorly effective long QT treatment, did not affect the EMw or prevent TdP induction.

CONCLUSIONS AND IMPLICATIONS

The EMw is a marker, other than QT prolongation, of TdP risk in the FEAB model. Therefore, we suggest examining the EMw as a risk marker in cardiovascular safety studies and as a potential biomarker to improve clinical management of long QT syndrome patients, especially in patients with borderline QT prolongation.

LINKED ARTICLE

This article is commented on by Vargas, pp. 1441–1443 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.00980.x     

Effect of experimental hyperlipidaemia on the electrocardiographic effects of repeated doses of halofantrine in rats

BACKGROUND AND PURPOSE

Halofantrine can cause a prolongation of the cardiac QT interval, leading to serious ventricular arrhythmias. Hyperlipidaemia elevates plasma concentration of halofantrine and may influence its tissue uptake. The present study examined the effect of experimental hyperlipidaemia on QT interval prolongation induced by halofantrine in rats.

EXPERIMENTAL APPROACH

Normolipidaemic and hyperlipidaemic rats (induced with poloxamer 407) were given 4 doses of halofantrine (i.v., 4–40 mg·kg⁻¹·d⁻¹) or vehicle every 12 h. Under brief anaesthesia, ECGs were recorded before administration of the vehicle or drug and 12 h after the first and last doses. Blood samples were taken at the same time after the first and last dose of halofantrine. Hearts were also collected 12 h after the last dose. Plasma and heart samples were assayed for drug and desbutylhalofantrine using a stereospecific method.

KEY RESULTS

In the vehicle group, hyperlipidaemia by itself did not affect the ECG. Compared to baseline, QT intervals were significantly higher in both normolipidaemic and hyperlipidaemic rats after halofantrine. In hyperlipidaemic rats, plasma but not heart concentrations of the halofantrine enantiomers were significantly higher compared to those in normolipidaemic rats. Despite the lack of difference in the concentrations of halofantrine in heart, QT intervals were significantly higher in hyperlipidaemic compared to those in normolipidaemic rats.

CONCLUSIONS AND IMPLICATIONS

The unbound fraction of halofantrine appeared to be the controlling factor for drug uptake by the heart. Our data suggested a greater vulnerability to halofantrine-induced QT interval prolongation in the hyperlipidaemic state.     

Assessment of QTc-prolonging potential of BX471 in healthy volunteers. A 'thorough QTc study' following ICH E14 using various QT correction methods

AIMS

Within the framework of the clinical development of BX471, this study was intended to provide experience in conducting ‘thorough QT_c studies’ according to ICH E14. A broad range of QT correction methods and analysis strategies was employed.

METHODS

A double-blind, placebo- and positive-controlled, single-centre, three-way cross-over study was conducted in 74 healthy volunteers. Electrocardiograms were read by blinded experts. QT correction methods included Bazett''s (QT_cB), Fridericia''s (QT_cF) and several regression-based corrections.

RESULTS

There was a significant QT_cF prolongation of 10.26 ms by the positive control compared with placebo [95% confidence interval (7.83, 12.70)]. BX471 at therapeutic doses did not cause substantial QT_c prolongation [QT_cF estimate 2.93 ms, 95% confidence interval (1.00, 4.86); QT_cB estimate 3.30 ms, 95% confidence interval (0.85, 5.74)]. Regression-based QT correction methods yielded similar results to Fridericia''s correction [e.g. using a linear regression across the study population, QT_c estimate 2.39 ms, 95% confidence interval (0.55, 4.23)]. Differences between the various regression-based correction methods were small. Results were not affected by whether the QT corrections were performed per ECG or per beat.

CONCLUSIONS

BX471 does not cause meaningful QT_c prolongation. Three QT correction methods may be sufficient in future studies: Bazett''s (required by regulatory authorities), Fridericia''s (as the most reliable fixed formula) and a regression-based correction (individually or population-based), each performed per ECG (i.e. applied to the means of several beats of one ECG recording).     

Population pharmacokinetics and pharmacodynamics of escitalopram in overdose and the effect of activated charcoal

AIMS

To describe the pharmacokinetics and pharmacodynamics (PKPD) of escitalopram in overdose and its effect on QT prolongation, including the effectiveness of single dose activated charcoal (SDAC).

METHODS

The data set included 78 escitalopram overdose events (median dose, 140 mg [10–560 mg]). SDAC was administered 1.0 to 2.6 h after 12 overdoses (15%). A fully Bayesian analysis was undertaken in WinBUGS 1.4.3, first for a population pharmacokinetic (PK) analysis followed by a PKPD analysis. The developed PKPD model was used to predict the probability of having an abnormal QT as a surrogate for torsade de pointes.

RESULTS

A one compartment model with first order input and first-order elimination described the PK data, including uncertainty in dose and a baseline concentration for patients taking escitalopram therapeutically. SDAC reduced the fraction absorbed by 31% and reduced the individual predicted area under the curve adjusted for dose (AUC_i/dose). The absolute QT interval was related to the observed heart rate with an estimated individual heart rate correction factor (α = 0.35). The heart rate corrected QT interval (QT_c) was linearly dependent on predicted escitalopram concentration [slope = 87 ms/(mg l^–1)], using a hypothetical effect-compartment (half-life of effect-delay, 1.0h). Administration of SDAC significantly reduced QT prolongation and was shown to reduce the risk of having an abnormal QT by approximately 35% for escitalopram doses above 200 mg.

CONCLUSIONS

There was a dose-related lengthening of the QT interval that lagged the increase in drug concentration. SDAC resulted in a moderate reduction in fraction of escitalopram absorbed and reduced the risk of the QT interval being abnormal.     

No cardiac effects of therapeutic and supratherapeutic doses of rupatadine: results from a ‘thorough QT/QTc study’ performed according to ICH guidelines

AIMS

To evaluate the effects of therapeutic and supratherapeutic doses of rupatadine on cardiac repolarization in line with a ‘thorough QT/QTc study’ protocol performed according to International Conference on Harmonization guidelines.

METHODS

This was a randomized (gender-balanced), parallel-group study involving 160 healthy volunteers. Rupatadine, 10 and 100 mg day⁻¹, and placebo were administered single-blind for 5 days, whilst moxifloxacin 400 mg day⁻¹ was given on days 1 and 5 in open-label fashion. ECGs were recorded over a 23-h period by continuous Holter monitoring at baseline and on treatment days 1 and 5. Three 10-s ECG samples were downloaded at regular intervals and were analysed independently. The primary analysis of QTc was based on individually corrected QT (QTcI). Treatment effects on QTcI were assessed using the largest time-matched mean difference between the drug and placebo (baseline-subtracted) for the QTcI interval. A negative ‘thorough QT/QTc study’ is one where the main variable is around ≤5 ms, with a one-sided 95% confidence interval that excludes an effect >10 ms.

RESULTS

The validity of the trial was confirmed by the fact that the moxifloxacin-positive control group produced the expected change in QTcI duration (around 5 ms). The ECG data for rupatadine at both 10 and 100 mg showed no signal effects on the ECG, after neither single nor repeated administration. Furthermore, no pharmacokinetic/pharmacodynamic relationship, gender effects or clinically relevant changes in ECG waveform outliers were observed. No deaths or serious or unexpected adverse events were reported.

CONCLUSIONS

This ‘thorough QT/QTc study’ confirmed previous experience with rupatadine and demonstrated that it had no proarrhythmic potential and raised no concerns regarding its cardiac safety.     

Comparison of the efficacy and tolerability of telmisartan and enalapril in patients of mild to moderate essential hypertension

Background:

Theoretically, angiotensin II receptor blockers (ARBs) have certain advantages over angiotensin-converting enzyme inhibitors, but the contribution of these advantages to the clinical effect of ARBs is not known.

Objective:

To compare the efficacy and tolerability of telmisartan with enalapril in patients of essential hypertension.

Materials and Methods:

Patients of mild to moderate hypertension were randomized to receive either 40 mg of telmisartan or enalapril 10 mg once a day orally for 12 weeks. At each visit, the systolic blood pressure (BP), diastolic BP and heart rate of each patient were recorded. Investigations such as hemogram hemoglobin, total leucocytes count (Hb, TLC), serum creatinine, serum glutamic oxaloacetic transaminase, serum glutamic pyruric transaminase (SGOT, SGPT) random blood sugar and urine examination were performed at baseline and after 12 weeks of the treatment period.

Results:

The mean reduction in systolic BP in the telmisartan/enalapril group was 26.38 ± 10.98/26.74 ± 8.24 mmHg while the mean reduction in diastolic BP in the telmisartan/enalapril group was 14 ± 2.98/9.71 ± 4.23 mmHg, respectively, at 12 weeks. When the reduction in systolic BP in the two groups was compared, there was no significant difference between the groups (P > 0.05). However, the mean reduction in diastolic BP achieved with telmisartan at 12 weeks was significantly higher (P < 0.001) than that achieved with enalapril after the corresponding period. The overall frequency of adverse-effects was similar. However, in the enalapril group, the incidence of dry cough was higher as compared to that in the telmisartan group (11.43% vs. 0%, respectively; P < 0.05).

Conclusion:

Telmisartan produces a greater reduction in diastolic BP than enalapril and is free from the adverse-effect of dry cough that is commonly encountered with enalapril.     

Evaluation of a QT nomogram for risk assessment after antidepressant overdose

AIMS

A QT-heart rate nomogram has recently been proposed as a means of identifying patients at risk of torsades de pointes after antidepressant overdose, based on published cases of drug-induced torsades de pointes. The present study sought to examine the performance of the nomogram in patients who ingest an antidepressant overdose but do not develop arrhythmia.

METHODS

A retrospective case control study of patients presenting to hospital after overdose of citalopram, mirtazapine and venlafaxine was carried out. The primary outcome variable was QT higher than the nomogram, and was compared with occurrence of QT_c (QT corrected by Bazett''s formula) greater than ≥440 ms and QT_c≥500 ms, with comparison between drugs. Data are expressed as proportions in each group with 95% confidence intervals.

RESULTS

There were 858 electrocardiograms from 541 patients. QT was higher than the nomogram in 2.4% (1.4, 4.1%), whereas QT_c was ≥440 ms in 23.1% (95% CI 19.8, 26.8%), and QT_c was ≥500 ms in 1.1% (0.5, 2.5%). Citalopram overdose was more likely to be associated with QT higher than the nomogram compared with the other agents (difference 7.0%, 95% CI 2.9, 11.9%, P = 0.001) and more likely to be associated with QT_c≥440 ms (difference = 11.0%, 95% CI 2.6, 19.0%, P = 0.013).

CONCLUSIONS

The QT nomogram was associated with a lower false positive rate than widely accepted QT_c criteria, and allowed detection of different effects of individual drugs. The nomogram offers potential advantages over QT_c criteria and merits further investigation in a clinical setting.     

Assessment of manual blood pressure and heart rate measurement skills of pharmacy students: a follow-up investigation

Objectives

To evaluate the impact of a laboratory course on the manual blood pressure (BP) and heart rate (HR) measurement skills of pharmacy students.

Methods

After 1 lecture and 1 laboratory session on vital sign technique, pharmacy students enrolled in a patient assessment laboratory course were randomly paired with a classmate and manually measured the classmate''s BP and HR. Within 2 minutes, the BP and HR were measured by an Omron 711-AC automatic monitor. The same assessment procedures with manual and automatic measurements were repeated near the end of the laboratory course. Student skills were also evaluated through direct observation by faculty members.

Results

Student and machine measurements of systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR significantly correlated at the final assessment (r = 0.92, 0.83, and 0.91 respectively; p < 0.001 for each. The proportion of student and device values agreeing to within 5 units (mmHg and beats-per-minute) at baseline versus at the final assessment significantly improved from 38% to 67% for SBP, 51% to 77% for DBP, and 52% to 79% for HR (p < 0.001 for each). The percentage of students correctly performing all 13 AHA endorsed steps for BP measurement improved significantly from 4.6% to 75.6% (p < 0.001).

Conclusions

Significant improvement and the attainment of competency in manual vital signs measurement were demonstrated by pharmacy students after 11 weeks of skill rehearsal in a laboratory course.     

Intrathecal neurotensin is hypotensive, sympathoinhibitory and enhances the baroreflex in anaesthetized rat

BACKGROUND AND PURPOSE

The neuromodulatory effects of the gut-neuropeptide neurotensin on sympathetic vasomotor tone, central respiratory drive and adaptive reflexes in the spinal cord, are not known.

EXPERIMENTAL APPROACH

Neurotensin (0.5 µM–3 mM) was administered into the intrathecal (i.t.) space at the sixth thoracic spinal cord segment in urethane-anaesthetized, paralysed, vagotomized male Sprague–Dawley rats. Pulsatile arterial pressure, splanchnic sympathetic nerve activity (sSNA), phrenic nerve activity, ECG and end-tidal CO₂ were recorded.

KEY RESULTS

Neurotensin caused a dose-related hypotension, sympathoinhibition and bradycardia. The maximum effects were observed at 3000 µM, where the decreases in mean arterial pressure (MAP), heart rate (HR) and sSNA reached −25 mmHg, −26 beats min⁻¹ and −26% from baseline, respectively. The sympathetic baroreflex was enhanced. Changes in central respiratory drive were characterized by a fall in the amplitude of the phrenic nerve activity. Finally, administration of SR 142948A (5 mM), a potent, selective antagonist at neurotensin receptors, caused a potent hypotension (−35 mmHg), bradycardia (−54 beats min⁻¹) and sympathoinhibition (−44%). A reduction in the amplitude and frequency of the phrenic nerve activity was also observed.

CONCLUSIONS AND IMPLICATIONS

The data demonstrate that neurotensin plays an important role in the regulation of spinal cardiovascular function, affecting both tone and adaptive reflexes.     

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein

AIMS

To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein (CETP).

METHODS

The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20–45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60–5521 (n = 28) or were treated with a placebo (n = 10).

RESULTS

In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60–5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h.

CONCLUSIONS

BAY 60–5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated.     

Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials

Background and Purpose

Understanding drug effects on the heart is key to safety pharmacology assessment and anti-arrhythmic therapy development. Here our goal is to demonstrate the ability of computational models to simulate the effect of drug action on the electrical activity of the heart, at the level of the ion-channel, cell, heart and ECG body surface potential.

Experimental Approach

We use the state-of-the-art mathematical models governing the electrical activity of the heart. A drug model is introduced using an ion channel conductance block for the hERG and fast sodium channels, depending on the IC₅₀ value and the drug dose. We simulate the ECG measurements at the body surface and compare biomarkers under different drug actions.

Key Results

Introducing a 50% hERG-channel current block results in 8% prolongation of the APD₉₀ and 6% QT interval prolongation, hERG block does not affect the QRS interval. Introducing 50% fast sodium current block prolongs the QRS and the QT intervals by 12% and 5% respectively, and delays activation times, whereas APD₉₀ is not affected.

Conclusions and Implications

Both potassium and sodium blocks prolong the QT interval, but the underlying mechanism is different: for potassium it is due to APD prolongation; while for sodium it is due to a reduction of electrical wave velocity. This study shows the applicability of in silico models for the investigation of drug effects on the heart, from the ion channel to the ECG-based biomarkers.