Efficacy and safety of ezetimibe coadministered with statins: randomised, placebo-controlled, blinded experience in 2382 patients with primary hypercholesterolemia.

We assessed pooled safety and lipid-regulating efficacy data from four similarly designed trials of ezetimibe coadministered with statins in 2382 patients with primary hypercholesterolemia. Patients were randomised to one of the following double-blind treatments for 12 weeks: placebo; ezetimibe 10 mg; statin; or statin + ezetimibe. Statin doses tested were 10, 20, 40 mg/day (atorvastatin, simvastatin, pravastatin or lovastatin) or 80 mg/day (atorvastatin, simvastatin). Treatment with ezetimibe + statin led to significantly greater reductions in low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and increases in HDL-C, compared to statin alone. At each statin dose, treatment with ezetimibe + statin led to a greater LDL-C reduction compared to the next highest statin monotherapy dose. Ezetimibe + statin had a safety profile similar to statin monotherapy. Coadministration of ezetimibe + statin offers a well-tolerated, highly efficacious new treatment strategy for patients with hypercholesterolemia.

Long-term safety and tolerability profile of ezetimibe and atorvastatin coadministration therapy in patients with primary hypercholesterolaemia.

Long-term safety and tolerability of ezetimibe plus atorvastatin (EZE + ATV) coadministration therapy were compared to those of ATV monotherapy in patients with primary hypercholesterolaemia. Upon completion of a 12 week randomised, double-blind, placebo-controlled study comparing EZE 10 mg; ATV 10, 20, 40 or 80 mg; EZE + ATV 10, 20, 40 or 80 mg or placebo, 246 patients were enrolled in a 12-month extension, with reassignment to double-blind EZE 10 mg (n = 201) or matching placebo (n = 45) coadministered daily with open-label ATV 10 mg. At intervals of 6 weeks, patients not at National Cholesterol Education Program Adult Treatment Panel II LDL-C goals were titrated to the next higher ATV dose. Safety evaluations included adverse event (AE) reports and laboratory test results. EZE + ATV and ATV monotherapy groups were similar with regard to incidence of all AEs (71 vs. 67%), treatment-related AEs (22 vs. 27%) and discontinuations due to AEs (9 vs. 7%) or treatment-related AEs (6 vs. 7%), respectively. Neither clinically significant elevations in hepatic transaminases or creatine kinase nor any cases of myopathy or rhabdomyolysis were observed in either group during the extension study. After 6 weeks, EZE + ATV 10mg produced greater reductions in low-density lipoprotein cholesterol (LDL-C; -53 vs. -37%), total cholesterol (TC; -38.8 vs. -26.0%) and triglycerides (TG; -28 vs. -12%) and similar increases in high-density lipoprotein cholesterol (4.6 vs. 4.5%) compared to ATV 10 mg, respectively, and these changes were maintained and significant at 1 year (p < 0.01 for LDL-C, TC and TG). More EZE + ATV patients achieved LDL-C goal than ATV patients at study endpoint (91 vs. 78%, respectively; p = 0.02). Thus, the coadministration of EZE + ATV for 12 months was well tolerated and more efficacious than ATV monotherapy.

Evaluation of the efficacy, safety, and tolerability of ezetimibe in primary hypercholesterolaemia: a pooled analysis from two controlled phase III clinical studies.

Ezetimibe is a novel cholesterol absorption inhibitor that blocks intestinal absorption of dietary and biliary cholesterol. Data from 1719 patients who participated in two multicentre, double-blind studies of ezetimibe were pooled to evaluate the drug's efficacy and safety in patients with primary hypercholesterolaemia. Following dietary stabilisation, a two- to 12-week washout period, and a four-week, single-blind, placebo lead-in period, patients were randomised to ezetimibe 10 mg or placebo once daily in the morning for 12 consecutive weeks. The primary efficacy endpoint was percent reduction in plasma low-density lipoprotein (LDL)-cholesterol from baseline at endpoint. Ezetimibe reduced LDL-cholesterol by a mean of 18.2% compared with an increase of 0.9% with placebo (p<0.01) and resulted in favourable, statistically significant changes in HDL-cholesterol, triglycerides and apo B. The response to ezetimibe was consistent across all subgroups analysed. Ezetimibe was well tolerated, with a safety profile similar to placebo.

Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia.

AIMS: This randomized, double-blind, placebo-controlled, parallel-group study evaluated the safety and efficacy of ezetimibe 10 mg/day in patients with primary hypercholesterolemia. METHODS AND RESULTS: Following dietary stabilization, a 2-12-week washout period, and a 4-week, single-blind, placebo lead-in period, 827 patients with baseline low-density lipoprotein cholesterol (LDL-C) > or =3.36 mmol/l (130 mg/dl) to < or =6.47 mmol/l (250 mg/dl) and triglycerides < or =3.95 mmol/l (350 mg/dl) were randomized 3:1 to receive ezetimibe 10 mg or placebo orally once daily in the morning for 12 weeks. The primary efficacy endpoint was percentage reduction in direct plasma LDL-C. Ezetimibe reduced direct LDL-C by a mean of 17.7% from baseline to endpoint, compared with an increase of 0.8% with placebo (P<0.01). Response to ezetimibe was generally consistent across all subgroups analyzed. Ezetimibe also significantly improved levels of plasma total cholesterol, apolipoprotein B, high-density lipoprotein(2)-cholesterol and lipoprotein(a), and elicited a trend toward lower triglyceride levels. Ezetimibe did not alter the serum concentrations of lipid-soluble vitamins or significantly affect baseline or stimulated cortisol production. Ezetimibe was well tolerated, with a safety profile similar to that of placebo. CONCLUSIONS: Ezetimibe, which significantly reduces LDL-C and favorably affects other lipid variables, may provide a well tolerated and effective new option for lipid management in the future.

The plasma concentration and LDL-C relationship in patients receiving ezetimibe.

Ezetimibe is a novel selective inhibitor of intestinal cholesterol absorption, which has been shown to significantly decrease low-density lipoprotein cholesterol (LDL-C). In this article, the relationship between plasma ezetimibe concentrations and lowering of LDL-C is determined using Emax and regression models. Data from two phase II double-blind placebo-controlled studies (n = 232 and 177) were used in which daily doses of ezetimibe ranging from 0.25 to 10 mg were administered for 12 weeks. Ezetimibe concentrations correlated significantly with percentage change in LDL-C from baseline (%LDL-C). Reductions in %LDL-C of 10%, 15%, and 20% were achieved with concentrations in the ranges 0 to 2, 2 to 15, and > 15 ng/ml, respectively, as compared with placebo. To achieve > 15% reduction in LDL-C, patients need to maintain trough concentrations > 15 ng/ml, taking plasma concentrations as a surrogate for concentrations at the enterocyte. Based on the doses administered, the 10 mg dose had the highest likelihood of sustaining such concentrations, confirming that a daily 10 mg dose of ezetimibe is an optimal therapeutic dose in the treatment of hypercholesterolemia.

Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies.

BACKGROUND: Ezetimibe (SCH 58235) is a novel cholesterol absorption inhibitor that selectively and potently blocks intestinal absorption of dietary and biliary cholesterol. OBJECTIVE: Data from 2 multicenter, placebo-controlled, double-blind, randomized, parallel-group, 12-week studies of ezetimibe were pooled to evaluate the drug's effect on lipid parameters in patients with primary hypercholesterolemia. METHODS: After dietary stabilization (National Cholesterol Education Program Step I diet or a stricter diet), washout of lipid-altering drugs, and a 6-week placebo lead-in period, patients with baseline plasma low-density lipoprotein cholesterol (LDL-C) levels > or = 130 and < or = 250 mg/dL and plasma triglyceride (TG) levels < or = 300 mg/dL were randomized to receive either ezetimibe 0.25, 1, 5, or 10 mg, or placebo administered once daily before the morning meal in study A (dose-response study) or ezetimibe 5 or 10 mg or placebo administered once daily before the morning meal or at bedtime in study B (dose-regimen study). RESULTS: A total of 432 patients were included in this pooled analysis, 243 in study A and 189 in study B. The 5- and 10-mg doses of ezetimibe significantly reduced LDL-C levels by 15.7% and 18.5%, respectively (P < 0.01 vs placebo) and significantly increased high-density lipoprotein cholesterol (hDL-C) levels by 2.9% and 3.5%, respectively (P < 0.05 vs placebo). A reduction in plasma TG levels was observed (P = NS). With the 10-mg dose of ezetimibe, 67.8% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 22.0% achieved > or = 25% reduction. With the 5-mg dose, 54.0% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 15.3% achieved > or = 25% reduction. The decrease in plasma LDL-C levels was significantly greater with ezetimibe 10 mg compared with ezetimibe 5 mg (P < 0.05). Ezetimibe was well tolerated, with an adverse event profile similar to that of placebo. CONCLUSIONS: In these two 12-week studies, ezetimibe significantly decreased plasma LDL-C levels and increased plasma HDL-C levels, with a tolerability profile similar to that of placebo.

Reduction of LDL cholesterol in patients with primary hypercholesterolemia by SCH 48461: results of a multicenter dose-ranging study.

SCH 48461, an inhibitor of gastrointestinal absorption of cholesterol, was evaluated for its effects on lipid parameters in patients with primary hypercholesterolemia in a multicenter, double-blind, randomized, parallel-group study. Following the baseline phase, which consisted of a 2- to 10-week drug washout and dietary stabilization phase and a 4-week placebo lead-in (placebo baseline phase), 190 patients were randomized to an 8-week double-blind active drug (SCH 48461 1, 6.25, 25, 100, 200, or 400 mg) or 40 mg lovastatin once daily each morning or placebo treatment phase. By week 2, patients who received SCH 48461 6.25 to 400 mg or lovastatin demonstrated greater reduction from baseline in directly measured low-density lipoprotein cholesterol (LDL-C) levels than patients in the placebo group (p < or = 0.03). Overall, the percent reductions in LDL-C from baseline increased as the dose of SCH 48461 increased, with 0.6% to 15.5% reductions from the minimum dose of 1 mg to the maximum dose of 400 mg. Lovastatin 40 mg/day reduced LDL-C by 30.7% (p < 0.01). Statistically significant decreases were also seen for total cholesterol and apolipoprotein B (apo B) with doses of 25 mg to 400 mg of SCH 48461 and lovastatin. SCH 48461 was well tolerated. There was a similar incidence of adverse events in each SCH 48461- or lovastatin-treated group compared to placebo. This study demonstrated a clinically and statistically significant cholesterol-lowering effect of SCH 48461 in patients with primary hypercholesterolemia.

Double-wave reentry in orthodromic atrioventricular reciprocating tachycardia: paradoxical shortening of the tachycardia cycle length with development of ipsilateral bundle branch block.

INTRODUCTION: Attempts to terminate reentrant tachyarrhythmias by rapid pacing may accelerate the tachycardia. One mechanism for acceleration is double-wave reentry, where two simultaneous wavefronts travel around the same circuit. METHODS AND RESULTS: We report pacing acceleration of AV reciprocating tachycardia (AVRT) due to double-wave reentry in a patient with Wolff-Parkinson-White syndrome. The patient had presented with atrial fibrillation and rapid conduction across a left lateral bypass tract. Intravenous procainamide was given during electrophysiologic study because of incessant atrial fibrillation and restored sinus rhythm. Orthodromic AVRT was induced and attempts to terminate the AVRT with right ventricular pacing initiated two alternate tachycardias, both with a left bundle branch block (LBBB) morphology. The first tachycardia, as expected for bundle branch block ipsilateral to the bypass tract, had a longer cycle length (CL) than the original tachycardia (366 msec compared to 297 msec). The second tachycardia had a paradoxically shorter CL, 238 msec compared to 297 msec. Electrogram analysis revealed that the circuit traversed by the accelerated LBBB tachycardia was the same as the slower LBBB tachycardia. The activation sequence revealed two independent wavefronts, traversing this common circuit. As described previously in experimental models, double-wave reentry was initiated when an antidromic-stimulated impulse blocked before colliding with the previous orthodromic impulse, thus allowing two orthodromic impulses to circulate within the circuit. CONCLUSION: We speculate that conduction slowing by procainamide combined with the intrinsic AV nodal delay resulted in the necessary increase in the excitable gap required to develop double-wave reentry. This is the first description of sustained double-wave reentry in humans.

Differential effects of bupivacaine on cardiac K channels: role of channel inactivation and subunit composition in drug-channel interaction.

INTRODUCTION: We examined the effects of a nonspecific ion channel blocker, bupivacaine, on K channels encoded by hERG, rKv1.4, rKv4.3, and hKvLQT1 along with hIsK. Their native counterparts in the heart are important for the function of I(Kr), I(to) and I(Ks) and, thus, play an important role in repolarization. METHODS AND RESULTS: To elucidate the mechanisms and sites of bupivacaine's actions, we correlated the voltage and time dependencies of drug effects with those of channel gating. We also studied the effects of altering the C-type (hERG) or N-type (rKv1.4) inactivation process or the subunit composition (hKvLQT1 with or without hIsK) on bupivacaine's actions. The results suggest that, except for hKvLQT1 co-expressed with hIsK, bupivacaine binding occurred at depolarized voltages coinciding with channel activation. With hKvLQT1 co-expressed with hIsK, bupivacaine bound preferentially at negative voltages when channels were in the closed state, and unbound at depolarized voltages when channels opened. The C-type inactivation of hERG enhanced, whereas the N-type inactivation of rKv1.4 hindered, bupivacaine's effects. CONCLUSION: We propose that bupivacaine's actions on these K channels can be described as a nonspecific pore blockade in the inner mouth region. However, the apparent binding affinity and voltage dependence of binding can be differentially influenced by the inactivation processes occurring at two ends of the pore (C-type inactivation at the outer end and N-type inactivation at the inner end), or by the interaction between hIsK and hKvLQT1 subunits.

An analogue of cAMP mimics developmental change in neonatal rat ventricular myocyte sodium current kinetics.

During development, the voltage dependence of single rat ventricular sodium channels shifts to more negative potentials. This shift is mimicked by coculture of neonatal myocytes with sympathetic neurons or by a 96-h exposure to 8-(4-chlorophenylthio) adenosine 3',5'-cyclic monophosphate (CPT-cAMP). The prolonged exposure to CPT-cAMP suggests that this is not a short-term modulatory effect on the sodium channel, but rather may reflect a trophic action. Here we examine the effect of CPT-cAMP using whole cell recording to investigate further the time period required for the effect. Sodium current was measured in a 50 mM NaCl bath solution at 20 +/- 1 degree C using the whole cell patch-clamp technique after exposure of myocytes to CPT-cAMP (0.25 mM) for 0,0.5,20, or 24 h. The relationship between the time constant of decay (tauh) of the sodium current and test voltage (V1) showed a shift to more hyperpolarizing voltages after exposure to CPT-cAMP for 24 h. In addition, the midpoint of the steady-state inactivation curve (V 1/2) was shifted from -75.8 +/- 1.1 mV (0-h exposure) to -83.3 +/- 1.6 mV (24-h exposure) (P < 0.05). Exposure for 0.5 h to CPT-cAMP did not alter the tauh or V 1/2 of the sodium current. However, exposure to CPT-cAMP for 20 h, followed by a 4-h washout period, produced an effect similar to that of the 24-h exposure. Thus the lack of effect of acute (0.5 h) exposure to CPT-cAMP and the persistence of the effect after washout of CPT-cAMP for 4 h suggest that adenosine 3',5'-cyclic monophosphate may play a trophic role in sodium channel development.

Relative sodium current block by bupivacaine and lidocaine in neonatal rat myocytes.

Bupivacaine is more cardiotoxic than lidocaine and can produce fatal arrhythmias during accidental overdose or intravascular injection. Studies using Vmax in adult guinea pig myocytes suggest that this toxicity is due to the greater inhibition of sodium current by bupivacaine. Human neonates and cardiac tissue from neonatal animals show resistance to the cardiac effects of many local anesthetic and antiarrhythmic drugs, and a slower onset of use-dependent block. We used whole-cell patch clamp (20 degrees C, [Na]o = 50 mmol/L) to examine directly the kinetics of sodium current block by bupivacaine and lidocaine in ventricular myocytes from 1- to 2-day-old rats. We found that 1 microgram/mL bupivacaine and 5 micrograms/mL lidocaine produced equivalent amounts of use-dependent block for protocols corresponding to 30-200 depolarizations per minute (cell resting potential of -85 mV). Block due to bupivacaine surpassed that from lidocaine (37.6% +/- 3.4% vs 26.4% +/- 2.7%) (P < 0.01) only after the resting membrane potential was hyperpolarized to -110 mV and the length of depolarization and repolarization were increased to nonphysiologic durations (1 s and 0.5 s, respectively). Double-pulse protocols were used to measure the underlying rate of onset and recovery from block. At these concentrations, blockade development was more than seven times slower for bupivacaine (4.11 +/- 0.32 s vs 0.57 +/- 0.06 s) (P < 0.01, and recovery from block was five times slower (10.81 +/- 0.54 s vs 2.14 +/- 0.50 s) (P < 0.01). In these neonatal myocytes, bupivacaine does not produce more use-dependent block than lidocaine, and the effect of bupivacaine is limited by its slow binding to the sodium channel.

Does chlorpromazine produce cardiac arrhythmia via the central nervous system?

The influence of the central nervous system in the production of phenothiazine-induced arrhythmia and death was examined in this study. In a series of cats, spinal cords were transected at the atlanto-occipital junction prior to the 1 mg/kg/min, i.v. infusion of chlorpromazine or thioridazine. No protection against drug-induced arrhythmia or death was afforded by this procedure. In other cats, 6OH-dopamine was administered prior to intravenous injection of atropine and infusion of chlorpromazine, 1 mg/kg/min. In these in situ denervated heart preparations, there was no protection against chlorpromazine-induced arrhythmia or death. In alpha-chloralose anesthetized cats, 0.5 mg chlorpromazine administered intracerebroventricularly did not induce arrhythmia or death, although blood pressure decreased initially. Thus, chlorpromazine or thioridazine do not appear to produce arrhythmia or death via a central locus and may instead be acting directly on myocardial conduction to produce arrhythmia and death.

Digitalis glycosides: a discussion of the similarities and differences in actions and existing controversies.

The writing of this review was initiated to answer the question of whether differences in the actions of the various digitalis glycosides exist and to discuss current controversies in the research area of the digitalis glycosides. Data obtained in our laboratory indicated that the effect of digoxin on postganglionic cardiac sympathetic neural discharge in the minute prior to the occurrence of arrhythmia differed from that of ouabain. This raised the question of whether data published in other laboratories would support the contention that differences in glycosides do exist. To answer this question, a review of the literature was begun. Our survey of these studies are cited in the tables of this review. These tables summarize the actions of glycosides in vivo and in vitro in different animal models. The reader should bear in mind that the data included within the tables do not represent an inclusive summary of all studies in the literature. For detailed review articles, the reader is referred to the following references: Gillis et al; Gillis and Quest; Roberts et al; Lathers and Roberts; Farah and Alousi; Benthe; Levitt et al; Smith and Haber; Somberg; Lee and Klaus; Mason; Schwartz. Furthermore the summary of the results for each particular study cited in the table may not, in all cases, include each finding of the published data. Nevertheless, the tables do provide a summary of data obtained in various species with different glycosides in several different areas of research, and as such, represent an abridged compendium for the research working in the field of digitalis glycosides. This review has been organized firstly to consider glycoside-induced alterations in the autonomic nervous system and, secondly, to examine their direct actions on the heart.

Psychoactive agents, seizure production, and sudden death in epilepsy.

Major tranquilizers as well as antidepressant agents have been associated with clinical seizures in patients administered these agents. The incidence of such seizures is generally low when these drugs are administered in therapeutic doses. However, administration of large doses of these agents has been associated with many cases of convulsion production. The effects that these drugs have on animal models of epilepsy have been examined. It appears that the phenothiazines act as convulsant agents at lower doses, whereas, at higher doses, they act as anticonvulsant drugs. Antidepressants, on the other hand, appear to exert an anticonvulsant effect at low doses and convulsant effects at high doses. The mechanism by which these agents alter the seizure threshold is not yet known. Clinically, drugs of lower seizure production potential should be substituted for those drugs with greater potential in treating epileptic patients for psychiatric ailments. The problem of sudden death in epileptic patients is one that must be confronted. Sudden death has most frequently been attributed to autonomic dysfunction and cardiac arrhythmia in these patients. The contribution of stress in sudden death production also must be taken into account. In addition, some psychoactive agents have been associated with sudden death as well as cardiac arrhythmia and seizure production. Thus, in light of the possible additivity of the factors involved in the production of sudden death, the administration of a psychoactive agent to an epileptic patient should be approached with caution. Those agents that do not alter cardiac rhythm or seizure threshold should be administered if a psychoactive agent is deemed necessary for the management of psychiatric illness in the epileptic patient.

The effect of C1 spinal cord transection or bilateral adrenal vein ligation on thioridazine-induced arrhythmia and death in the cat.

The phenothiazine thioridazine 1 mg/kg/min was infused intravenously into three groups of cats: (1) thioridazine alone (N = 5), (2) after bilateral adrenal ligation (N = 4), and (3) after spinal cord section at the atlanto-occipital junction (C1; N = 6). The times to arrhythmia and death with thioridazine alone were 47.8 +/- 7.8 and 72.8 +/- 5.6 minutes respectively. After bilateral adrenal ligation, arrhythmia and death occurred at 41.1 +/- 5.2 and 53.1 +/- 5.8 minutes, respectively, which showed no increase (P greater than .05) from thioridazine alone. After spinal cord section, thioridazine-induced arrhythmia and death occurred at 74.0 +/- 13.7 and 85.7 +/- 13.8 minutes, respectively, which were not increased (P greater than .05) when compared with thioridazine alone. The results of this study suggest that neither adrenomedullary catecholamines nor the central sympathetic component above C1 plays a significant role in acute thioridazine-induced arrhythmia. The action of thioridazine to induce arrhythmia in spite of transection of the spinal cord or bilateral adrenal vein ligation suggests that its cardiotoxicity is a result of a direct myocardial effect. Thioridazine depressed blood pressure without producing the sustained reflex tachycardia normally seen with hypotension. This suggests that the agent may modify the baroreceptor reflex arc.

Chlorpromazine: cardiac arrhythmogenicity in the cat.

To determine the effect of chlorpromazine on ouabain-induced arrhythmia and death, dial-urethane anesthetized cats were pretreated with chlorpromazine (5, 10, 20, 30, 40, or 60 mg/kg, i.v.) and then administered ouabain (2 microgram/kg/min, i.v.). Blood pressure, heart rate and lead II electrocardiogram (ECG) were monitored. The dosages of ouabain necessary to induce premature ventricular contractions, ventricular tachycardia and death were determined. No significant correlation between the dose of chlorpromazine given and the dose of ouabain required to produce arrhythmia or death was found. These doses of chlorpromazine could, therefore, be considered neither arrhythmogenic nor antiarrhythmic in the ouabain model. To determine whether chlorpromazine produced arrhythmia in the dial-urethane anesthetized cat model, the drug was infused at a rate of 1 mg/kg/min, i.v. Chlorpromazine produced arrhythmia at 185 +/- 4.3 minutes and death via cardiovascular collapse at 128 +/- 4.7 minutes. Bilateral adrenal vein ligation, employed to eliminate the influence of adrenal catecholamines, decreased the dosage of chlorpromazine necessary to produce arrhythmia and death to 67.8 +/- 17.7 and 84.7 +/- 15.7 mg/kg, respectively. Thus, adrenal catecholamines did not appear to contribute to chlorpromazine-induced arrhythmia, although the procedure of bilateral adrenal vein ligation appeared to be deleterious in combination with chlorpromazine. In all experiments, chlorpromazine depressed blood pressure without producing the reflex tachycardia normally seen with hypotension. This suggests that the drug may be interfering with the baroreceptor reflex arc. As chlorpromazine modifies the autonomic parameters of blood pressure, heart rate, and cardiac electrophysiology, sudden unexplained death in patients managed with this agent may be due to drug-induced arrhythmia.