Single-pill amlodipine/atorvastatin helps patients of diverse ethnicity attain recommended goals for blood pressure and lipids (the Gemini-AALA study).

The Gemini-AALA (Australia, Asia, Latin America, Africa/Middle East) study evaluated the efficacy and safety of single-pill amlodipine/atorvastatin (Caduet) for the treatment of patients of diverse ethnicity with concomitant hypertension and dyslipidaemia. This was a 14-week, open-label study including patients from 27 countries across the Middle East, Asia-Pacific, Africa and Latin America. Eight dosage strengths of single-pill amlodipine/atorvastatin (5/10, 10/10, 5/20, 10/20, 5/40, 10/40, 5/80 and 10/80 mg) were titrated to improve blood pressure and lipid control. Blood pressure and lipid goals were determined according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) guidelines, respectively (blood pressure, <140/90 or <130/80 mm Hg; low-density lipoprotein cholesterol (LDL-C), <4.1 to <2.6 mmol l(-1) (<160 to <100 mgdl(-1))). Overall, 1649 patients received study medication. Most patients (91.4%) had >or=1 cardiovascular risk factor (as defined by NCEP ATP III guidelines) in addition to hypertension/dyslipidaemia, and 61.7% had coronary heart disease/risk equivalent. At baseline, mean blood pressure was 146.6/88.3 mm Hg and LDL-C was 3.4 mmol l(-1) (130.2 mgdl(-1)). At week 14, 55.2% of patients reached both blood pressure and lipid goals, 61.3% reached blood pressure goal and 87.1% reached lipid goal (34.0% were at lipid goal at baseline). Mean blood pressure reduction was 20.2/11.4 mm Hg. For patients who were lipid-lowering drug naive at baseline, mean reduction in LDL-C was 41.0%. Treatment-related adverse events led to the discontinuation of 3.6% of patients. Single-pill amlodipine/atorvastatin therapy was well tolerated and effective for the reduction of blood pressure and lipids to recommended goals in patients from diverse ethnic backgrounds.

A novel programme to evaluate and communicate 10-year risk of CHD reduces predicted risk and improves patients' modifiable risk factor profile.

AIMS: We assessed whether a novel programme to evaluate/communicate predicted coronary heart disease (CHD) risk could lower patients' predicted Framingham CHD risk vs. usual care. METHODS: The Risk Evaluation and Communication Health Outcomes and Utilization Trial was a prospective, controlled, cluster-randomised trial in nine European countries, among patients at moderate cardiovascular risk. Following baseline assessments, physicians in the intervention group calculated patients' predicted CHD risk and were instructed to advise patients according to a risk evaluation/communication programme. Usual care physicians did not calculate patients' risk and provided usual care only. The primary end-point was Framingham 10-year CHD risk at 6 months with intervention vs. usual care. RESULTS: Of 1103 patients across 100 sites, 524 patients receiving intervention, and 461 receiving usual care, were analysed for efficacy. After 6 months, mean predicted risks were 12.5% with intervention, and 13.7% with usual care [odds ratio = 0.896; p = 0.001, adjusted for risk at baseline (17.2% intervention; 16.9% usual care) and other covariates]. The proportion of patients achieving both blood pressure and low-density lipoprotein cholesterol targets was significantly higher with intervention (25.4%) than usual care (14.1%; p < 0.001), and 29.3% of smokers in the intervention group quit smoking vs. 21.4% of those receiving usual care (p = 0.04). CONCLUSIONS: A physician-implemented CHD risk evaluation/communication programme improved patients' modifiable risk factor profile, and lowered predicted CHD risk compared with usual care. By combining this strategy with more intensive treatment to reduce residual modifiable risk, we believe that substantial improvements in cardiovascular disease prevention could be achieved in clinical practice.

Beta-estradiol acutely potentiates the depression of cardiac excitability by lidocaine and bupivacaine.

Pregnancy is known to increase myocardial susceptibility to bupivacaine-induced cardiovascular collapse, and prolonged pretreatment of rabbits with high doses of progesterone potentiates bupivacaine's depression of the maximal rate of increase (Vmax) of the cardiac action potential. Short-term effects of progesterone are not detected in vitro, but other steroids elevated during pregnancy might be acutely active in this model. These experiments tested whether acute exposure to beta-estradiol potentiates local anesthetic/antiarrhythmic depression of Vmax and conduction velocity in rabbit cardiac tissue in vitro. Standard intracellular microelectrodes were used to measure electrophysiologic changes produced by beta-estradiol, local anesthetics, or both in dissected segments of heart containing the Purkinje fiber and ventricular muscle cells from ovariectomized rabbits. In tissues preincubated in beta-estradiol (3.3 nM), addition of bupivacaine (10.4 microM), or lidocaine (85.4 and 129 microM) decreased Vmax significantly more than in steroid-free Tyrode's (p<0.001). Alone, beta-estradiol had no effect on Vmax and depression of Vmax by the nonanesthetic Na+ channel blocker tetrodotoxin (TTX, 3 microM) was not potentiated by beta-estradiol. In preparations initially exposed to bupivacaine for 30 min, subsequent addition of beta-estradiol decreased Vmax further within 10 min (p<0.05). Bupivacaine's greater depression of Vmax at higher frequencies (3 Hz) was exaggerated by beta-estradiol. However, the rate-dependent slowing of conduction by bupivacaine was lessened or even reversed by beta-estradiol addition. Such rapid physiologic changes cannot be due to genomic actions by the hormone that take hours to manifest. Nor is the potentiation due to a general decrease in membrane excitability because the comparable inhibition by TTX is insensitive to estradiol. Because beta-estradiol potentiates the inhibition of myocardial excitability, but alleviates the slowing of impulse conduction between the Purkinje fiber and ventricular muscle produced by local anesthetics, the hormone must produce changes in more than one ionic conductance. Both pregnancy and conditions that abnormally alter levels of steroid hormones have ramifications for local anesthetic-induced cardiotoxicity and antiarrhythmic pharmacotherapeutics.

Cardiac electrophysiologic effects of articaine compared with bupivacaine and lidocaine.

Articaine is a local anesthetic structurally different from lidocaine and bupivacaine in that it contains a thiophene ring. We compared its cardiodepressant effects with those of lidocaine and bupivacaine in a randomized, blinded study using the isolated rabbit heart preparation. The hearts were removed quickly from thiamylal anesthetized/killed animals. The right septal wall was placed in a warm, aerated, Tyrode's solution-perfused chamber. The effects of the three local anesthetics on action potentials from the Purkinje fiber (PF) and ventricular muscle (VM) tissues were determined. Bupivacaine (17.4 microM) and articaine (141 microM) depressed action potential overshoot, amplitude, and maximal rate of depolarization (Vmax) by similar amounts. Bupivacaine's effects persisted significantly longer than articaine and lidocaine (P < 0.05). Rate-dependent decreases in steady-state (SS) Vmax were obtained with all three drugs. At their highest concentrations, bupivacaine (17 microM) and lidocaine (85 microM) produced decreases in SS Vmax from the first Vmax response. However, articaine (141 microM) increased SS Vmax at 1 and 2 Hz and only decreased SS Vmax at 3 Hz. During superfusion of a "bolus concentration" of the local anesthetics, bupivacaine blocked PF-VM conduction significantly longer than either articaine or lidocaine (P < 0.001). Articaine, at ten times its observed clinical blood concentration was significantly less cardiodepressant in these in vitro experiments than bupivacaine at five times its observed clinical blood concentration.

Effect of progesterone on the cardiac electrophysiologic alterations produced by ropivacaine and bupivacaine.

Bupivacaine-induced cardiotoxicity is enhanced in pregnant laboratory animals and in progesterone-pretreated isolated cardiac tissues. Ropivacaine is a new local anesthetic chemically related to bupivacaine. Although clinically equipotent with bupivacaine, ropivacaine is less cardiodepressant. Progesterone levels are elevated during pregnancy, and exogenously increasing progesterone levels in rabbits has increased bupivacaine's depressive effects on excitability. In neural tissues, bupivacaine's increased onset of block and depression of compound action potentials in tissues from progesterone-treated animals was similar to its effect in nerves from pregnant animals. This study determined whether exogenously increased progesterone levels can increase myocardial sensitivity to ropivacaine. Female ovariectomized rabbits were pretreated with progesterone for 4 days. After killing, the hearts were removed and Purkinje fibers (PFs) and ventricular muscle (VM) action potential parameters recorded. Tissues from animals receiving either progesterone or placebo were exposed to either ropivacaine or bupivacaine at concentrations ranging from 3.5 to 18.7 microM. Preparations were routinely paced at 2 Hz except where rate-dependent effects on the maximal rate of depolarization of phase zero (Vmax) were determined. Progesterone increased depression of myocardial Vmax only to bupivacaine (P less than 0.05). Ropivacaine was generally 3-5 times less potent in depressing cardiac electrophysiologic parameters. Bupivacaine demonstrated rate-dependent depression of Vmax that at higher frequencies was greater than ropivacaine's effects (P less than 0.05). Ropivacaine is less cardiodepressant than bupivacaine in this isolated PF-VM preparation. Exogenously increasing progesterone levels in vivo does not increase ropivacaine's depression of myocardial Vmax in isolated PF-VM tissues as it does to bupivacaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of progesterone on the cardiac electrophysiologic action of bupivacaine and lidocaine.

Pregnancy is accompanied by an increased cardiac and neural sensitivity to some local anesthetic agents such as bupivacaine. The current study was initiated to investigate the relationship between increased progesterone concentrations and the electrophysiologic effects of bupivacaine, and lidocaine in isolated Purkinje fiber (PF)-ventricular muscle (VM) preparations. Twenty-four oophorectomized female white rabbits were killed after receiving 30 mg.kg-1.day-1 of progesterone intramuscularly or peanut oil alone for 4 days. PF and VM action potentials were recorded using standard electrophysiologic procedures. Plasma progesterone concentrations were 5 +/- 2.9 ng/ml in control animals compared to 59.8 +/- 11.0 ng/ml in progesterone-treated animals (P less than 0.05). Bupivacaine (3.5-17.4 microM) depressed the maximal rate of depolarization (Vmax) of PF to a significantly greater extent in tissues from progesterone-treated animals as compared to control animals. For example, at 3.5 microM bupivacaine decreased PF Vmax 52% in progesterone-treated tissues compared to 32% in controls (P less than 0.05); the Vmax of VM was also depressed to a greater extent in tissues from progesterone-treated animals (P less than 0.001). Lidocaine did not demonstrate an enhanced depressant effect in tissues from progesterone-treated animals. These results indicate that progesterone selectively increases the cardiac membrane depressant effects of bupivacaine but not lidocaine. This may contribute to the enhanced toxicity of bupivacaine in pregnant animals.

Acute progesterone treatment has no effect on bupivacaine-induced conduction blockade in the isolated rabbit vagus nerve.

Pregnancy decreases anesthetic requirements during regional anesthesia. Using an in vitro animal model, this study attempts to elucidate the mechanism of hormonal effects on nerve conduction in desheathed rabbit vagus nerve. The acute effects of progesterone administration on neural blockade induced by bupivacaine were investigated in terms of changes in compound action potentials of A, B, and C fibers. No change in baseline compound action potential was found after 30 min of perfusion of the nerve with progesterone. Exposure of the nerve to progesterone before exposure to bupivacaine did not significantly increase the degree of conduction blockade produced by bupivacaine, and a radioactive assay demonstrated that progesterone was taken up acutely by neural tissue over a 45-min measurement period. These results indicate that although progesterone was taken up in significant amounts by neural tissue, an acute exposure does not increase the sensitivity of the nerves to bupivacaine. Hence, the increased sensitivity of nerves to local anesthetics seen with pregnancy or with chronic progesterone treatment requires some period of time to occur. The mechanism is therefore unlikely to be a direct effect of progesterone on the cell membrane but may involve hormonal effects on protein synthesis.

Hypertonic saline reverses bupivacaine-induced depression of rabbit Purkinje fiber depolarization Vmax.

The present study describes the effect of a hypertonic increase in sodium chloride concentration on electrophysiological parameters. Membrane depolarization was recorded from rabbit Purkinje fibers superfused with warm, aerated Tyrode solution. An amount of 5% NaCl above that in normal Tyrode solution (HyNaCl, 344 mOsm) was added to the bathing medium for 30 min, significantly increasing the maximal rate of depolarization (Vmax +15% vs -7% for control), with minor effects on other parameters. When bupivacaine was superfused over the preparation for 30 min either in normal Tyrode or in HyNaCl, Vmax was significantly decreased (33% and 15%, respectively). HyNaCl protected the cardiac tissues from the depressive effect of 0.5 microgram/ml bupivacaine. We suggest that the infusion of hypertonic saline in intact animals may prove effective in preventing or reversing the cardiodepressant effect of bupivacaine.

Hypertonic saline reverses bupivacaine-induced depression of rabbit Purkinje fiber depolarization Vmax

The present study describes the effect of a hypertonic increase in sodium chloride concentration on electrophysiological parameters. Membrane depolarization was recorded from rabbit Purkinje fibers superfused with warm, aerated Tyrode solution. An amount of 5% NaCl above that in normal Tyrode solution (HyNaCl, 344 mOsm) was added to the bathing medium for 30 min, significantly increasing the maximal rate of depolarization (Vmax + 15% vs - 7% for control), with minor effects on other parameters. When bupivacaine was superfused over the preparation for 30 min either in normal Tyrode or in HyNaCl, Vmax was significantly deveased (33% and 15%, respectively). HyNaCl protected the cardiac tissues from the depressive effect of 05micron/ml bupivacaine. We suggest that the infusion of hypertonic saline in intact animals may prove effective in preventing or reversing the cardiodepressant effect of bupivacaine

Cardiac electrophysiologic effects of lidocaine and bupivacaine.

The cardiac electrophysiologic effects of bupivacaine (B) and lidocaine (L) were evaluated in an isolated rabbit Purkinje fiber-ventricular muscle model to determine the effects of a) progressively increasing and b) decreasing concentrations of B and L on transmembrane action potentials. Bupivacaine (3 and 5 micrograms/ml) significantly decreased diastolic resting potential, maximum rate of depolarization, and action potential amplitude. Lidocaine (10-20 micrograms/ml) also decreased maximum rate of depolarization and action potential amplitude, but the decreases were significantly different from those produced by B. High concentrations of B (30 micrograms/ml) and L (100 micrograms/ml) resulted in delayed conduction between Purkinje fibers and ventricular muscle cells and, ultimately, conduction blockade. The duration of conduction blockade was significantly longer with B than with L. The results of this study indicate that B produces electrophysiologic changes in cardiac tissue that may produce ventricular arrhythmias of a reentrant type.