Laurence Galanti

Beneficial neurohormonal profile of spironolactone in severe congestive heart failure: results from the RALES neurohormonal substudy.

OBJECTIVES We sought to evaluate the effects of spironolactone on neurohormonal factors in patients with severe congestive heart failure (CHF). BACKGROUND In the Randomized ALdactone Evaluation Study (RALES), spironolactone, an aldosterone receptor antagonist, significantly reduced mortality in patients with severe CHF. However, the mechanism of action and neurohormonal impact of this therapy remain to be clarified. METHODS The effects of spironolactone (25 mg/day; n = 54) or placebo (n = 53) on plasma concentrations of the N-terminal portion of atrial natriuretic factor (N-proANF), brain natriuretic peptide (BNP), endothelin-1 (ET-1), norepinephrine (NE), angiotensin II (AII), and aldosterone were assessed in a subgroup of 107 patients (New York Heart Association functional class III to IV; mean ejection fraction 25%) at study entry and at three and six months. RESULTS Compared with the placebo group, plasma levels of BNP (-23% at 3 and 6 months; p = 0.004 and p = 0.05, respectively) and N-proANF (-19% at 3 months, p = 0.03; -16% at 6 months, p = 0.11) were decreased after spironolactone treatment. Over time, spironolactone did not modify the plasma levels of NE and ET-1. Angiotensin II increased significantly in the spironolactone group at three and six months (p = 0.003 and p = 0.001, respectively). As expected, a significant increase in aldosterone levels was observed over time in the spironolactone group (p = 0.001). CONCLUSIONS Spironolactone administration in patients with CHF has opposite effects on circulating levels of natriuretic peptides (which decrease) and aldosterone and AII (which increase). The reduction in natriuretic peptides might be related to changes in left ventricular diastolic filling pressure and/or compliance, whereas the increase in AII and aldosterone probably reflects activated feedback mechanisms. Further studies are needed to link these changes to the beneficial effects on survival and to determine whether the addition of an AII antagonist could be useful in this setting.

Effect of erythromycin on gastric motility in mechanically ventilated critically ill patients: a double-blind, randomized, placebo-controlled study.

OBJECTIVE To document the action of erythromycin on gastric emptying and motility in mechanically ventilated patients. DESIGN Crossover, double-blind, randomized, placebo-controlled study. SETTING General intensive care unit in a university hospital. PATIENTS Ten patients, mechanically ventilated, in a stable hemodynamic condition. INTERVENTIONS Erythromycin (200 mg i.v. over 30 mins) and placebo were infused at mid-morning, on two consecutive days, in a random order. Pressure changes in the gastric antrum were recorded by means of a multi-lumen manometric tube (perfused catheter technique) over a period of 300 mins, beginning with the institution of the erythromycin or placebo infusion. Gastric emptying was simultaneously assessed by the kinetics of the absorption of acetaminophen delivered into the stomach (1 g with 20 mL of water) immediately before the infusion. MEASUREMENTS AND MAIN RESULTS Motility was quantified by determining the number of contractions, the amplitude of contractions, and the Motility Index (Motility Index = natural logarithm [sum of amplitude x number of contractions] + 1). Comparison between placebo and erythromycin was made for the first hour after the infusion and for the whole recording session. The maximal acetaminophen concentration, the time to reach the peak acetaminophen concentration, and the area under the concentration-time curve at 60 mins were obtained from serial determinations of plasma acetaminophen concentrations. Compared with placebo, the mean number of contractions (104 +/- 34 vs. 5 +/- 8; p = .003), the mean amplitude of contractions (52 +/- 16 vs. 20 +/- 17 mm Hg; p = .005), and the Motility Index (13.06 +/- 0.95 vs. 4.45 +/- 3.54; p = .004) were significantly increased during the first hour after erythromycin infusion compared with placebo. Number of contractions (p = .017) and Motility Index (p < .001) after erythromycin infusion remained significantly higher when values throughout the whole recording session were considered. The following data were noted after erythromycin was infused: a) the time to reach the peak acetaminophen concentration was shorter (32 +/- 8 vs. 171 +/- 93 mins; p = .007); b) the maximal acetaminophen concentration was higher (22.09 +/- 6.23 vs. 5.38 +/- 3.80 micrograms/mL; p = .007); and c) the area under the concentration-time curve at 60 mins increased markedly (730 +/- 269 vs. 72 +/- 42 micrograms/min/mL; p = .002) as compared with placebo. CONCLUSION In mechanically ventilated patients, intravenous erythromycin (200 mg over 30 mins) increases indices of antral motility and accelerates gastric emptying as assessed by the kinetics of acetaminophen absorption.

Serum Lipoprotein(a) in Patients With Diabetes Mellitus

OBJECTIVE To investigate subjects with different types of diabetes mellitus regarding their serum levels of lipoprotein(a). High serum Lp(a) concentration is associated with a high risk of coronary heart disease. Diabetic patients are prone to developing coronary heart disease. RESEARCH DESIGN AND METHODS The subjects were 66 type I diabetic patients, 100 type II diabetic patients treated with diet alone or diet combined with oral hypoglycemic agents, and 46 insulin-requiring type II diabetic patients. Subjects were compared with 142 nondiabetic outpatients. RESULTS Subjects with insulin-requiring type II diabetes mellitus were found to have an increase both in serum Lp(a) concentration and in prevalence of serum Lp(a) concentration >30 mg/dl compared with the other groups of diabetic patients and nondiabetic control subjects. A nonsignificant increase in the prevalence of coronary heart disease was also found in insulin-requiring type II diabetic patients. The levels of serum concentrations of Lp(a) were not significantly related to the degree of glycemic control, duration of diabetes, presence of macrovascular disease, or intake of female hormone therapy. High levels of Lp(a) in this group of diabetic patients could not be explained by the presence of albuminuria. CONCLUSIONS Insulin-requiring type II diabetic patients have high levels of Lp(a). Chronic hyperinsulinemia might be an eventual causal factor.

Does in utero exposure to heavy maternal smoking induce nicotine withdrawal symptoms in neonates

Maternal drug use during pregnancy is associated with fetal passive addiction and neonatal withdrawal syndrome. Cigarette smoking—highly prevalent during pregnancy—is associated with addiction and withdrawal syndrome in adults. We conducted a prospective, two-group parallel study on 17 consecutive newborns of heavy-smoking mothers and 16 newborns of nonsmoking, unexposed mothers (controls). Neurologic examinations were repeated at days 1, 2, and 5. Finnegan withdrawal score was assessed every 3 h during their first 4 d. Newborns of smoking mothers had significant levels of cotinine in the cord blood (85.8 ± 3.4 ng/mL), whereas none of the controls had detectable levels. Similar findings were observed with urinary cotinine concentrations in the newborns (483.1 ± 2.5 μg/g creatinine versus 43.6 ± 1.5 μg/g creatinine; p = 0.0001). Neurologic scores were significantly lower in newborns of smokers than in control infants at days 1 (22.3 ± 2.3 versus 26.5 ± 1.1; p = 0.0001), 2 (22.4 ± 3.3 versus 26.3 ± 1.6; p = 0.0002), and 5 (24.3 ± 2.1 versus 26.5 ± 1.5; p = 0.002). Neurologic scores improved significantly from day 1 to 5 in newborns of smokers (p = 0.05), reaching values closer to control infants. Withdrawal scores were higher in newborns of smokers than in control infants at days 1 (4.5 ± 1.1 versus 3.2 ± 1.4; p = 0.05), 2 (4.7 ± 1.7 versus 3.1 ± 1.1; p = 0.002), and 4 (4.7 ± 2.1 versus 2.9 ± 1.4; p = 0.007). Significant correlations were observed between markers of nicotine exposure and neurologic-and withdrawal scores. We conclude that withdrawal symptoms occur in newborns exposed to heavy maternal smoking during pregnancy.

Role of Endogenous Endothelin-1 in Experimental Renal Hypertension in Dogs

BACKGROUND Endothelin-1, a vasoconstrictive peptide released by endothelium, may be involved in the pathophysiology of hypertension. The goal of the present study was to evaluate the role of endogenous endothelin-1 in renal hypertension in dogs. The model of hypertension consisted of silk tissue wrapping of the left kidney, which produced hypertension associated with perinephritis after 6 to 8 weeks. METHODS AND RESULTS Thirty-two anesthetized open chest dogs were studied randomly: 8 dogs with perinephritic hypertension received the nonpeptidic ETA-ETB receptor antagonist bosentan (group 1); 8 other hypertensive dogs received the vehicle solution (group 2); 8 healthy dogs received bosentan (group 3); and 8 healthy dogs received the vehicle solution (group 4). Bosentan was injected as an intravenous bolus (3 mg/kg) followed by a 1-hour infusion at a rate of 7 mg.kg-1.h-1. In hypertensive dogs, bosentan produced a similar decrease (P = .0001) of both left ventricular systolic and mean aortic pressures, which averaged 38 mm Hg (-22% and -24%, respectively). These parameters remained unchanged with the vehicle solution. Left ventricular end-diastolic and left atrial pressures also declined significantly with bosentan (P = .0005 and P < .05, respectively). Left ventricular lengths tended to decrease. The other cardiovascular parameters (heart rate, peak [+]dP/dt, time constant of relaxation, and coronary vascular resistance) did not change significantly. In healthy dogs, bosentan decreased mean aortic pressure by 19 mm Hg (P = .004). Vehicle solution had no effect. Plasma endothelin-1 levels, similar under basal conditions in healthy and hypertensive dogs, increased 30-fold with bosentan (P = .0001). CONCLUSIONS Specific endothelin-1 receptor antagonism markedly lowers blood pressure in experimental hypertension but is less effective on blood pressure of healthy animals. This suggests that endothelin-1 plays a role in the pathophysiology of hypertension but contributes to a lesser extent to the maintenance of normal blood pressure. This role of endothelin-1 is unrelated to its plasma levels. The increase of plasma endothelin-1 with bosentan, due either to a displacement of endothelin-1 from its receptor or to a feedback mechanism, does not prevent this blood pressure reduction.

Long‐term stability of cefuroxime and cefazolin sodium in intravenous infusions

Cefazolin and cefuroxime sodium are often used as antibiotic infusions for hospitalized patients. Because advance preparation of these intravenous solutions is efficient, the stability of both antibiotics stored at 4 °C in polyvinyl chloride (PVC) bags was studied.

Effects of endothelin-1 at pathophysiologic concentrations on coronary perfusion and mechanical function of normal and postischemic myocardium.

We assess hemodynamic, vascular, and hormonal effects of endothelin-1 (ET-1) at pathophysiologic levels on normal and ischemic myocardium. Thirty conscious chronically instrumented dogs were studied before, during, and after a 10-min coronary artery occlusion (CAO) performed either during ET-1 infusion (2.5 ng/ kg min, n = 15) or during placebo infusion (n = 15). ET-1 infusion produced an increase in plasma ET-1 (from 1.3 ± 0.1 to 11.5 ± 1.1 pAf, p < 0.0001) during CAO (pathophysiologic value). Left anterior descending artery (LAD) blood flow (measured by Doppler flow probe) decreased similarly during CAO with ET-1 or placebo (p = 0.0001, NS, ET-1 vs. placebo). Both endocardial and epicardial blood flows in ischemic regions also decreased (p = 0.0001) during CAO but were threefold greater with ET-1 than with placebo (endocardium 42 ± 7 vs. 14 ± 2 ml/min/100 g, p = 0.003). No significant difference in myocardial blood flows between groups was observed in control regions. CAO produced increases (p < 0.005) in heart rate (HR), mean aortic pressure (AOP), and ventricular pressures but no change in atrial pressures. The changes in these parameters were comparable in the ET-1 and placebo groups. Despite the greater residual flow during CAO, however, ET-1 decreased the function of the ischemic zone during reperfusion as assessed by systolic shortening (p < 0.05). Atrial natriuretic factor (ANF), unchanged during CAO with placebo, increased from 38.3 ± 6.1 to 53.3 ± 10 pM with ET-1 (p = 0.02). Thus, ET-1, at pathophysiologic levels, increases collateral blood flow in ischemic myocardium without affecting perfusion of normal myocardium. It decreases postischemic myocardial recovery and directly stimulates ANF release.

Effect of the freezing conditions and microwave thawing power on the stability of cefuroxime in dextrose 5% infusion polyolefin bags at 4 degrees C.

BACKGROUND Intravenous cefuroxime sodium solution could be prepared in advance by a centralized hospital pharmacy service to improve safety and time management. OBJECTIVE To investigate the effect of freezing and microwave thawing on the solution stability of cefuroxime. METHODS Cefuroxime 1.5 g in 100 mL of dextrose 5% in polyolefin bags was frozen individually (group A) or in one package (group B) for 98 days at −20 °C. The solutions were then thawed using microwaves at 270 (light cycle) or 800 watts (hard cycle) and stored at 4 °C. The cefuroxime concentration was measured by HPLC. Visual inspection was performed and pH was measured at that time. Stability of the solution was defined as a concentration remaining superior to 90% of the initial concentration by regression analysis. RESULTS No color change or precipitation in the solutions was observed. In group A, stability was at least 23 and 21 days after light and hard cycle thawing, respectively. In group B, stability was at least 21 and 18 days, respectively, with the pH increasing without affecting chromatographic parameters. CONCLUSIONS The optimal conditions for advance preparation of a solution containing cefuroxime 1.5% in dextrose 5% may be freezing of individual containers followed by a light cycle of microwave thawing.

Doxorubicin-loaded drug-eluting beads (DC Bead®) for use in transarterial chemoembolization: A stability assessment

Purpose: Evaluation of doxorubicin stability over time when stored into the DC Bead embolic agent, in various containers, which are used for the delivery of the doxorubicin-loaded beads to the patients for up to 14 days under refrigerated conditions. Methods: The doxorubicin was loaded through the ionic exchange mechanism into the calibrated polyvinyl alcohol-based hydrogel beads (DC Bead), with the loading process carried out either in the original DC Bead glass vials or within a polypropylene plastic syringe. The loaded samples were eluted at given time points and the extracted doxorubicin was analysed by high-performance liquid chromatography for concentration and chromatographic area response purity. Results: The variance on the doxorubicin concentration of the samples stored in the syringes under refrigerated conditions was less than 10% over the 14 days period. The chromatographic purity of doxorubicin eluted from the DC Bead in their primary glass vial packaging was measured at 99.7%. The dissolution test showed that the elution rate and amount recovered from samples stored in vials were statistically similar between Day 0 and Day 14. The chromatographic purity of the doxorubicin loaded into DC Bead in presence of non-ionic contrast medium was >99.0% for 7 days under refrigerated conditions. Conclusions: Doxorubicin-loaded DC Bead® are shown to have adequate physicochemical stability over a period of 14 days when stored in syringes or vials under refrigerated conditions for up to 14 days. The admixtures of doxorubicin-loaded beads with contrast medium are stable for up to 7 days under refrigerated conditions.

Tobacco smoking and alcohol and drug consumption in a large, young healthy population.

The relationships between tobacco smoking and both alcohol and drug consumption were investigated in 2 431 healthy individuals aged 18-29 y. We used a questionnaire to evaluate smoking habits and alcohol and drug intake, and these parameters (i.e., cotinine-to-creatinine concentration ratio, amphetamines, cannabinoids, opiates, and cocaine) were quantified via urine analyses. Urinary cotinine concentration was significantly higher in current smokers (mean +/- standard deviation: 717 +/- 61 ng/mg creatinine, n = 881) than in non- or exsmokers (32 +/- 16 ng/mg creatinine, n = 1550). Information gleaned from the questionnaires revealed that there was a greater proportion of current smokers among consumers of alcohol than among nonconsumers. Significantly (p < .001) more current smokers than non- or exsmokers self-reported that they consumed sedatives, stimulants, or illegal drugs. Urinary cotinine concentrations were highest in consumers of alcohol and in self-reported consumers of sedatives (p < .0001), stimulants (p = .01), and illegal drugs (p < .0001). We found higher urinary cotinine concentrations in subjects who had positive urinary amphetamines, cannabinoids, or opiates. Even though the prevalence of alcohol and drug consumption remained low in the population we studied, such behaviors were clearly related to tobacco smoking.