Neuroendocrine prediction of left ventricular function and heart failure after acute myocardial infarction. The Christchurch Cardioendocrine Research Group.

OBJECTIVE: To determine the relations of plasma levels of brain natriuretic peptide (BNP), atrial natriuretic factor (ANF), N-terminal ANF (N-ANF), cyclic guanosine monophosphate (cGMP; the cardiac peptide second messenger), and plasma catecholamines to left ventricular function and to prognosis in patients admitted with acute myocardial infarction. DESIGN: Plasma hormones and ventricular function (radionuclide ventriculography) were measured 1-4 days after myocardial infarction in 220 patients admitted to a single coronary care unit. Radionuclide scanning was repeated 3-5 months after infarction. Clinical events were recorded over a mean period of 14 months. RESULTS: Both early and late left ventricular ejection fraction (LVEF) were most closely related to plasma BNP (r = -0.60, n = 220, p < 0.001; and r = -0.53, n = 192, p < 0.001, respectively), followed by ANF, N-ANF, cGMP, and the plasma catecholamines. Early plasma BNP concentrations less than twofold the upper limit of normal (20 pmol/l) had 100% negative predictive value for LVEF < 40% at 3-5 months after infarction. In multivariate analysis incorporating all the neurohormonal factors, only BNP remained independently predictive of LVEF < 40% (p < 0.005). Survival analysis by median levels of candidate predictors identified BNP as the most powerful discriminator for death (p < 0.0001). No early deaths (within 4 months) occurred in patients with plasma BNP concentrations below the group median (27 pmol/l), and over follow up only three of 26 deaths occurred in this subgroup. Of all episodes of left ventricular failure, 85% occurred in patients with plasma BNP above the median (p < 0.001). In multivariate analyses, BNP alone gave additional predictive information beyond sex, age, clinical history, LVEF, and plasma noradrenaline for both subsequent onset of LVF and death. CONCLUSIONS: Plasma BNP measured within 1-4 days of acute myocardial infarction is a powerful independent predictor of left ventricular function, heart failure, or death over the subsequent 14 months, and superior to ANF, N-ANF, cGMP, and plasma catecholamines.

Seroprevalence of Helicobacter pylori in the adult population of Christchurch: risk factors and relationship to dyspeptic symptoms and iron studies.

AIM: To determine the prevalence of Helicobacter pylori infection in subjects randomly selected from the Christchurch population and to determine the risk factors and symptoms related to the infection. METHODS: A list of names was randomly generated from the 1996 electoral roll and subjects were sequentially contacted and invited to participate. A questionnaire on dyspeptic symptoms was completed and the subject's serum was analysed for H. pylori antibodies using the Roche method. Equivocal samples were retested by the Meridian method. RESULTS: One thousand and sixty-four subjects participated in the study. In four subjects results for H. pylori were indeterminate and these subjects were excluded from analysis. Of the remaining 1060 subjects, 254 (24.0%) were seropositive for H. pylori. The seropositivity in males (n=444) was 25.9% and in females (n=616) 22.6%. On multivariate analysis age, ethnicity, low income and smoking > 20 cigarettes per day were all independent predictors of H. pylori seropositivity. H. pylori positive subjects had shorter stature compared to those who were seronegative. The symptom scores for dyspepsia were similar in both the seropositive and seronegative subjects. In males the serum iron levels were lower in seropositive subjects but there were no significant differences in serum ferritin in either males or females between seropositive and seronegative subjects. CONCLUSION: H. pylori is a common infection in the Christchurch community with the prevalence increasing significantly with age. H. pylori positive subjects had shorter stature and in males lower serum iron levels were observed. Infection was not associated with an increased risk of dyspeptic symptoms.

Experience of once-daily aminoglycoside dosing using a target area under the concentration-time curve.

BACKGROUND: Many centres are changing to once-daily aminoglycoside administration. However, proposed methods for this practice often have theoretical and practical difficulties. We have developed a method in which a target area under the concentration-time curve (AUC) is used instead of traditional peak and trough serum concentrations. AIMS: To analyse our experience with the target AUC method in the first 100 courses of once-daily aminoglycoside administration in the Christchurch, New Zealand hospitals. METHODS: Following a starting dose of 5-7 mg/kg, administered by 30-minute infusion, the AUC was calculated using two serum aminoglycoside concentrations taken at one and six-14 hours after the start of the infusion. Dose adjustment was made to correct for any difference between the calculated AUC and a target AUC (72-101 mg.1(-1).h). The method was assessed for practicality and precision in 100 courses of treatment. The incidence of aminoglycoside toxicity was documented. RESULTS: The mean final dose of 6.68 mg/kg, and AUC of 92.8 mg.1(-1).h, were significantly different from the mean starting dose and AUC of 5.67 mg/kg and 74.0 mg.1(-1).h, respectively. The method appeared to be more precise than empirical dosing at achieving the target AUC even though the final recommended dose had more variability than the starting dose. Although the study was uncontrolled, observed nephrotoxicity (2%) and ototoxicity (up to 6.9%) were no greater than expected from the results of other studies. There were no deaths related to antibiotic failure. CONCLUSIONS: The AUC method was practical, and more appropriate for once-daily dosing than the conventional method of aiming for target peak and trough concentrations. Dose adjustment can be made before the next dose.

The pharmacokinetics of oral fleroxacin and ciprofloxacin in plasma and sputum during acute and chronic dosing.

AIMS: To examine the pharmacokinetics of ciprofloxacin and fleroxacin in plasma and sputum of patients with an acute exacerbation of chronic bronchitis or bronchiectasis following the first dose and again during the third day of treatment. METHODS: Twelve patients, aged >35 years, with acute infective exacerbation of bronchitis or bronchiectasis were allocated randomly to treatment with either fleroxacin 400 mg daily or ciprofloxacin 500 mg twice daily in an open, parallel group design. Plasma and sputum were collected during the first and third days of treatment. The time course of concentrations in sputum was modelled assuming that it acted as a negligibly small compartment of distribution. RESULTS: The mean sputum to plasma ratios of both ciprofloxacin and fleroxacin were approximately 1 on both days 1 and 3. Peak concentrations of ciprofloxacin in sputum were achieved 1.6 (95% CI on mean difference 0.8-2.3) and 1.2 (0.4-1.9) h later than in plasma on day 1 and day 3, respectively (mean difference +/- 95% confidence interval). For fleroxacin, the corresponding delay in time to peak concentrations was less marked and not significant. Fleroxacin accumulated in plasma (accumulation index 1.52+/-0.07) and sputum (accumulation index 1.79+/-0.39) from day 1 to day 3. Accumulation did not occur for ciprofloxacin because the dose interval (12 h) was considerable longer than its half life (3-4 h). CONCLUSIONS: The sputum to plasma ratio of ciprofloxacin and fleroxacin is approximately 1. The time to peak concentrations of ciprofloxacin in sputum is slightly delayed compared with plasma. Fleroxacin accumulates over time in both plasma and sputum consistent with its longer half-life.

Paroxetine in human milk.

AIMS: The primary aims of the study were to estimate the exposure of infants to paroxetine via breast milk and to determine the maternal milk:plasma ratio (M/P) of paroxetine. Secondary aims were to compare single point and area under the curve (AUC) estimates of M/P, to assess variability of M/P in fore and hind milk, and to compare the observed M/P with that predicted by a model. METHODS: Two studies were performed. In one study, six nursing mothers who were being treated with paroxetine were studied over a 24 h dose interval at steady-state. The total amount of paroxetine in the milk was measured, which represented the 'dose' to the infant. The M/PAUC was calculated and compared with a predicted value. In the second study, four nursing mothers who were being treated with paroxetine, were studied at steady-state, around a normal infant feeding time. A single plasma sample and a prefeed milk sample were taken approximately 3 h after the morning dose of paroxetine, and a postfeed milk sample taken around 1 h later. The dose received by the infant was estimated from the average milk concentrations of the pre and postfeed samples using standard assumptions, and M/P calculated directly. Plasma concentrations of paroxetine were measured in 8 of the 10 infants in the two studies. RESULTS: The mean dose of paroxetine received by the infants in the first study was 1.13% (range 0.5-1.7) of the weight adjusted maternal dose. The mean M/PAUC was 0.39 (range 0.32-0.51). The predicted M/P was 0.22. The mean dose of paroxetine received by the infants in the second study was 1.25% (range 0.38-2.24) of the weight adjusted maternal dose. The mean M/P was 0.96 (range 0.31-3.33) and did not differ between fore and hind milk. The drug was not detected in the plasma of seven of the infants studied and was detected but not quantifiable (<4 microg l-1 ) in one infant. No adverse effects were observed in any of the infants. CONCLUSIONS: Measured M/P and estimated infant dose were similar in the two studies, although the range was wider for the single point study. Paroxetine can be considered 'safe' during breast feeding because the dose transferred to the infant is well below the recommended safety limit of 10% of the weight adjusted maternal dose, concentrations in the infants were generally undetectable, and no adverse effects were reported.

Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: new neurohormonal predictors of left ventricular function and prognosis after myocardial infarction.

BACKGROUND: Newly discovered circulating peptides, N-terminal pro-brain natriuretic peptide (N-BNP) and adrenomedullin (ADM), were examined for prediction of cardiac function and prognosis and compared with previously reported markers in 121 patients with myocardial infarction. METHODS AND RESULTS: The association between radionuclide left ventricular ejection fraction (LVEF) and N-BNP at 2 to 4 days (r=-.63, P<.0001) and 3 to 5 months (r=-.58, P<.0001) after infarction was comparable to that for C-terminal BNP and far stronger than for ADM (r=-.26, P<.01), N-terminal atrial natriuretic peptide (N-ANP), C-terminal ANP, cGMP, or plasma catecholamine concentrations. For prediction of death over 24 months of follow-up, an early postinfarction N-BNP level > or = 160 pmol/L had sensitivity, specificity, positive predictive value, and negative predictive values of 91%, 72%, 39%, and 97%, respectively, and was superior to any other neurohormone measured and to LVEF. Only 1 of 21 deaths occurred in a patient with an N-BNP level below the group median (Kaplan-Meier survival analysis, P<.00001). For prediction of heart failure (left ventricular failure), plasma N-BNP > or = 145 pmol/L had sensitivity (85%) and negative predictive value (91%) comparable to the other cardiac peptides and was superior to ADM, plasma catecholamines, and LVEF. By multivariate analysis, N-BNP but not ADM provided predictive information for death and left ventricular failure independent of patient age, sex, LVEF, levels of other hormones, and previous history of heart failure, myocardial infarction, hypertension, or diabetes. CONCLUSIONS: Plasma N-BNP measured 2 to 4 days after myocardial infarction independently predicted left ventricular function and 2-year survival. Stratification of patients into low- and high-risk groups can be facilitated by plasma N-BNP or BNP measurements, and one of these could reasonably be included in the routine clinical workup of patients after myocardial infarction.