Granulocyte-macrophage colony-stimulating factor (GM-CSF) to increase efficacy of intensive sequential chemotherapy with etoposide, mitoxantrone and cytarabine (EMA) in previously treated acute myeloid leukemia: a multicenter randomized placebo-controlled trial (EMA91 Trial).

The EMA86 study showed efficacy of intensive sequential chemotherapy with mitoxantrone, 12 mg/m2 day on days 1-3, etoposide, 200 mg/m2/day as a continuous infusion on days 8-10 and cytarabine (araC), 500 mg/m2/day as continuous infusion on days 1-3 and 8-10 (EMA regimen) in previously treated patients with AML. The goal of the EMA91 study was to determine whether administration of GM-CSF between the two sequences of EMA chemotherapy and during the second sequence could increase therapeutic efficacy by potentially increasing leukemic cell recruitment into the S phase of cell cycle before the second sequence. One hundred and ninety-two patients aged less than 65 years with previously treated AML received GM-CSF, 5 microg/kg/day or placebo from day 4 to day 8 of EMA chemotherapy. One hundred and twenty were refractory and 72 were in first relapse after a complete remission (CR) of more than 6 months duration. CR rates after one course of chemotherapy were 65% in the GM-CSF group (refractory: 51%; first relapse: 89%), not significantly different from the 59% CR rate (refractory: 46%; first relapse: 81%) in the placebo group. Median time to recovery of neutrophils was 38 and 37 days and median time to last platelet transfusion 32 and 32 days respectively in the GM-CSF and placebo groups. WHO grade > or = 3 non-hematologic toxicities were mainly sepsis (45% and 51%, respectively) and mucositis (34% and 31%) and did not differ between the two groups. Toxic death rate was 5% and 8%, respectively, in the GM-CSF and placebo groups. Patients achieving CR were scheduled to receive six courses of maintenance with reduced-dose EMA. Time to progression tended to be longer in the GM-CSF group (median 154 vs 115 days, progression-free rate at 18 months 33% vs 19%, P = 0.08), particularly in refractory patients (P = 0.06). However, at the current follow-up, this did not translate into a significantly longer disease-free survival and survival. Cell cycle studies showed increased recruitment of cells in the S phase between day 4 and day 8 in the GM-CSF group compared to placebo (P = 0.006). However, this did not significantly relate to prognosis in this cohort of patients. GM-CSF might marginally increase efficacy of sequential chemotherapy without increasing its toxicity in the absence of any detected relationship between this effect and observed leukemic cell recruitment into the cell cycle.

Ramipril-induced regression of left ventricular hypertrophy in treated hypertensive individuals. HYCAR Study Group.

The objective of this trial was to assess the effects of 6-month daily treatment with two doses of ramipril on left ventricular mass and the dependence of this on blood pressure changes in hypertensive patients with left ventricular hypertrophy. After a selection phase of 4 to 6 weeks with patients under antihypertensive therapy with 20 mg furosemide daily, 115 patients with either controlled or uncontrolled hypertension and left ventricular hypertrophy were randomized in a double-blind manner to receive either placebo (n = 40), 1.25 mg (low dose, n = 38), or 5 mg (regular dose, n = 37) ramipril daily for 6 months. Treatment with furosemide was continued unchanged during this phase. The main outcome measured was left ventricular hypertrophy regression as assessed from central blind reading of echocardiograms recorded at randomization and after 6 months. No significant differences were observed for changes in casual or ambulatory blood pressure between the three groups. Left ventricular mass index was found to be significantly reduced in patients receiving 5 mg ramipril compared with those receiving placebo (-10.8 +/- 3.7 versus +4.1 +/- 4.0 g/m2, P = .008); in patients receiving 1.25 mg ramipril, the difference was close to borderline significance compared with placebo (-7.0 +/- 4.3 g/m2, P = .06). Similar results were observed for changes in left ventricular mass (-20.3 +/- 6.6 and -13.0 +/- 7.8 g in the 5- and 1.25-mg ramipril groups, respectively, versus +9.1 +/- 7.2 g in the placebo group; P = .004 and .04, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Population pharmacokinetics of recombinant factor VIIa in volunteers anticoagulated with acenocoumarol.

This study establishes a population PK model for FVII clotting activity (FVII:C) after injection of recombinant activated factor VII (rFVIIa) to healthy volunteers. Twenty eight volunteers, anticoagulated with acenocoumarol, received one or two rFVIIa injections, with dose ranging from 5 to 320 microg/kg. The FVII:C kinetic was fitted to a 2 compartment model, with continuous "endogenous perfusion" mimicking endogenous activity. Estimated clearance was 2.4 1/h (20% inter-individual variability and 9% inter-period variability). The volume of distribution at steady-state appeared to be significantly dose dependent: 78 ml/kg for doses < or = 20 microg/kg and 88 ml/kg for doses > 20 microg/kg respectively, with 16% inter-individual variability. The dose producing 50% of the maximum drop of INR was estimated to be 2.2 microg/kg. The model will be used to better define the dosage regimen for future clinical developments.

[Remission of left ventricular hypertrophy with ramipril independently of blood pressure changes: the HYCAR study (cardiac hypertrophy and ramipril)]. / Régression de l'hypertrophie ventriculaire gauche par le ramipril, indépendamment des variations tensionnelles: l'étude HYCAR (hypertrophie cardiaque et ramipril).

Most studies of the regression of left ventricular hypertrophy by antihypertensive treatment have methodological weaknesses and have not shown if regression of left ventricular hypertrophy can be obtained independently of blood pressure reduction. In the HYCAR study, after an inclusion phase of 4 to 6 weeks on furosemide (20 mg/day), 115 patients with left ventricular hypertrophy were randomised in a double blind manner to placebo group (N = 40), ramipril, 1.25 mg/day, (N = 38) or 5 mg/day (N = 37) for a period of 6 months. Furosemide was continued during the double blind treatment period. Echocardiography and ambulatory blood pressure monitoring were performed just before the randomisation and at 6 months. At the end of the study, there was no significant difference between the casual and ambulatory blood pressure changes. Expressed in g/m, the left ventricular mass index decreased significantly with respect to placebo in the ramipril 5 mg group (-12.2 +/- 3.9 versus +5.5 +/- 4.3 g/m2, p = 0.003) and in the 1.25 mg group (-7.5 +/- 4.6 g/m2, p = 0.04). The reduction in left ventricular mass index expressed in g/m2 was significant in the 5 mg ramipril (p = 0.008) but not in the 1.25 mg ramipril group (p = 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)

[Diagnostic contribution of abnormal delayed-type hypersensitivity to Candida albicans. Characterization test by activation of cells sensitized to successive dilutions of Candida]. / Apport au diagnostic de l'hypersensibilité de type retardé anormale à Candida albicans. Essai de caractérisation par activation de cellules sensibilisées avec des dilutions successives de Candida albicans.

By measuring the activation of different cell models (lymphocytes and lymphocytic subsets) in the presence of Candida albicans with flow cytometry reading, it is possible to show that successive dilutions of Candida albicans can lead to lymphocyte activation in abnormally-sensitized subjects. In a first trial, 10 subjects were tested in duplicate. The decrease of activity of the dilutions does not appear to be regular in relation to the progression of the dilutions. The activity of the dilutions wanes relatively rapidly with the first dilutions, then recurs later very distinctly, at the 6th dilution, then ebbs, then reappears in similar manner at the 9th, the 14th, and finally, the 19th dilution. Cell reactivity appears to differ depending on the subject. It can be represented through the calculated slope of the regression line, for each series of data. It therefore appears feasible to determine a threshold of reactivity and a scale of sensitivity, to make it possible to specify the degree of abnormal reactivity existing at a given time for a given subject. The constancy of the activity of the different dilutions tested, on 10 cultures of a single cell suspension, is especially well demonstrated in the second trial, showing unusually small standard deviations. Thus, the question arises as to the exact nature of the observed phenomenon and of its analysis from a physical-chemical point of view, with regard to the pharmacological effect of successive dilutions of Candida albicans.

[Diagnosis of delayed type hypersensitivity to Candida albicans. Evaluation of lymphocyte activation by flow cytometry (171 observations)]. / Diagnostic de l'hypersensibilité de type retardé pathologique à Candida albicans. Intérêt de l'évaluation de l'activation lymphocytaire en cytométrie en flux (à propos de 171 observations.

Abnormal delayed-type hypersensitivy to Candida albicans, since it results in an excessive reaction of the immune system, is very difficult to diagnose. This study shows that the syndromic reaction observed after intradermal injection of an extract of Candida albicans, in patients suspected of abnormal delayed-type hypersensitivy to this antigen, is associated with the presence of specific circulating T cells, detectable through cell culture in the presence of Candida albicans. There is a very significant correlation between the clinical symptoms, the cutaneous tests, and the lymphocyte activation tests. This abnormal reactivity essentially involves the CD8 cells.

Survey of the attitudes to management of acute pyelonephritis in children. GEP.

Although urinary tract infections are of particular concern in young children, as they may lead to permanent health problems, there is no consensus for their acute management. We carried out a mailed survey of 455 general practitioners, 143 paediatricians (randomly selected from a list of physicians in the Rhône-Alpes region of France) and 45 paediatric nephrologists (all the members of the "Société de Néphrologie Pédiatrique") to examine their attitudes to the management of a fictitious case of a young girl with symptoms indicative of acute pyelonephritis. The responses given by the general practitioners and paediatricians were similar, whereas those given by the paediatric were similar, whereas those given by the paediatric nephrologists were often different, for example 20% of the general practitioners and 17% of the paediatricians said they would hospitalize the child, compared with 69% of the paediatric nephrologists. The majority of the general practitioners and paediatricians favoured single oral antibiotic therapy, whereas the paediatric nephrologists were split between single and combined antibiotic therapy, but preferred intravenous administration. The most frequently prescribed drug was a penicillin. The heterogeneity of the results from this survey stresses the need for the assessment of various strategies in terms of their efficacy for preventing kidney scarring and their risk-to-benefit ratios in well-designed randomised controlled trials.

Platelet-aggregation inhibition and hemodynamic effects of beraprost sodium, a new oral prostacyclin derivative: a study in healthy male subjects.

The antiaggregation and hemodynamic effects of the new prostacyclin analogue beraprost sodium were investigated in a randomized, placebo-controlled, double-blind clinical trial of Latin-square design. Twelve healthy Caucasian males randomly received 8-day oral treatments of 20, 40, and 60 micrograms of beraprost sodium and a placebo. One-week washout periods followed each treatment. Pharmacokinetic and pharmacodynamic measurements were performed on days 1 and 8 for each period of treatment. All three doses of beraprost sodium significantly inhibited platelet aggregation on day 8 (compared with placebo) during the 1st h after drug intake. Incubation of the 60-micrograms beraprost sodium samples with ADP (2, 5, and 10 microM) and collagen (1.25 micrograms/mL) decreased platelet aggregation by 10, 19, 16, and 6 +/- 4% (mean +/- SE), respectively, compared with placebo. No significant hemodynamic effects on blood pressure, heart rate, and digital pulse were observed. The 60-micrograms dose of beraprost sodium did significantly decrease the IRZ index (which may reflect the left ventricular pre-ejection period) on days 1 and 8. Some subjects experienced headache and facial flushing, effects that were dose dependent and reversible. Beraprost sodium at 20- to 60-micrograms doses exerts platelet antiaggregation (day 8 of therapy) and slight hemodynamic (days 1 and 8 of treatment) effects in Caucasian males. Beraprost sodium hemodynamic effects and potential benefits in patients with cardiovascular disease should be explored further.