Recombinant human GM-CSF enhances T cell-mediated cytotoxic function after ABMT for hematological malignancies.

The interactions of GM-CSF with cells of lymphoid lineage are not well understood and their clinical use has been focused on the acceleration of hematopoietic recovery. However, several reports have shown that human GM-CSF can affect certain T lymphocyte in vitro cytotoxic functions. To assess whether recombinant human GM-CSF (rhGM-CSF) has a more broadly based activity in the immune system, we studied its in vivo effects on endogenously-generated killer function in patients undergoing ABMT for hematologic malignancies. Eleven patients received rhGM-CSF after ABMT: eight received rhGM-CSF as a 2-h infusion daily from days +3 to +17 and three received rhGM-CSF until reaching > 500 x 10(6)/l granulocytes. Eight patients not enrolled in the rhGM-CSF therapy protocol served as controls. Natural killer (NK) cell activity and activated killer (AK) cell activity were studied before conditioning, during rhGM-CSF therapy and after withdrawal of GM-CSF. rhGM-CSF therapy does not affect NK activity. Circulating lymphocytes with the ability to kill AK-sensitive targets appear spontaneously in control ABMT patients. AK activity was 1.6 +/- 0.8% before ABMT increasing to 9 +/- 2.5% and 14 +/- 2.1% at 2 and 3 weeks after ABMT, respectively (p = 0.002). In rhGM-CSF-treated patients this phenomenon also occurs. AK activity increased from 2.4 +/- 1.5% before ABMT to 33.6 +/- 8.1% during rhGM-CSF administration (p = 0.001) and 17.5 +/- 3.4% after withdrawal (p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) administration after autologous bone marrow transplantation for acute myeloblastic leukemia enhances activated killer cell function and may diminish leukemic relapse.

Leukemic relapse is the major complication following autologous bone marrow transplantation (BMT) in acute myeloblastic leukemia (AML). Previously, we have shown that recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) infusion after autologous BMT has the ability to augment endogenous activated killer (AK) cell function which may play a role in the eradication of minimal residual disease. However, the clinical application of rhGM-CSF in patients with AML has been limited by its potential stimulatory effect on the malignant clone. Here we report the effect of rhGM-CSF 5 micrograms/kg/day infusion on AK cell function in 20 patients with AML undergoing autologous BMT. AK cell function was investigated before autologous BMT, during rhGM-CSF therapy and after withdrawal. In addition, its influence on the actuarial risk of relapse is analyzed and compared with a historical control group of 20 patients transplanted immediately before initiation of this study. rhGM-CSF significantly enhanced AK cell function. During rhGM-CSF treatment, median AK cell function rose from 1.8% before autologous BMT (range 0-8%) to 35% (range 3-80%) and remained increased after cessation of rhGM-CSF (median 20%; range 0-36%; P < 0.001). After a median follow-up of 24 months, the actuarial risk of relapse is 37.4% in rhGM-CSF-treated patients compared with 49.5% in controls (P = 0.05). Interestingly, none of the 7 patients with an AK cell activity > or = 20% in the first 2-5 weeks after autologous BMT have relapsed compared with 6 of 9 patients with an AK cell activity < 20% (P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Autologous bone marrow transplantation as consolidation therapy for non-Hodgkin's lymphoma patients with poor prognostic features.

Theoretical considerations and preliminary results of clinical trials support the earlier use of autologous bone marrow transplantation (ABMT) in poor prognosis non-Hodgkin's lymphoma (NHL). A prognostic analysis of 50 patients with intermediate or high grade NHL younger than 60 years, who achieved at least one complete remission and were not treated with BMT, was performed. Patients with bulky tumor at diagnosis and/or serum LDH greater than or equal to 600 U/l do poorly with conventional chemotherapy. Twelve patients with these high-risk initial characteristics in first complete remission (CR) and six patients in second or third CR were treated with cyclophosphamide (60 mg/kg x 2) and total body irradiation (1000-1200 cGy) followed by ABMT. Overall disease-free survival was 65% at a median follow-up of 35 months. No differences were found between the first and later CR patients. The rate of toxic death was 11%. Disease-free survival after first CR was better for 1st CR ABMT patients than for a historical chemotherapy control group with similar poor prognosis features (p = 0.008). These results support the use of ABMT in selected, high-risk NHL patients in first CR.

Use of antithrombin III in critical patients.

OBJECTIVE: To evaluate the effect of the AT III concentrates upon the clinical evolution and hemostatic parameters. DESIGN: Prospective, open, randomized trial. PATIENTS AND PARTICIPANTS: Septic and multiple trauma patients admitted to our Intensive Care Unit. SETTING: Levels of AT III below 70% were used as criteria to choose 36 patients, 20 of whom received treatment with AT III and 16 did not. INTERVENTIONS: AT III concentrates were administered at an initial dose of 60 U/kg followed by 10 U/kg every six hours. RESULTS: The administration of AT III neither contributes to alterations in haemostasis, nor the clinical evolution (evaluated according to Apache II score). CONCLUSIONS: The results suggest that the administration of AT III concentrates to critical patients with acquired low levels, but without manifest DIC, may not be justified; although further studies on a larger population are required to establish definite conclusions.

Assessment of the time course of drugs with inhibitory effects on hepatic metabolic activity using successive salivary caffeine tests.

In clinical practice is very important to know the time course of the inhibitory effects of drugs to avoid side effects when several agents are taken concomitantly. We attempted to validate the effectiveness of successive salivary caffeine tests establishing the time for cimetidine to inhibit hepatic metabolism. The time of cimetidine's inhibitory effect as reported in other studies was chosen as the reference. In this open-label, prospective longitudinal, 16-day study, five healthy volunteers were treated with cimetidine 1 g/day for 5 days. After the intake of caffeine 300 mg, salivary caffeine tests were carried out on days -1 (control value), 1, 4, 8, 12, and 16. The mean systemic caffeine clearance was decreased after 24 hours of cimetidine. The drug's maximum inhibitory effect was reached after 5 days of administration, returning to previous values progressively 1-7 days after discontinuing cimetidine. No change occurred in the apparent volume of distribution. The time course of cimetidine's inhibitory effect was similar to that described with other methodologies. Although this was a pilot trial and the results have to be confirmed, it seems that successive salivary caffeine measurements could be a safe, reliable, noninvasive test for exploring the time course of the inhibitory effects of drugs on hepatic metabolism.

[Bone marrow autotransplantation in patients with acute myeloblastic leukemia in primary remission]. / Autotrasplante de medula ósea en pacientes con leucemia mieloblástica aguda en primera remisión.

Fifteen bone marrow autotransplants (BMAT) in patients with acute myeloblastic leukemia (AML) were performed after the first remission. The mean age was 37 years (range 12 to 60 years). According to the morphological classification FAB, 8 patients had monocytic leukemia (M4, M5) and 7 myeloid leukemia (M1, M2, M3). The mean interval elapsed between the date of complete remission and the BMAT was 3.9 months (range 1 to 5-9 months). In 8 patients this interval was longer than 6 months and in 7 cases it was shorter than 6 months. After achievement of the complete remission all patients underwent certain cycles of intensification before the BMAT. Eight patients received only a cycle whereas 7 patients received more than one cycle (between 2 and 4). The conditioning protocol consisted of cyclophosphamide (CP) (60 mg/kg x 2) and total body radiotherapy (TBR) (10 Gy) in 9 patients; CP and busulfan in five; and CP, cytarabine at high doses and melphalan in one case. Marrow extraction was performed after completion of chemotherapy of intensification. In 5 cases the bone marrow was depleted of leukemic cells by previous in vitro treatment with ASTA-Z. There are at present 8 alive patients. The survival free of illness was 51.8%. Seven patients died: 3 cases because relapse of the leukemia, 3 due to attachment failure of the transplantation, and one patient suffered a viral myocarditis. The survival free of illness was significantly longer in those patients transplanted after 6 months of the complete remission.

[Infectious complications in bone marrow transplantation]. / Complicaciones infecciosas en el trasplante de medula ósea.

BACKGROUND: Initially, the aim of the present study was to evaluate the incidence and implicated organisms in the infections in patients receiving a bone marrow transplants (BMT). METHODS: 194 febrile episodes (FE) were evaluated in 115 patients having received a BMT between 1980 and 1987. The analysis was carried out at three different moments: during the period of most marked neutropenia (period I) to the 100th day after BMT (period II) and beyond the 100th day (period III). RESULTS: The unequivocal confirmation that FE was infective was found in 62% of cases (confirmation was microbiological in 46% and clinical in 16%), while 31% of FE were considered as possible infections and the remaining 7% as doubtful infections. The causative organisms were bacteria (73%), viruses (10%), fungi (8%), and combinations of them (polymicrobial infections) (9%). Gram negative and Gram positive organisms were more common, respectively, in period I and in periods II and III (p = 0.02). Bacteremia was the commonest cause of confirmed infection. The overall mortality rate due to infection was 18%. There was a remarkably high mortality from pneumonia (54%) and a low mortality in patients with sepsis (6%) (p less than 0.0001). The number of FE was lower in patients with autografts than those with allografts (p = 0.08). 33% of the FE in patients with allografts were coincident with acute or chronic graft-versus-host disease, and in two thirds of them infections was confirmed. CONCLUSIONS: Infection represents a major complication of BMT. The different antimicrobial treatments used in association with bone marrow grafting allowed us to control most FEs. Pneumonia was the most severe infective localization and the leading cause of death. Mortality rate due to sepsis was small.

A pilot study of the effect of antipyrine on caffeine kinetics in six healthy volunteer subjects.

The potential interaction is described between caffeine and antipyrine, two drugs with a high probability of being concomitantly administered for the evaluation of liver metabolism. In order to determine the influence of antipyrine on the elimination of caffeine, salivary caffeine clearance was measured in six healthy volunteers prior to and 2 and 5 days after the administration of a single oral dose of 1000 mg of antipyrine. Total caffeine clearance increased on average by 24% (from 1.65 to 2.05 ml/min, P = 0.1) 2 days after antipyrine dosing, and 25% (from 1.65 to 2.06 ml/min, P < 0.01) 5 days after the administration of antipyrine, whereas the half-life decreased by around 24% (from 5.3 to 4 h, P = 0.09) after 2 days and 26% (from 5.3 to 3.9 h, P = 0.05) after 5 days. The apparent volume of distribution did not change. These results suggest that antipyrine is able to increase the elimination of caffeine, probably by means of inducing its hepatic metabolism. When both drugs are used sequentially in the same patient to assess the drug metabolizing activity of the liver, the caffeine test should be performed first.

[Initial dosage of vancomycin in neutropenic hematologic patients]. / Dosis inicial de vancomicina en pacientes hematológicos neutropénicos.

PURPOSE: To evaluate the percentage of neutropenic patients who reach the therapeutic threshold when vancomycin is given at standard initial doses of 500 mg/6 hr, and to assess the creatinine clearance and body vancomycin clearance in such patients. MATERIAL AND METHODS: The study was performed on 37 haematological patients with normal renal function. They received intravenous vancomycin at an initial 500 mg/6 hr doses. The plasma concentration of the drug was assessed 48-72 hr later, pharmacokinetic parameters being calculated. Creatinine clearance was estimated by two different methods. RESULTS: The concentration attained was beyond the therapeutic threshold in 100% of the patients. The correlations between vancomycin and creatinine clearance were r = 0.42 and r = 0.47 when the Cockroft-Gault's and the Jellife's methods, respectively, were used. Administration of vancomycin at initial doses of 500 mg/6 hr renders a very high percentage of patients with plasma concentration of the drug beyond the therapeutic margin. CONCLUSIONS: 1) The poor correlation between creatinine and vancomycin clearance in the patients with normal renal function does not allow using nomograms based on such values for estimation of the initial doses. 2) The estimation of initial doses based on the patient's weight (20-25 mg/kg) may render a higher percentage of patients with therapeutic concentrations from the beginning of treatment. The maintenance doses can be adjusted at 48-72 hr, after measuring the plasma concentrations. 3) Therefore, it seems advisable to perform further clinical assays on different groups in order to verify an increase of the drug's efficacy with no higher toxicity when the initial vancomycin doses is adjusted according to the patient's weight, as recommended here.

Comparison of a monoclonal antibody fluorescent polarization immunoassay with monoclonal antibody radioimmunoassay for cyclosporin determination in whole blood.

We have compared the whole blood concentrations of parent cyclosporin A (CsA) using monoclonal fluorescence polarization immunoassay (FPIA) and radioimmunoassay (RIA) as well as polyclonal FPIA in kidney, heart, and bone marrow transplant patients (n = 89). A good correlation was found between monoclonal FPIA and monoclonal RIA (r = 0.96) and a slightly worse one between polyclonal and monoclonal FPIA (r = 0.90). The interassay coefficient of variation was satisfactory for all the methods-less than 5% for monoclonal FPIA. The monoclonal FPIA assay with Abbott TDx appears to provide rapid, precise, and accurate measurement of parent CsA. It is therefore useful for therapeutic monitoring of CsA in whole blood in kidney, heart, and bone marrow transplant patients.

Use of salivary caffeine tests to assess the inducer effect of a drug on hepatic metabolism.

OBJECTIVE: To validate the use of successive salivary caffeine tests in evaluating how long inducer drugs affect hepatic metabolism. The time course of the inducer effect of rifampin found in other studies using different methodologies was chosen as the time course of reference. DESIGN: Open-label, prospective, longitudinal study. SETTING: A university hospital. PARTICIPANTS: Five healthy volunteers. MAIN OUTCOME MEASURES: Rifampin 600 mg/d was administered for 21 days. Anhydrous caffeine 300 mg was concurrently administered on each study day. Salivary caffeine tests were carried out on the following days: predose (baseline), and days 1, 5, 9, 13, and 17. Salivary tests were performed for up to 13 days after the last dose of rifampin (study days 21, 25, 29, and 33). RESULTS: The mean systemic caffeine clearance was increased for up to 17 days after the intake of rifampin, reaching the maximum inducer effect between days 5 and 9, and returning to previous values progressively during several days after rifampin was discontinued. CONCLUSIONS: Our results suggest that successive salivary caffeine measurements could be a safe, reliable, noninvasive, and suitable test for exploring the time course of the inducer effect of drugs on hepatic metabolism activity.