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.

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.

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.

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)

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.

Cerebrospinal fluid concentrations of caffeine following oral drug administration: correlation with salivary and plasma concentrations.

Twelve hospitalized adult patients received 300 mg of oral caffeine 1 h before a diagnostic lumbar puncture. Caffeine concentrations were determined simultaneously in saliva, plasma, and cerebrospinal fluid (CSF). Mean caffeine concentrations in plasma, saliva, and CSF were 5.9 +/- 2.1, 4.4 +/- 1.5, and 2.9 +/- 1.1 micrograms/ml, respectively, with coefficients of correlation plasma-saliva, saliva-CSF, and plasma-CSF of 0.89, 0.79, and 0.77, respectively, all statistically significant (p < 0.001).

Diltiazem treatment impairs theophylline elimination in patients with bronchospastic airway disease.

On the basis of reports that diltiazem may bind to the hepatic microsomal enzymes and inhibits the metabolism of some co-administered drugs, and to determine the effects of diltiazem on theophylline pharmacokinetics in patients with bronchospastic airway disease, we have investigated the effect of a 180-mg daily dose of oral diltiazem during 5 days on theophylline clearance in eight patients with that disease. Theophylline half-life increased 24%, from 5.7 +/- 1 to 7.5 +/- 1.8 h (p < 0.05), and total body theophylline clearance showed a decrease of 22%, from 87.3 +/- 20 to 68.3 +/- 18.6 ml/min (p < 0.05) after diltiazem therapy. The apparent volume of distribution was unchanged. This reduction in theophylline clearance is likely produced by inhibition of its metabolism by diltiazem. A clinically important drug interaction may occur with theophylline when diltiazem therapy is given concurrently in patients with bronchospastic airway disease.

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)

Probable acenocoumarol-amoxycillin interaction.

We present the case of a woman undergoing treatment with acenocoumarol for deep vein thrombosis, who maintained an international normalized ratio (INR) of between 2.5 and 4 for 2 months. Seven days after the introduction of amoxycillin (500 mg/8 h) for a probable respiratory infection, the patient developed spontaneous bruising, with an INR of 7.1. Treatment with amoxycillin was discontinued, and 3 weeks later the INR had returned to previous values. In this case, the increase in the INR value with associated bruising after the addition of amoxycillin suggests a drug interaction between acenocoumarol and amoxycillin, other possible causes having been eliminated.