Paracetamol (acetaminophen) warfarin interaction: NAPQI, the toxic metabolite of paracetamol, is an inhibitor of enzymes in the vitamin K cycle

Paracetamol (acetaminophen) is generally considered to be the analgesic of choice for patients undergoing oral anticoagulant therapy. Occasionally, however, interactions have been reported with therapeutic doses of the analgesic, e.g. if the drug is taken for a longer period of time. The mechanism of this interaction is not clearly understood. We investigated the effects of paracetamol and its toxic metabolite N-acetyl-para-benzoquinoneimine (NAPQI) on in vitro vitamin K-dependent gamma-carboxylase (VKD-carb) and vitamin K epoxide reductase (VKOR) activities. Paracetamol had no effect in either enzymatic reactions. NAPQI, on the other hand, appeared to interfere with VKD carb activity via two mechanisms; 1) oxidation of the cofactor vitamin K-hydroquinone, 2) inactivation of the enzyme. The inactivation, in micromolar ranges, is not reversible and may be the result of covalent binding of NAPQI with functional amino acids. NAPQI also inhibited VKOR, but at higher concentrations. Unexpectedly, N-acetylcysteine was found to inhibit VKOR activity at concentrations that are obtained during rescue therapy of paracetamol intoxication. We conclude that, the potentiation of the oral anticoagulant effect by paracetamol is likely to result from NAPQI-induced inhibition of enzymes of the vitamin K cycle, particularly VKD-carb.     

Detecting life-threatening lactic acidosis related to nucleoside-analog treatment of human immunodeficiency virus-infected patients,and treatment with L-carnitine

OBJECTIVE: Our first objective was to determine a blood lactate threshold predictive of survival in human immunodeficiency virus patients experiencing lactic acidosis related to nucleoside analogs, and second, to test l-carnitine for the treatment of patients exceeding that threshold. DESIGN: a) Retrospective study using data from personal and published observations to determine the lactate threshold between survivors and nonsurvivors in human immunodeficiency virus patients being treated with nucleoside analogs. b) Prospective multicenter open trial to test l-carnitine treatment of human immunodeficiency virus patients receiving nucleoside analogs. SETTING: Medical intensive care units of four teaching hospitals and one general hospital. PATIENTS: Retrospective analysis of data from 39 human immunodeficiency virus patients (five personal cases and 34 patients from the literature) receiving nucleoside-analog treatment from which lactate values were available. An additional six patients with high lactate values were included as a pilot study testing the use of l-carnitine therapy. MEASUREMENTS AND MAIN RESULTS: An initial lactate level of 9 mmol/L, which gave good positive and negative predictive values, was determined as a threshold between survivors and nonsurvivors for the patients receiving nucleoside-analog treatment. Six patients with initial lactate levels >10 mmol/L were prospectively treated with l-carnitine; three survived beyond the end of the study. CONCLUSIONS: The blood lactate levels in human immunodeficiency virus patients receiving nucleoside-analog therapy can predict mortality in these patients. The preliminary data from this pilot study suggest that l-carnitine may be helpful for patients who have nucleoside-analog-related lactic acidosis with blood lactate levels >10 mmol/L. Further studies will be necessary to affirm the therapeutic efficacy of l-carnitine in this setting.     

Echocardiographic and physiological performance characteristics of triathletes

BACKGROUND: Endurance sports require a variety of physiological adaptations. OBJECTIVE: To examine the structural and functional heart adaptations and their hemodynamic implications in triathletes. PATIENTS AND METHODS: A group of 52 male triathletes was compared with a control group of 22 healthy male nonathletes. All of the subjects were given a bidimensional cardiac Doppler echocardiography examination and administered maximal exercise tests with lactic acid determinations, on a bicycle ergometer and a treadmill. Results: The triathletes showed clear structural and functional heart adaptations with concentric and eccentric hypertrophy with evidence of a supernormal diastolic left ventricular function. The performance capacity of the triathlete differed significantly from that of the control subject. The maximal oxygen consumption and the maximal oxygen consumption per kilogram on the bicycle and on the treadmill were significantly higher in the triathletes. The same results and conclusions were obtained concerning aerobic capacities and power outputs on a bicycle ergometer at blood lactate concentrations of 2, 3 and 4 mmol/L. The heart rate 6 min after the start of exercise is a significant parameter for the evaluation of the physical condition of a subject. The lactic acid determinations during the recovery phase enabled important conclusions to be drawn about the physical condition of the subjects. CONCLUSIONS: The triathletes showed evidence of important structural and functional heart adaptations with hemodynamic implications. The maximal performing capacities, on the bicycle as well as on the treadmill, were distinctly higher in the triathlete group. Furthermore, the aerobic and anaerobic capacities were significantly different between the groups. In this context, the heart rate 6 min after the start of exercise and the blood lactate concentrations 20 min after the maximal exercise test were significant parameters. It was not always the best triathletes who had the most significant structural cardiac adaptations. Thus, the 'athletic heart' syndrome as a physiological entity is questioned.     

Physiological or pseudophysiological ECG changes in endurance-trained athletes

"Sudden cardiac death" in seemingly healthy, active, and asymptomatic people has always been a tragic fact and is now occurring more frequently. Thus, the preventive detection of "subjects at risk" becomes a priority. A traditional resting electrocardiogram can sometimes give useful indications. Fifty-two competitive triathletes were compared with 22 control persons with similar anthropometric parameters. All subjects underwent the same noninvasive cardiac exploration with electrocardiography, bidimensional echo-Doppler examination, and maximal spiro-ergometric exercise tests, on a stationary bicycle as well as on a treadmill. In the triathletes we noted manifest signs of eccentric as well as concentric left ventricular hypertrophy with arguments for a supernormal diastolic left ventricular function, with important hemodynamic adjustments and with consequences on the resting electrocardiogram. We described "ten commandments" in evaluating the resting electrocardiogram of healthy competitive athletes. We suspect that the occurrence of ventricular premature beats at peak load of a maximal exercise could be the first expression of a pathological cardiac adaptation to sports activities. The resting electrocardiogram can show interesting details in detecting the "subjects at risk" for problems such as possible lethal arrhythmias and "sudden cardiac death." The analysis of the four subgroups of triathletes compels us to feel dubious about the "athletic heart syndrome" as a physiological entity. In several cases the "athletic heart" is possibly a transitional situation to a pathological hypertrophic and dilated cardiomyopathy. Received: July 3, 2000 / Accepted: February 9, 2001