Pharmacokinetic evaluation of voriconazole treatment in critically ill patients undergoing continuous venovenous hemofiltration.

INTRODUCTION: Voriconazole represents an essential part of antimicrobial therapy in critically ill patients. The aim of this study was to exclude a significant alteration in voriconazole pharmacokinetics in critically ill patients undergoing continuous venovenous hemofiltration (CVVH). METHODS: Six patients dependent on CVVH with evidence of an invasive mycotic infection treated with intravenous voriconazole at the standard dosing regimen were investigated. The total serum concentration of voriconazole in arterial blood and the concentration in ultrafiltrate were measured by reverse-phase high-performance liquid chromatography with ultraviolet detection. The authors profiled a 5-point pharmacokinetic concentration-time curve during the 12-hour standard maintenance dosing interval and derived the basic pharmacokinetic parameters. RESULTS: The serum voriconazole concentration did not decrease <1.0 mg/L at any time point, and the mean was 4.3 ± 2.6 mg/L and the median (range) 3.6 (9.0) mg/L. The sieving coefficient of the drug did not exceed 0.30 in any patient (0.22 ± 0.08). The mean serum AUC0-12, the mean total clearance, and the mean clearance via CVVH were 53.52 ± 29.97 mg·h/L [the median (range) of 57.74 (62.34) mg·h/L], 0.11 ± 0.07 L·h-1·kg-1, and 0.007 ± 0.003 L·h-1·kg-1, respectively. The clearance by the CVVH method ranged from 4% to 20% of the total drug clearance. The disposition of voriconazole was not compromised. The mean elimination half-life was 27.58 ± 35.82 hours [the median of 13.10 (92.21) hours], and the mean distribution volume value was 3.28 ± 3.10 L/kg [the median of 2.01 (8.10) L/kg]. Marked variability in serum concentrations, elimination half-life, distribution volume, and total clearance was seen. Half of the patients showed some drug accumulation. CONCLUSIONS: The clearance of voriconazole by CVVH is not clinically significant. In view of this finding, voriconazole dose adjustment in patients undergoing the standard method of CVVH is not required. However, the observed potential for an unpredictable voriconazole accumulation suggests the usefulness for monitoring its levels in critically ill patients.

Serum Concentration of Erlotinib and its Correlation with Outcome and Toxicity in Patients with Advanced-stage NSCLC.

BACKGROUND: Erlotinib is a tyrosine kinase inhibitor targeting epidermal growth factor receptor (EGFR); it is used in the treatment of advanced non-small cell lung cancer (NSCLC). We focused on the role of serum concentration of erlotinib and its association with outcome and toxicity in patients with advanced NSCLC harbouring the wild-type EGFR gene or squamous histology. PATIENTS AND METHODS: Clinical data of 122 patients were analyzed. Serum samples were collected within four weeks after the initiation of treatment. RESULTS: There was no significant association of erlotinib concentration with PFS nor OS (p=0.352 and p=0.6393). Significant associations of erlotinib concentration with grade of skin rash and diarrhoea (p<0.0001 and p<0.0001) were found. Skin rash and diarrhoea were significantly associated with PFS (p=0.0338 and p=0.0001) and OS (p=0.0064 and p=0.0353). CONCLUSION: Erlotinib concentration was not associated with outcome. Erlotinib concentration was associated with occurrence and severity of skin rash and diarrhoea; the outcome was associated with erlotinib toxicity.

Effect of Folic Acid, Betaine, Vitamin B6, and Vitamin B12 on Homocysteine and Dimethylglycine Levels in Middle-Aged Men Drinking White Wine.

UNLABELLED: Moderate regular consumption of alcoholic beverages is believed to protect against atherosclerosis but can also increase homocysteine or dimethylglycine, which are putative risk factors for atherosclerosis. We aimed (1) to investigate the effect of alcohol consumption on vitamins and several metabolites involved in one-carbon metabolism; and (2) to find the most effective way of decreasing homocysteine during moderate alcohol consumption. METHODS: Male volunteers (n = 117) were randomly divided into five groups: the wine-only group (control, 375 mL of white wine daily for one month) and four groups combining wine consumption with one of the supplemented substances (folic acid, betaine, and vitamins B12 or B6). Significant lowering of homocysteine concentration after the drinking period was found in subjects with concurrent folate and betaine supplementation. Vitamin B12 and vitamin B6 supplementation did not lead to a statistically significant change in homocysteine. According to a multiple linear regression model, the homocysteine change in the wine-only group was mainly determined by the interaction between the higher baseline homocysteine concentration and the change in dimethylglycine levels. Folate and betaine can attenuate possible adverse effects of moderate alcohol consumption. Dimethylglycine should be interpreted together with data on alcohol consumption and homocysteine concentration.

The effect of intravenous iron on oxidative stress in hemodialysis patients at various levels of vitamin C.

BACKGROUND/AIMS: Vitamin C levels decrease during hemodialysis (HD), which deteriorates antioxidant defense. Vitamin C may also act pro-oxidatively, via reduction in Fe(III). We sought to determine whether intravenous iron (Fe(iv))-induced oxidative stress differs in HD patients with low and physiological vitamin C levels and whether intravenous vitamin C (C(iv)) administration during HD would change the response to Fe(iv). PATIENTS AND METHODS: Twenty patients with vitamin C deficiency (median 15.7 micromol/l, range 8.0-22.7) received Fe(iv) (100 mg iron sucrose between 150 and 180 min of HD). After 4 weeks of oral supplementation, the levels of vitamin C were comparable with those of controls (60.1 micromol/l, range 47.4-70.9). Patients were subsequently treated with (1) Fe(iv), (2) Fe(iv) and continuous 2 mg/min C(iv) throughout HD, (3) saline (S), and (4) S+C(iv). Plasma thiobarbituric acid reacting substances (TBARS) and vitamin C were assessed before, during and after FE(iv)(S), and 15, 30 and 60 min after infusion. RESULTS: Fe(iv) induced a comparable rise in TBARS in patients with vitamin C deficiency (before Fe(iv), 1.9 micromol/l, range 1.4-1.9; after Fe(iv), 2.6 micromol/l, range 2.3-2.9; p < 0.01) and in those with normal vitamin C (before Fe(iv), 1.9 micromol/l, range 1.7-2.1; after Fe(iv), 2.6 micromol/l, range 2.5-2.9; p < 0.01). Fe(iv)+C(iv) resulted in a greater increase in TBARS (after Fe(iv), 3.1 micromol/l, range 2.8-3.2) compared with Fe(iv) (p < 0.01). CONCLUSION: Iron sucrose-induced oxidative stress is comparable in HD patients with vitamin C deficiency and in those with normal vitamin C. We documented a pro-oxidative effect of vitamin C during Fe(iv)+C(iv) administration.

Treatment of hyperhomocysteinemia with folic acid: effects on homocysteine levels, coagulation status, and oxidative stress markers.

The aim of the study was to determine whether folic acid treatment in subjects with homocysteinemia would change their coagulation and oxidative status. Thirty-three patients with peripheral vascular disease and 26 elderly subjects with no symptoms of atherosclerosis, all of whom had total homocysteine >20 microM, were treated with folic acid (5 or 10 mg) for 3 months. In the 33 patients with peripheral vascular disease, homocysteine levels decreased from a median of 26.7 microM at baseline to 20.0 microM (p < 0.0001), whereas in the 26 asymptomatic elderly subjects, homocysteine level decreased from 24.4 microM to 18.6 microM (p < 0.0001). Plasma fibrinogen decreased whereas plasminogen and anti-thrombin increased; the differences between pre- and posttreatment values were significant in both patients and healthy subjects. Oxidative status markers showed a shift toward lower oxidative stress. This effect was observed in both study groups. An association of the therapeutic effect with the genetic polymorphism of 5,10-methylenetetrahydrofolate reductase was not detected. Folic acid supplementation to hyperhomocysteinemic subjects resulted in a decrease in total blood homocysteine concentrations; moreover, there was a tendency to reverse the coagulation status and oxidative stress.