Is treatment with N-acetylcysteine to prevent contrast-induced nephropathy when using bicarbonate hydration out of date?

AIMS: Chronic renal failure (CRF) is a major risk factor for contrast-induced nephropathy (CIN) and could be prevented by bicarbonate hydration. The effect of N-acetylcysteine (NAC) in preventing CIN in patients treated by bicarbonate hydration has never been investigated. METHODS: Patients admitted for cardiac angiography from January 2002 to November 2004, with stable CRF (glomerular filtration rate (GFR) < 56 ml/min, Cockcroft-Gault formula) were included in a prospective, randomized, double-blind study comparing the efficacy of oral NAC + bicarbonate hydration vs oral placebo + bicarbonate hydration to prevent CIN. NAC 1,200 mg twice daily or placebo was given on Day -1 and Day 0 (Day 0 = cardiac angiography). A 1.4% bicarbonate solution (1 ml/ kg/h) was administered 12 hours before and after cardiac angiography. The overall CIN incidence on Day 2 was defined by one or more of the following criteria: increase in serum creatinine > 44.2 micromol/l, increase in serum creatinine > 25% or decrease in GFR > 5 ml/ min. RESULTS: Between NAC group (n = 28) and placebo group (n = 32) there was no difference in baseline demographics (age, sex ratio, weight, arterial hypertension, diabetes), in Day 0 characteristics (serum creatinine, GFR, hematocrit, protidemia) and in Day 0 cardiac angiography procedure (diagnostic or interventional, number of stents, type and volume of contrast media infused). The overall incidence of CIN in the NAC and placebo groups was 7.1 vs 9.3% (p = 1), respectively, and the rates of the observed criteria a, b, and c were 0 vs 6.3% (p = 0.49), 3.5 vs 6.3% (p = 1), and 7.1 vs 9.3% (p = 1). CONCLUSION: In CRF patients undergoing cardiac angiography, the use of bicarbonate hydration is associated with a very low incidence of CIN. In these conditions, on the basis of our results, we cannot draw any meaningful conclusion on the effect of NAC on the prevention of CIN.

Methionine dependency and cancer treatment.

Conventional chemotherapies have showed their limits, notably for patients with advanced cancer. New therapeutic strategies must be identified, and the metabolic abnormalities of cancer cells offer such opportunities. Many human cancer cell lines and primary tumors have absolute requirements for methionine, an essential amino acid. In contrast, normal cells are relatively resistant to exogenous methionine restriction. The biochemical mechanism for methionine dependency has been studied extensively, but the fundamental mechanism remains unclear. A number of investigators have attempted to exploit the methionine dependence of tumors for therapeutic effects in vivo. To reduce in vivo methionine in plasma and tumours, dietary and pharmacological treatments have been used. Methionine-free diet or methionine-deprived total parenteral nutrition causes regression of a variety of animal tumours. Alternatively, methionine depletion was achieved by the use of methioninase. This enzyme specifically degrades methionine and inhibits tumour growth in preclinical models. Because of potential toxicity and quality of life problems, prolonged methionine restriction with diet or with methioninase is not suitable for clinical use. Methionine restriction may find greater application in association with various chemotherapeutic agents. Several preclinical studies have demonstrated synergy between methionine restriction and various cytotoxic chemotherapy drugs. The experimental results accumulated during the last three decades suggest that methionine restriction can become an additional cancer therapeutic strategy, notably in association with chemotherapy.

Pharmacokinetic study of cystemustine, administered on a weekly schedule in cancer patients.

BACKGROUND: Cystemustine is a chloroethylnitrosourea mostly active in humans against glioma and melanoma. The present report describes the results of a new phase I trial with cystemustine administered on a weekly schedule. The pharmacokinetic and pharmacodynamic properties of cystemustine were investigated. PATIENTS AND METHODS: Forty-three patients entered this study. Cystemustine was administered at dose levels ranging from 30 to 60 mg/m2. The drug was given on days 1, 8, 15 and 22, followed by a 4-week rest period. RESULTS: Thrombocytopenia was the dose-limiting toxicity and appeared to be reversible, but probably cumulative. This toxicity appeared dose-related, both in frequency and severity. The maximum tolerated dose was 60 mg/m2. Nonhematological toxicity was generally mild. Three partial responses were observed at dose levels of 50 and 60 mg/m2. Pharmacokinetics analysis showed mono- or biphasic cystemustine blood disposition with a mean a half-life of 4 min and mean terminal half-life of 49 min. CONCLUSIONS: There was a clear linear relationship between the area under the blood drug concentration-time curve (AUC) and the dose of cystemustine (P < 0.001). There was also a significant relationship between the AUC and the toxic effects of cystemustine on platelets, granulocytes and leukocytes (P < 0.001). A reasonable starting dose for phase II studies is 40 mg/m2, with dose escalation based on blood cell counts.

Circadian variation in O6-alkylguanine-DNA alkyltransferase activity in circulating blood mononuclear cells of healthy human subjects.

Cytotoxic agents such as chloroethylnitrosoureas (CENUs) mostly alkylate DNA on the O6-guanine position. This highly mutagenic lesion can be repaired by O6-alkylguanine-DNA alkyltransferase (AGT), which removes the alkyl group by accepting it to the cysteine residue of its active site. AGT activity displayed a circadian rhythm in mouse liver, coincident with that of CENU tolerability. We investigated whether AGT activity displayed a circadian rhythm in human circulating mononuclear cells (MNCs). The study was performed in 12 healthy volunteers aged 19 to 31 years. Circadian synchronization was verified with rest/activity cycle as assessed with wrist actigraphy and plasma cortisol and melatonin rhythms. Subjects were hospitalized for 24 hr and blood samples were obtained at 08:00, 12:00, 16:00, 20:00, 22:00, 00:00, 02:00, 04:00 and 08:00 overnight. MNCs were isolated on Ficoll immediately after blood sampling and frozen at -196 degrees C until AGT activity determination by HPLC. Mean AGT activity (+/- SEM) varied from 821 +/- 67 fmol/mg of total proteins at noon (trough), up to 1,055 +/- 80 fmol/mg at midnight (peak), i.e., by approximately 30%. A circadian rhythm was statistically validated with both analysis of variance (p < 0.009) and cosinor (p < 0.02) for AGT activity in MNCs (acrophase +/- SD at 00:30 +/- 210 min) as well as for MNC circulating count and for plasma cortisol and melatonin concentrations. Despite individual variations in the extent of AGT activity rhythm (more or less pronounced according to subject), AGT activity displayed a circadian rhythm in human MNCs of our healthy study group subjects. The results warrant to further investigate AGT rhythmicity both in circulating MNCs and in target tissues of cancer patients, as a prerequisite for clinical testing of chronotherapy with alkylating agents.