Pharmacokinetic profile of two different administration schemes of teicoplanin. Single 400 mg intravenous dose vs double-refracted 200 mg intramuscular doses in healthy volunteers

Objective: To evaluate the pharmacokinetic appropriateness of a possible switch in dosing schedule for outpatients after hospital discharge, i.e. the bioequivalence of a single 400 mg intravenous daily dose versus double-refracted 200 mg intramuscular doses. Subjects and Methods: This study was conducted in 10 normal healthy volunteers using a two-way randomised, open-label, two-period crossover design. Each subject received two different drug regimens of teicoplanin: a single 400 mg intravenous daily dose versus double daily refracted 200 mg intramuscular doses. Teicoplanin serum concentrations were analysed by means of a fluorescence polarisation immunoassay system in samples collected for up to 72 hours after each regimen. Pharmacokinetic evaluations were performed by means of a 3-compartment open model with first-order elimination using the WinNonlin pharmacokinetic software package. Results: Teicoplanin peak serum concentrations were 97.96 \ub1 23.49 mg/L, 3.47 \ub1 1.00 mg/L and 6.99 \ub1 1.52 mg/L after a single 400 mg intravenous dose, and after the first and second intramuscular administrations, respectively. The trough level at 24 hours (C 24 ) was 4.55 \ub1 1.04 mg/L after the 400 mg intravenous dose, and 6.67 \ub1 1.75 mg/L after double 200 mg intramuscular doses. The ratio between C 24 intramuscular and intravenous treatment was 1.46 \ub1 0.17. Total body exposure (AUC(O- 1e)) was 474.22 \ub1 111.77 mg/L\ub7h post-intravenous dose, and 424.84 \ub1 113.53 mg/L\ub7h post-intramuscular doses. Intramuscular bioavailability suggested substantial bioequivalence with intravenous administration (89.58 \ub1 14.35%). Dose-normalised data indicated that the intersubject variability was mainly related to interindividual differences in bodyweight. Conclusion: These findings indicated that a total daily dosage of teicoplanin 400 mg administered in two refracted doses by the intramuscular route could produce steady-state trough levels that are even higher than those achievable after once-daily intravenous administration during maintenance treatment. Since the time during which the serum concentration persists above MIC is actually thought to be a possible major determinant for the outcome of treatment with glycopeptides, this intramuscular schedule could enhance the pharmacokinetic exposure to teicoplanin. Therefore, a timely conversion from intravenous to intramuscular therapy in outpatients at the moment of hospital discharge (changing therapy from 400 mg intravenously once daily to 200 mg intramuscularly twice daily) may be reliably proposed, allowing better compliance without reducing efficacy

Somatomedin C (insulin-like growth factor 1) levels decrease during acute changes of stress related hormones. Relevance for fibromyalgia.

Objective. To determine the effects of stress hormones on insulin-like growth factor 1 (IGF-1). Methods. Insulin induced hypoglycemia ( < 3 mmol/l) and clonidine induced depression of noradrenergic tone were used to assess the acute effects of cortisol, human growth hormone (hGH), and norepinephrine (NE). Results. Despite the increase of hGH during hypoglycemia, a statistically significant decrease of IGF-1 was observed along with the expected rise of cortisol and NE. To eliminate the role played by NE, NE tone was depressed by administering clonidine. A statistically significant decrease of IGF-1 was also observed. Conclusion. Acute cortisol release or a NE decrease induce low IGF-1 levels

Liposomal daunorubicin plasmatic and renal disposition in patients with acute leukemia

Liposomal formulations of anthracyclines have been developed to increase their delivery to solid tumors while reducing toxicity in normal tissues. DaunoXome (DNX, NeXstar) is a liposomal-encapsulated preparation of daunorubicin registered for treatment of Kaposi's sarcoma that during prior in vitro studies showed a toxicity to leukemic cells at least comparable to that of free da unorubicin. The aim of our study was to determine DNX pharmacokinetics in 11 poor-risk patients with acute leukemia treated with DNX 60 mg/m 2 IV on days 1, 3, and 5. Blood and urine samples were collected at appropriate intervals after each of the three DNX administrations. The total amount of daunorubicin (free and entrapped) (t-DNR) and of its metabolite daunorubicinol (DNRol) was assayed by HPLC. The main pharmacokinetic parameters (t(1/2\u3b1) 4.54 \ub1 0.87 h; Vd(ss) 2.88 \ub1 0.93 l/m 2 ; Cl 0.47 \ub1 0.26 l/h/m 2 ) showed that in patients with acute leukemia liposomal-entrapped daunorubicin pharmacokinetics greatly differed from that observed for the conventional formulation. In fact, DNX produced mean plasma AUC levels (t-DNR AUC(0- 1e) 456.27 \ub1 182.64 \u3bcg/ml/h) about 100- to 200-fold greater than those reported for the free drug at comparable doses due to a very much lower total body clearance. Volume of distribution at steady state was 200-to 500-fold lower than for the free drug. Plasma AUC of DNRol (17.62 \ub1 7.13 \u3bcg/ml \ub7 h) was similar to or even greater than that observed with free daunorubicin for comparable doses. Cumulative urinary excretion showed that about 6% and 12% of the total dose of DNX administered was excreted in urine as daunorubicin and daunorubicinol, respectively. No major toxicity was encountered. Therefore, pharmacokinetic characteristics suggest that DNX may be more convenient than free daunorubicin in the treatment of acute leukemia. In fact, liposomal formulation may allow a reduction of dauno-rubicin captation in normal tissues, thus minimizing toxicity at least for the parent drug, and guarantee an unimpeded access to leukemic cells in the bloodstream and bone marrow, thus theoretically improving efficacy