Improved efficacy of ciprofloxacin administered in polyethylene glycol-coated liposomes for treatment of Klebsiella pneumoniae pneumonia in rats.

Animal and clinical data show that high ratios of the area under the concentration-time curve and the peak concentration in blood to the MIC of fluoroquinolones for a given pathogen are associated with a favorable outcome. The present study investigated whether improvement of the therapeutic potential of ciprofloxacin could be achieved by encapsulation in polyethylene glycol (PEG)-coated long-circulating sustained-release liposomes. In a rat model of unilateral Klebsiella pneumoniae pneumonia (MIC = 0.1 microg/ml), antibiotic was administered at 12- or 24-h intervals at twofold-increasing doses. A treatment period of 3 days was started 24 h after inoculation of the left lung, when the bacterial count had increased 1,000-fold and some rats had positive blood cultures. The infection was fatal within 5 days in untreated rats. Administration of ciprofloxacin in the liposomal form resulted in delayed ciprofloxacin clearance and increased and prolonged ciprofloxacin concentrations in blood and tissues. The ED(50) (dosage that results in 50% survival) of liposomal ciprofloxacin was 3.3 mg/kg of body weight/day given once daily, and that of free ciprofloxacin was 18.9 mg/kg/day once daily or 5.1 mg/kg/day twice daily. The ED(90) of liposomal ciprofloxacin was 15.0 mg/kg/day once daily compared with 36.0 mg/kg/day twice daily for free ciprofloxacin; 90% survival could not be achieved with free ciprofloxacin given once daily. In summary, the therapeutic efficacy of liposomal ciprofloxacin was superior to that of ciprofloxacin in the free form. PEG-coated liposomal ciprofloxacin was well tolerated in relatively high doses, permitting once daily administration with relatively low ciprofloxacin clearance and without compromising therapeutic efficacy

Perfluorocarbon compounds: Effects on the rheological properties of sickle erythrocytes in vitro

The effects of oxygenated perfluorotributylamine (Fluosol‐43) on the rheological properties of sickle (HbSS) erythrocytes have been determined by means of microviscometry and positive pressure cell filtration. Incubation of deoxygenated sickled erythrocytes (pO2 = 30 mmHg) with oxygenated Fluosol‐43 reduced the percentage of sickled erythrocytes from about 63 to 33%. Deoxygenation of 40% suspension of sickle erythrocytes in autologous plasma increased the viscosity by about 160% at shear rate of 1.15 sec−1. Incubation of the deoxygenated sickled erythrocytes with oxygenated Fluosol‐43 significantly reduced the viscosity at the low shear rates. Filtration of 0.2% suspension of deoxygenated sickle erythrocytes through capillarysized Nuclepore filters showed high resistance at low flow rates. Oxygenated Fluosol‐43 increased the deformability of HbSS erythrocytes and thereby reduced the resistance at flow rates less than 1 ml/min. These data suggest that perfluorocarbons may be useful in reducing the propensity of hemoglobin S polymeriztion and sickling and thereby prevent tissue infarction in vaso‐occlusive crisis. Therefore, the concept of examining the potential application of perfluorochemicals for alleviating severe vasoocclusive events may be useful. Copyright © 1985 Wiley‐Liss, Inc., A Wiley Compan

Plasmodium falciparum: Activity of artemisinin against Plasmodium falciparum cultured in sickle trait hemoglobin AS and normal hemoglobin AA red blood cells

The presence of sickle hemoglobin causes accumulation of hemoglobin degradative products that favor oxidative reaction in erythrocytes. Artemisinin derivatives exert antiparasite effects through oxidative reactions within infected erythrocytes. Using [3H]-hypoxanthine incorporation, we therefore did an in vitro comparison of IC50 values for artemisinin in Plasmodium falciparum-infected erythrocytes from sickle cell trait (AS) and normal (AA) individuals. IC50 values for chloroquine served as control. Without drugs, parasite growth was similar in AA and AS erythrocytes. Gender, age and blood group of donors had no significant effects on parasite growth. IC50 value for artemisinin was 27 ± 14 nM in AS (N = 22) compared to 24 ± 9 nM (N = 27) in AA erythrocytes (P = 0.4). IC50 values for chloroquine were also similar in AA (22 ± 8 nM) and AS (20 ± 11 nM) erythrocytes. These results show no evidence of elevated artemisinin activity on P. falciparum in AS erythrocytes in vitro. © 2008 Elsevier Inc. All rights reserved

Anti-plasmodial activity of aroylhydrazone and thiosemicarbazone iron chelators : effect on erythrocyte membrane integrity, parasite development and the intracellular labile iron pool

Iron chelators inhibit the growth of the malaria parasite, Plasmodium falciparum, in culture and in animal and human studies. We previously reported the anti-plasmodial activity of the chelators, 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), 2-hydroxy-1-naphthylaldehyde 4-methyl-3- thiosemicarbazone (N4mT), and 2-hydroxy-1-naphthylaldehyde 4-phenyl-3- thiosemicarbazone (N4pT). In fact, these ligands showed greater growth inhibition of chloroquine-sensitive (3D7) and chloroquine-resistant (7G8) strains of P. falciparum in culture compared to desferrioxamine (DFO). The present study examined the effects of 311, N4mT and N4pT on erythrocyte membrane integrity and asexual parasite development. While the characteristic biconcave disk shape of the erythrocytes was unaffected, the chelators caused very slight hemolysis at IC50 values that inhibited parasite growth. The chelators 311, N4mT and N4pT affected all stages of the intra-erythrocytic development cycle (IDC) of P. falciparum in culture. However, while these ligands primarily affected the ring-stage, DFO inhibited primarily trophozoite and schizont-stages. Ring, trophozoite and schizont-stages of the IDC were inhibited by significantly lower concentrations of 311, N4mT, and N4pT (IC₅₀ = 4.45 ± 1.70, 10.30 ± 4.40, and 3.64 ± 2.00 ?M, respectively) than DFO (IC₅₀ = 23.43 ± 3.40 ?M). Complexation of 311, N4mT and N4pT with iron reduced their anti-plasmodial activity. Estimation of the intracellular labile iron pool (LIP) in erythrocytes showed that the chelation efficacy of 311, N4mT and N4pT corresponded to their anti-plasmodial activities, suggesting that the LIP may be a potential source of non-heme iron for parasite metabolism within the erythrocyte. This study has implications for malaria chemotherapy that specifically disrupts parasite iron utilization.9 page(s