Eun J. Yoon

Synthesis of highly antibacterial nanocrystalline trivalent silver polydiguanide.

Highly monodispersed nanoparticles of a trivalent silver polydiguanide complex are synthesized by oxidation of the monovalent silver, followed by stabilization of the oxidized higher-valent metal through complexation with a polydiguanide ligand in a reverse microemulsion at room temperature. The synthesized nanoparticles have excellent photostability and displayed superior antibacterial activity toward Gram-positive and Gram-negative prokaryotes of clinical interest in vitro compared to silver sulfadiazine. These nanoparticles may serve as a new generation antibacterial metallopharmaceutical in wound care.

Pharmacokinetics of methotrexate after intravenous infusion of methotrexate-rabbit serum albumin conjugate to rabbits

Abstract The pharmacokinetics of methotrexate (MTX) were compared after 30 min intravenous infusion of the same dose (10 mg/kg as MTX) of MTX (treatment I) or MTX-rabbit serum albumin (RSA) conjugate (treatment II) to rabbits. In treatment II, the mean peak plasma level of MTX was significantly lower (48.1 vs 13.8 μg/ml), and plasma levels declined more slowly thereafter (mean apparent half-lives of 3.26 vs 4.96 h) than those in treatment I. In treatment II, the values of AUC (2360 vs 1510 μg min ml − ) and CL R (2.49 vs 0.452 ml min −1 kg −1 ) were decreased, however, the values of V SS (0.311 vs 1.47 1/kg), MRT (1.62 vs 3.71 h), t 1 2 (3.26 vs 4.96 h), and CL NR (1.66 vs 6.13 ml min −1 kg −1 ) were significantly increased. The above data suggested that MTX resides longer in the rabbit, and that nonrenal metabolism of MTX increases in treatment II. It could be explained by the fact that MTX is released slowly from MTX-RSA conjugate, and that the disposition of MTX is saturable. The amounts of MTX (μg/g tissue) remaining in kidney, stomach, small intestine, and large intestine after 30 min infusion of MTX-RSA conjugate were 33, 6.1, 3.1, and 10 times lower, respectively, than those after 30 min infusion of free MTX. It might suggest that the administration of MTX-SA conjugate has less side effects of MTX in these organs or tissues than those of free MTX. The in vitro release of MTX from MTX-RSA conjugate in phosphate buffer of pH 7.4, the buffer with protease, rat liver homogenate, or human plasma was biphasic process. For example, an initial rapid release over approx. 6 h appears to be due to physically adsorbed MTX with the slower secondary release due to covalently bound drug. The release of MTX from the conjugate in vitro was accelerated in the presence of protease or liver homogenate.

Metallopharmaceuticals based on silver(I) and silver(II) polydiguanide complexes: activity against burn wound pathogens

OBJECTIVES The in vitro pharmacodynamics of silver(I) and silver(II) complexes of a polydiguanide ligand, chlorhexidine, were assayed to examine the value of the bactericidal endpoint as an alternative means of evaluating their antibacterial activities against burn wound pathogens. METHODS Synthesis of silver(I) chlorhexidine [Ag(I)CHX] was accomplished by in situ precipitation of the complex from a feebly acidic or neutral aqueous solution of AgNO(3) and chlorhexidine, whereas silver(II) chlorhexidine [Ag(II)CHX] was synthesized by oxidation of Ag(I), followed by complexation of the oxidized metal with chlorhexidine. Their antibacterial potencies were assessed in vitro by determining the MICs and MBCs for four Gram-positive and four Gram-negative bacteria. Time-kill assays using three different concentrations of these agents were also performed. RESULTS The MICs of Ag(I)CHX and Ag(II)CHX were much lower than those of chlorhexidine, AgNO(3) and silver sulfadiazine. The time-kill study provided quantitative information on actual times required to reach the bactericidal endpoint using a particular concentration of the active agent. The lethality rates of Ag(I)CHX and Ag(II)CHX against the tested bacteria were 2× to 8× faster than those of chlorhexidine or AgNO(3) at a concentration equal to or 4× MIC. CONCLUSIONS Ag(I)CHX and Ag(II)CHX showed superior antibacterial activity and faster killing kinetics compared with chlorhexidine and AgNO(3). These complexes may serve as new-generation antibacterial agents in wound care.

Pharmacokinetics of FT-ADM after intravenous administration of DA-125, a prodrug of FT-ADM or FT-ADM to rats. A new adriamycin analog containing fluorine

The pharmacokinetics of DA-125 or its active metabolite, M1 (FT-ADM), an adriamycin analog containing fluorine were compared after intravenous (i.v.) administration of DA-125 or M1 in rats. DA-125, 20 mg kg−1 was dissolved in 1 mM lactic acid/0.9% NaCl solution (treatment I) or 100% dimethylsulfoxide (DMSO, treatment II), and M1, 20 mgkg was dissolved in 100% DMSO (treatment III) due to its poor water solubility. The plasma concentrations of DA-125 and M1, and the pharmacokinetic parameters of DA-125, such as terminal half-life (t12, 1.64 vs 2.07 min), mean residence time (MRT, 1.52 vs 2.60 min), total body clearance (CL, 165 vs 186 ml min−1 kg−1) and apparent volume of distribution at steady state (Vdss, 254 vs 411 ml kg−1), and of M1 (based on plasma data up to 1 h), such as (t12 (30.2 vs 38.7 min), MRT (19.1 vs 31.6 min), CL (187 vs 189 ml min−1 kg−1) and Vdss(2670vs 5700 ml kg−1were similar between treatments I and II, indicating that the effect of 100% DMSO on the pharmacokinetics of DA-125 or M1 seemed to be negligible, if any. The plasma concentrations of M1, and the pharmacokinetic parameters of M1 (based on plasma data up to 8 h when the dose of M1, 20 mg kg−1 was normalized to the dose of DA-125, 20 mg kg−1), such as (t12 (255 vs 221 min), MRT (269 vs 235 min), CL (103 vs 112 ml min−1 kg−1) and Vdss (28 500 vs 26300 ml kg−1) were also similar between treatments II and III. The above results indicate that DA-125 is rapidly hydrolyzed to M1 after i.v. administration of DA-125. Therefore, the estimation of the pharmacokinetic parameters of M1 after i.v. administra- tion of DA-125 appeared not to cause any differences, if any when compared with the values after i.v. dose of M1. The rapid hydrolysis of DA-125 to M1 was demonstrated during an in vitro study; the (t12 values of hydrolysis of DA-125 were 1.97, 1.72, 0.54 and 0.54 min in the plasma from mouse, rat, dog and human, respectively, when the plasma containing DA-125 was incubated in a shaking water bath kept at 37°C and at a rate of 300 rpm.

Pharmacokinetics of 5-fluorouracil after intravenous infusion of 5-fluorouracil-acetic acid-human serum albumin conjugates to rabbits

Abstract The pharmacokinetics of 5-fluorouracil (5-FU) was compared after 30 min intravenous infusion of the same dose (20mg/kg as 5-FU) of 5-FU (treatment I), 5-FU-acetic acid (5-FU-AA, treatment II) and 5-FU-AA-human serum albumin conjugates (5-FU-AA-HSA, treatment III) to rabbits. After post-infusion, plasma levels of 5-FU declined rapidly with a mean half-life of 8.0 min from treatment I, however, they were not detected until 10–50 min and the mean plasma concentration of 1μg/ml was maintained from 3 to 24 h for treatment III. It might be possible to maintain constant plasma concentrations of 5-FU for a long period of time by 30 min infusion of 5-FU-AA-HSA conjugates instead of tedious time-consuming infusion of 5-FU. The mean values of 24 h AUC (623 vs 1290 μg min ml −1 ) were significantly higher from treatment III than that from treatment I. 5-FU was not detected from treatment II nor 5-FU-AA from treatment III in both plasma and urine samples. In treatment II, 5-FU-AA was eliminated rapidly with a mean apparent terminal half-life of 18.7 min based on urinary excretion rate data. 5-FU was not detected in brain after 30 min intravenous infusion of both 5-FU and 5-FU-AA, however, significant amounts of 5-FU were found in brain after administration of 5-FU-AA-HSA conjugates. The in vitro release of 5-FU from 5-FU-AA-HSA conjugates was increased in the presence of protease or liver homogenates, however, 5-FU was not detected for up to 24 h incubation of 5-FU-AA with the various solutions.

Pharmacokinetics and tissue distribution of adriamycin and adriamycinol after intravenous administration of adriamycin-loaded neutral proliposomes to rats

The pharmacokinetics and tissue distribution of adriamycin (ADM) and its metabolite, adriamycinol were investigated after intravenous (i.v.) injection of free ADM (treatment I), ADM-loaded neutral proliposomes (treatment II) and empty neutral proliposomes mixed manually with free ADM (treatment III), 16 mg per kg as free ADM, to rats, using HPLC assay. After 1 min i.v. infusion, the plasma concentrations of ADM (Cp), area under the plasma concentration-time curve (AUC, 159 vs 351 μg min ml−1), terminal half-life (t12, 65.2 vs 633 min), mean residence time (MRT, 27.5 vs 541 min) and apparent volume of distribution at steady state (Vss, 2480 vs 22800 ml kg−1) were significantly higher, however, the total body clearance (CL, 101 vs 45.6 ml min−1 kg−1), renal clearance (CLR, 9.81 vs 2.27 ml min−1 kg−1), nonrenal clearance (CLNR, 90.8 vs 42.8 ml min−1 kg−1) and the amount of ADM excreted in urine (Xu, 496 vs 297 μg) were significantly lower in treatment II than the values from treatment I. This could be due to the fact that some of the ADM-loaded liposomes (formed by hydration of ADM-loaded proliposomes) were entrapped in tissues and the rest were in plasma (higher MRT and Vss in treatment II), and ADM was slowly released from ADM-loaded liposomes (higher t12 in treatment II). In the present HPLC assay, the concentrations of ADM represent the sum of free ADM and ADM loaded in liposomes (higher Cp and AUC, slower CL in treatment II). After 1 min i.v. infusion, some pharmacokinetic parameters, such as t12, MRT and Xu were significantly different between treatments I and III, but not as distinct between treatments I and II. 30 min after i.v. infusion, the amount of ADM remaining in lymph node and the lymph node to plasma ratio were significantly higher in treatment II than in treatment I. This suggested that the i.v. administration of ADM-loaded proliposomes might have a better lymph node targeting ability than free ADM. The mean amount of ADM loaded in ADM-loaded proliposomes was 4.09 mg per g proliposome.

Simultaneous determination of a new anthracycline, DA-125, and its metabolites M1, M2, M3 and M4 in plasma and urine by high-performance liquid chromatography

A high-performance liquid chromatographic method was developed for the simultaneous determination of a new anthracycline, DA-125 (I), and its metabolites (M1, M2, M3, and M4) in rat plasma and urine using fluorescein as an internal standard. Compound I, a prodrug of M1, is a beta-alanine derivative of M1, and only M1 shows antineoplastic activity. The method involved extraction or deproteinization followed by injection of 80-100 microliters of the aqueous layer or supernatant onto a C18 reversed-phase column. The mobile phases were 1% acetic acid-isopropyl alcohol-methanol (70:20:10, v/v) or 5 mM of ion-pairing chromatography reagent (IPC B8)-isopropyl alcohol-methanol (70:20:10, v/v) for the extraction or deproteinization methods, respectively. The flow-rate was 1.5 ml/min for both methods. The column effluent was monitored by a fluorescence detector with excitation wavelength of 488 nm and emission wavelength of 556 nm. The detection limits for M1, M2, M3, and M4 in rat plasma and urine were 50 ng/ml for all compounds using the extraction method, and 100, 50, 50, 50, and 50 ng/ml for I, M1, M2, M3 and M4 in rat plasma respectively, using the deproteinization method. No interferences from endogenous substances, adriamycin or daunorubicin were found.

Pharmacokinetics, tissue distribution and biliary excretion of FT-ADM after intravenous administration of DA-125, a prodrug of FT-ADM to dogs. A new adriamycin analog containing fluorine

Abstract The pharmacokinetic parameters, tissue distribution and biliary excretion of M1-M4 were estimated after intravenous (i.v.) administration of DA-125, 2.5 mg per kg to beagle dogs. The mean values of the terminal half-life, mean residence time, total body clearance and apparent volume of distribution at steady state of M1 were 266 min, 170 min, 61.3 ml min −1 kg −1 and 9500 ml kg −1 , respectively (four male and four female dogs). M1 was highly concentrated in lung (five male and five female dogs), and this probably means that lung tumors are subjected to greater exposure to M1, an active metabolite of DA-125. The 8 h biliary excretion of M2 was significantly greater than that of M1, 53.6 vs 6860 μg (three male and two female dogs). The amount of glucuronide and/or sulfate conjugates of M1-M4 in the bile sample was negligible.

In Vitro and In Vivo Activities of DA-7867, a New Oxazolidinone, against Aerobic Gram-Positive Bacteria

ABSTRACT In vitro and in vivo activities of DA-7867 were assessed against methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and penicillin-resistant Streptococcus pneumoniae. All isolates were inhibited by DA-7867 at ≤0.78 μg/ml, a four-times-lower concentration than that of inhibition by linezolid. For murine infection models, DA-7867 also exhibited greater efficacy than linezolid against all isolates tested.

Dose-dependent pharmacokinetics of human granulocyte/macrophage colony-stimulating factor in rabbits

Abstract The pharmacokinetic parameters of HGM-CSF, such as t 1 2 (11.3, 10.4, 39.2, 39.2 vs 51.6 min), MRT (11.6, 10.9, 22.9, 20.3 vs 18.3 min), CL (25.0, 21.1, 6.98, 7.94 vs 6.51 ml min −1 kg −1 ), cl NR (24.6, 19.9, 6.87, 6.92 vs 4.24 ml min −1 kg −1 ) and V ss (292, 211, 162, 162 vs 120 ml kg −1 ) were dose-dependent after intravenous administration of the factor to rabbits at the doses of 0.05, 0.1, 0.5, 1.0 and 2.5 mg kg −1 , respectively: The dose-dependent pharmacokinetics of HGM-CSF in rabbits appeared to represent saturable metabolism of the factor at the dose ranges studied. HGM-CSF was highly concentrated in the kidney and liver, and less concentrated in other tissues or organs studied at 2 h after subcutaneous administration of the factor, 0.5 mg kg −1 to rabbits.