Exploration of 7-azaindole-coumaranone hybrids and their analogues as protein kinase inhibitors.

7-Azaindole has been labelled a privileged scaffold for the design of new potent inhibitors of protein kinases. In this paper, we determined the inhibition profiles of novel mono- and disubstituted derivatives of 7-azaindole-coumaranone hybrids on various disease-related protein kinases. Eight hit compounds were identified, including a potent Haspin inhibitor with an IC50 value of 0.15 µM. An interesting observation was that all active monosubstituted compounds displayed dual inhibition for Haspin and GSK-3ß, while disubstituted derivatives inhibited GSK-3ß and LmCK1 from Leishmania major parasite. Analyses of structure activity relationships (SARs) also revealed that mono-substitution with para-fluorobenzyloxy ring produced an equipotent inhibition of Haspin and GSK-3ß. Haspin and GSK-3ß are relevant targets for developing new anticancer agents while LmCK1 is an innovative target for leishmanicidal drugs. Novel compounds reported in this paper constitute promising starting points for the development of new anticancer and leishmanicidal drugs.

ABCB1 and ABCG2 Restrict Brain and Testis Accumulation and, Alongside CYP3A, Limit Oral Availability of the Novel TRK Inhibitor Selitrectinib.

Selitrectinib (BAY2731954; LOXO-195) is a promising oral tropomyosin receptor kinase (TRK) inhibitor currently in phase I/II clinical trials for the treatment of histology-agnostic cancers positive for TRK fusions. With therapeutic resistance eventually developing with first-generation TRK inhibitors, selitrectinib was designed to overcome resistance mediated by acquired kinase domain mutations. Using genetically modified mouse models and pharmacological inhibitors, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the drug-metabolizing CYP3A enzyme complex in selitrectinib pharmacokinetics. In vitro, selitrectinib was markedly transported by mouse Abcg2 and human ABCB1, and modestly by human ABCG2. Following oral administration at 10 mg/kg, selitrectinib brain-to-plasma ratios were increased in Abcb1a/1b-/- (twofold) and Abcb1a/1b;Abcg2-/- (5.8-fold) compared with wild-type mice, but not in single Abcg2-/- mice. Testis distribution showed similar results. mAbcb1a/1b and mAbcg2 each restricted the plasma exposure of selitrectinib: With both systems absent oral availability increased by 1.7-fold. Oral administration of the ABCB1/ABCG2 inhibitor elacridar boosted plasma exposure and brain accumulation in wild-type mice to the same levels as seen in Abcb1a/1b;Abcg2-/- mice. In Cyp3a-/- mice, plasma exposure of selitrectinib over 4 hours was increased by 1.4-fold and subsequently reduced by 2.3-fold upon transgenic overexpression of human CYP3A4 in liver and intestine. The relative tissue distribution of selitrectinib remained unaltered. Thus, selitrectinib brain accumulation and oral availability are substantially restricted by ABCB1 and ABCG2, and this can be reversed by pharmacological inhibition. Moreover, oral availability of selitrectinib is limited by CYP3A activity. These insights may be useful to optimize the clinical application of selitrectinib.

Dual-responsive click-crosslinked micelles designed for enhanced chemotherapy for solid tumors.

The design of multiple stimuli-responsive, stable polymeric drug carriers is key for efficient drug release against solid tumors. Herein, core-crosslinked micelles were readily prepared from a pair of redox/pH-sensitive clickable copolymers. The two copolymers comprised the same poly(ethylene glycol) (PEG)-poly(ε-benzyloxycarbonyl-l-lysine) (PZLL) block but with either disulfide-linked azadibenzocyclooctyne (DBCO) or azide (AZ) group-tagged branched polyethylenimine (BPEI, 1.8 kDa). The data showed that an equivalent of the two copolymers could self-assemble into nanosized micelles with the crosslinked core via the DBCO-AZ click chemistry. The click-crosslinked micelles showed excellent size stability under multiple dilutions but destabilization in an acidic or reductive environment. Besides, they could load doxorubicin (DOX), an anticancer drug, and mediate slow drug release in a neutral environment but sufficient drug unloading under acidic plus reductive conditions. In vitro, DOX-loaded crosslinked micelles led to higher DOX accumulation in the cellular nucleus in comparison with non-crosslinked micelles from the PEG-PZLL-BPEI copolymer (PP), thus causing more marked cytotoxicity in SKOV-3 cells. In vivo, DOX-loaded crosslinked micelles caused significant growth inhibition of SKOV-3 tumors xenografted in BALB/c nude mice, and showed superior anticancer efficacy to non-crosslinked PP micelles. Chemotherapy with core-crosslinked micelles had no adverse side effects on the health (serum levels and body weight) of the mice. This study highlights the design of clickable block copolymers to easily construct core-crosslinked and multiple stimuli-responsive micelles for enhanced anticancer therapy.

Trans-Cyclooctene-Functionalized PeptoBrushes with Improved Reaction Kinetics of the Tetrazine Ligation for Pretargeted Nuclear Imaging.

Tumor targeting using agents with slow pharmacokinetics represents a major challenge in nuclear imaging and targeted radionuclide therapy as they most often result in low imaging contrast and high radiation dose to healthy tissue. To address this challenge, we developed a polymer-based targeting agent that can be used for pretargeted imaging and thus separates tumor accumulation from the imaging step in time. The developed targeting agent is based on polypeptide-graft-polypeptoid polymers (PeptoBrushes) functionalized with trans-cyclooctene (TCO). The complementary 111In-labeled imaging agent is a 1,2,4,5-tetrazine derivative, which can react with aforementioned TCO-modified PeptoBrushes in a rapid bioorthogonal ligation. A high degree of TCO loading (up to 30%) was achieved, without altering the physicochemical properties of the polymeric nanoparticle. The highest degree of TCO loading resulted in significantly increased reaction rates (77-fold enhancement) compared to those with small molecule TCO moieties when using lipophilic tetrazines. Based on computer simulations, we hypothesize that this increase is a result of hydrophobic effects and significant rearrangements within the polymer framework, in which hydrophobic patches of TCO moieties are formed. These patches attract lipophilic tetrazines, leading to increased reaction rates in the bioorthogonal ligation. The most reactive system was evaluated as a targeting agent for pretargeted imaging in tumor-bearing mice. After the setup was optimized, sufficient tumor-to-background ratios were achieved as early as 2 h after administration of the tetrazine imaging agent, which further improved at 22 h, enabling clear visualization of CT-26 tumors. These findings show the potential of PeptoBrushes to be used as a pretargeting agent when an optimized dose of polymer is used.

Transferrin conjugates of triazacyclononane-based bifunctional NE3TA chelates for PET imaging: Synthesis, Cu-64 radiolabeling, and in vitro and in vivo evaluation.

Three different polyaminocarboxylate-based bifunctional NE3TA (7-[2-[carboxymethyl)amino]ethyl]-1,4,7-triazacyclononane-1,4-diacetic acid) chelating agents were synthesized for potential use in copper 64-PET imaging applications. The bifunctional chelates were comparatively evaluated using transferrin (Tf) as a model targeting vector that binds to the transferrin receptor overexpressed in many different cancer cells. The transferrin conjugates of the NE3TA-based bifunctional chelates were evaluated for radiolabeling with (64)Cu. In vitro stability and cellular uptake of (64)Cu-radiolabeled conjugates were evaluated in human serum and prostate (PC-3) cancer cells, respectively. Among the three NE3TA-Tf conjugates tested, N-NE3TA-Tf was identified as the best conjugate for radiolabeling with (64)Cu. N-NE3TA-Tf rapidly bound to (64)Cu (>98% radiolabeling efficiency, 1min, RT), and (64)Cu-N-NE3TA-Tf remained stable in human serum for 2days and demonstrated high uptake in PC-3 cancer cells. (64)Cu-N-NE3TA-Tf was shown to have rapid blood clearance and increasing tumor uptake in PC-3 tumor bearing mice over a 24h period. This bifunctional chelate presents highly efficient chelation chemistry with (64)Cu under mild condition that can be applied for radiolabeling of various tumor-specific biomolecules with (64)Cu for potential use in PET imaging applications.

Synthesis and assessment of a maleimide functionalized BF2 azadipyrromethene near-infrared fluorochrome.

The first water soluble maleimide bearing NIR BF2-azadipyrromethene (NIR-AZA) fluorochrome has been synthesised which is capable of rapid thiol conjugations in water with peptides such as glutathione, the cell penetrating peptide (CPP) C(ß-A)SKKKKTKV-NH2 and a thiol substituted cRGD. NIR fluorescence imaging showed rapid cellular delivery of the CPP conjugate and effective in vivo tumour localization for the cRGD conjugate.

Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1.

Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.

Ranking the Binding Energies of p53 Mutant Activators and Their ADMET Properties.

The guardian of the genome, p53, is the most mutated protein found in all cancer cells. Restoration of wild-type activity to mutant p53 offers promise to eradicate cancer cells using novel pharmacological agents. Several molecules have already been found to activate mutant p53. While the exact mechanism of action of these compounds has not been fully understood, a transiently open pocket has been identified in some mutants. In our study, we docked twelve known activators to p53 into the open pocket to further understand their mechanism of action and rank the best binders. In addition, we predicted the absorption, distribution, metabolism, excretion and toxicity properties of these compounds to assess their pharmaceutical usefulness. Our studies showed that alkylating ligands do not all bind at the same position, probably due to their varying sizes. In addition, we found that non-alkylating ligands are capable of binding at the same pocket and directly interacting with Cys124. The comparison of the different ligands demonstrates that stictic acid has a great potential as a p53 activator in terms of less adverse effects although it has poorer pharmacokinetic properties.

Intraocular concentration of moxifloxacin after intracameral injection combined with presoaked intraocular lenses.

PURPOSE: To evaluate the impact of intraocular lens (IOL) moxifloxacin presoaking time on the intraocular concentration of moxifloxacin achieved after intracameral moxifloxacin injection. SETTING: Harlan Biotech Israel, Rehovot, Israel. DESIGN: Laboratory study METHODS: Sixty eyes of 30 rabbits were divided into 2 groups after crystalline lens evacuation. In Group A (30 eyes), hydrophilic acrylic IOLs presoaked for 15 minutes in 5 mg/mL moxifloxacin were implanted. In Group B (30 eyes), the same hydrophilic acrylic IOLs presoaked in the same solution for 24 hours were implanted. Intracameral injection of 100 mcg/0.1 moxifloxacin was performed at the end of surgery in both groups. Aqueous humor samples were obtained 2, 4, 6, 8, and 10 hours after IOL implantation and were analyzed by high-performance liquid chromatography to determine the antibiotic concentration. RESULTS: Group A achieved mean postoperative moxifloxacin concentrations of 18.60 mcg/mL±8.80 (SD), 4.08±6.03 mcg/mL, 1.50±0.75 mcg/mL, 0.21±0.09 mcg/mL, and 0.12±0.04 mcg/mL at 2, 4, 6, 8, and 10 hours, respectively. Group B achieved mean moxifloxacin concentrations of 17.25±6.27 mcg/mL, 9.46±2.22 mcg/mL, 6.26±1.22 mcg/mL, 4.34±0.42 mcg/mL, and 3.62±1.02 mcg/mL, respectively. Moxifloxacin concentrations at 6, 8, and 10 hours were statistically significantly higher in Group B than in Group A (all P<.0001). CONCLUSIONS: Combining intracameral moxifloxacin injection with implantation of moxifloxacin-presoaked hydrophilic acrylic IOLs yielded high intraocular concentrations of moxifloxacin. Higher concentrations were found with longer presoaking. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Effects of probucol, a typical hERG expression inhibitor, on in vivo QT interval prolongation in conscious dogs.

The cholesterol-lowering drug, probucol, is known to induce QT interval prolongation and torsades de pointes in patients. Recent in vitro studies have indicated that probucol reduces hERG expression in the plasma membrane and does not directly block human ether-a-go-go-related gene (hERG) channels. The present study was performed to investigate the effects of probucol on in vivo QT interval prolongation. Epicardial electrocardiograms were recorded in conscious dogs given oral single or repeated (7 days) doses of probucol (100mg/kg), and in combination with moxifloxacin (20mg/kg). QTc intervals were analyzed by a probabilistic method with individual rate collection formulae. Values of change in QTc (QTc) interval and its integration from 1 to 21 h (AUC1-21h) were calculated to evaluate drug-induced QT prolongation. A single dose of probucol slightly but significantly increased the AUC1-21h QTc interval on days 2 and 3. The QT prolongation was markedly augmented by repeated doses of probucol in a time-dependent manner, despite the lack of increase in plasma concentration. The combination of probucol and moxifloxacin produced additive effects on QT interval prolongation. These results suggest that long-term exposure to the hERG expression inhibitor, probucol, is required to evaluate its maximal effects on in vivo QT interval prolongation. A combination of direct and indirect hERG inhibitors may produce simple additive effects on QT interval prolongation.

Comparative evaluation of aqueous and plasma concentration of topical moxifloxacin alone and with flurbiprofen in patients of cataract surgery.

OBJECTIVES: To determine the aqueous and plasma concentrations of moxifloxacin administered topically alone and with flurbiprofen in patients undergoing cataract surgery. MATERIALS AND METHODS: A total of 50 subjects scheduled for routine cataract surgery were randomly allocated to two groups (n = 25 each). Group-1 patients were treated with topical moxifloxacin alone: One drop 6 times/day for 3 days before surgery and one drop 4 times on the day of surgery: Group-2 patients were treated with topical moxifloxacin as in Group-1 and with topical flurbiprofen: One drop 4 times/day for 3 days before and on the day of surgery. The interval between two drugs was 30 min for last 3 days and 15 min on the day of surgery. Last dose was administered 1 h before aqueous humor and blood sampling for both the groups. The antibiotic concentration in aqueous humor and plasma were determined by using high performance liquid chromatography. RESULTS: The mean concentration of moxifloxacin in aqueous humor was 1.71 ± 0.82 mg/ml in Group-1 and 2.39 ± 1.34 mg/ml in Group-2. Concentrations of moxifloxacin in aqueous humor were significantly higher in Group-2 than that of Group-1. CONCLUSION: Flurbiprofen may increase the concentration of moxifloxacin in aqueous humor.

Comparison between intracameral moxifloxacin administration methods by assessing intraocular concentrations and drug kinetics.

BACKGROUND: Studies have indicated that intracameral administration of moxifloxacin (MFLX), a fourth-generation fluoroquinolone, is safe and effective. However, administration methods vary between studies, and no definite protocol exists. A prospective study clarifying the incidence of endophthalmitis and complication rates associated with each administration method would require an extremely large sample size because endophthalmitis has a low incidence rate. Therefore, we investigated appropriate intracameral MFLX administration methods by assessing intraocular concentrations following simple injection and flushing, and by measuring drug kinetics (half-life). METHODS: Experiment 1: (human eyes). Irrigation (flushing) with 33.33 µg/ml MFLX (150-fold dilution) and simple injection with 0.1 ml of 500 µg/ml MFLX (10-fold dilution) were assessed after cataract surgery. Experiment 2: (rabbits: kinetics study). Flushing with 30-fold or 150-fold dilutions of MFLX was assessed. Aqueous humor samples (0.1 ml) obtained immediately after irrigation and 1, 3, and 5 h after irrigation were analyzed using high-performance liquid chromatography. RESULTS: Experiment 1: MFLX (500 µg/ml) administered using simple injection in humans underwent a 3.3-fold dilution (152.33 µg/ml). Total anterior chamber displacement after flushing with 33.33 µg/ml MFLX resulted in a concentration of 29.54 µg/ml (90% displacement). Experiment 2: Concentrations at baseline were 52% at 1 and 15% at 3 h respectively, suggesting that the half-life of intracameral MFLX was >1 h. CONCLUSIONS: Considering that the half-life of MFLX was >1 h, a final concentration of 150 µg/ml results in a 2 h concentration of 38 µg/ml, which was beyond the minimum inhibitory concentration required to inhibit the growth of 90% of bacteria (MIC90) for most resistant pathogens. We postulate that a final concentration of 150 µg/ml is considerably effective and safe. However, more resistant bacteria will evolve in the future, and the standard MIC90 may change accordingly. Therefore, even if a suitable concentration is determined, it may not necessarily remain constant. This effective concentration should be continually revised on the basis of safety and effectiveness assessments.

Serum concentrations and pharmacokinetics of moxifloxacin in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass.

Although cephalosporins are recommended as primary agents, moxifloxacin may be a suitable second-line antibiotic in cardiac surgery, especially if additional Gram-negative coverage is warranted. Cardiopulmonary bypass (CPB) may alter the pharmacokinetics of drugs in numerous ways. Since no such data exist, the aim of this study was to assess the serum concentrations and pharmacokinetics of moxifloxacin in patients undergoing cardiac surgery with CPB. Fourteen coronary artery bypass graft surgery patients received an intravenous infusion of 400 mg moxifloxacin as peri-operative antibiotic prophylaxis. At 15 time points throughout a 24-h period, serum samples were obtained to measure moxifloxacin concentrations using high-performance liquid chromatography. In addition, a non-compartmental pharmacokinetic analysis, i.e. area under the concentration-time curve (AUC), volume of distribution at steady state (V(SS)), drug clearance (CL), elimination half-life (t(1/2)) and mean residence time (MRT), was performed in five patients. Apart from a slight transient decrease in moxifloxacin concentration at the onset, CPB did not affect the concentration-time curve. Mean ± standard deviation maximum drug concentration (C(max)) (5.12 ± 1.58 µg/mL), AUC (36.5 ± 5.40 µgh/mL), VSS (2.03 ± 0.30 L/kg), CL (11.2 ± 1.91 L/h), t(1/2) (9.47 ± 0.92 h) and MRT (12.9 ± 1.52 h) were comparable with historical data for healthy volunteers. We conclude that CPB does not alter the pharmacokinetics of moxifloxacin. No dose adjustments, especially with regard to the CPB circuit and its priming volume, are necessary in cardiac surgical patients.

Ocular pharmacokinetics, safety and efficacy of intracameral moxifloxacin 0.5% solution in a rabbit model.

PURPOSE: This study was carried out to determine the ocular pharmacokinetics, efficacy and potential endothelial toxicity of moxifloxacin (MF) after a single intracameral bolus injection of 500 µg/0.1 ml in a rabbit model. MATERIALS AND METHODS: Forty-eight eyes of 24 New Zealand White Rabbits were separated into six groups, each including four rabbits. 0.1 ml of 0.5% intracameral moxifloxacin (500 µg) injection was injected to the right eyes and 0.1 ml of balanced salt solution to the left eyes (control). Aqueous humor (AH) and vitreous samples were collected at the 0.5th, 1st, 3rd, 6th, 12th and 24th hours from both eyes of group 1, 2, 3, 4, 5 and 6, respectively. MF concentrations were determined by high performance liquid chromatography. These were compared with the minimum inhibitory concentrations (MIC) and mutant prevention concentrations (MPC) for frequent endophthalmitis pathogens. Electron and light microscopical evaluation of the corneas were performed. RESULTS: Moxifloxacin reaches higher concentration than the MIC of all common endophthalmitis pathogens in the AH and exceeds the mutant prevention concentration levels for Streptococcus pneumonia, Streptococcus viridans, flouroquinolone susceptible Coagulase-negative staphylococcus and flouroquinolone susceptible Staphylococcus aureus for 6 h. The half-life of moxifloxacin in the AH was 2.2 h. Electron and light microscopic evaluation revealed no noticeable sign of toxicity. CONCLUSIONS: Peroperative intracameral moxifloxacin injection for endophthalmitis prophylaxis is a safe and effective method in uncomplicated phacoemulsification surgery.

A randomized, double-blind, placebo-controlled study to evaluate the effect of repeated oral doses of pazopanib on cardiac conduction in patients with solid tumors.

PURPOSE: As tyrosine kinase inhibitors have been associated with cardiotoxicity, we evaluated the effect of pazopanib, an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, on electrocardiographic parameters in patients with cancer. METHODS: This double-blind, placebo-controlled, parallel-group study randomized patients (N = 96) to moxifloxacin (positive control) or placebo on Day 1 followed by pazopanib or placebo 800 mg/day (fasted) on Days 2-8 and 1,600 mg (with food) on Day 9. Treatment effects were evaluated by baseline-adjusted, time-matched, serial Holter electrocardiograms. RESULTS: Sixty-five patients were evaluable for preplanned analyses. On Day 1, the maximum mean difference in baseline-adjusted, time-matched Fridericia-corrected QT (QTcF) interval in moxifloxacin-treated patients versus placebo was 10.6 ms (90% confidence interval [CI]: 4.2, 17.0). The administration scheme increased plasma pazopanib concentrations approximately 1.3- to 1.4-fold versus the recommended 800 mg once-daily dose. Pazopanib caused clinically significant increases from baseline in blood pressure, an anticipated class effect, and an unexpected reduction in heart rate from baseline that correlated with pazopanib exposure. On Day 9, the maximum mean difference in baseline-adjusted, time-matched QTcF interval in pazopanib-treated patients versus placebo was 4.4 ms (90% CI: -2.4, 11.2). Mixed-effects modeling indicated no significant concentration-dependent effect of pazopanib or its metabolites on QTcF interval. CONCLUSIONS: Pazopanib as administered in this study achieved supratherapeutic concentrations, produced a concentration-dependent decrease in heart rate, and caused a small, concentration-independent prolongation of the QTcF interval.

Radiosynthesis and preclinical evaluation of 3'-Aza-2'-[(18)F]fluorofolic acid: a novel PET radiotracer for folate receptor targeting.

The folate receptor (FR) has been identified as a valuable target for the imaging of cancer and activated macrophages, involved in inflammatory and autoimmune diseases via positron emission tomography (PET). Therefore, conjugates of folic acid have been synthesized by coupling of a radiolabeled prosthetic group to the glutamate part of folic acid (pendent approach). In this work, we present a novel class of folates, where the phenyl ring of folic acid was isosterically replaced by a pyridine moiety for direct labeling with [(18)F]fluoride (integrated approach). 3'-Azafolic acid and its 2'-halogenated derivatives (2'-chloro and 2'-fluoro) were evaluated in vitro to determine their binding affinity. 3'-Aza-2'-[(18)F]fluorofolic acid ([(18)F]6) was obtained, starting from N(2)-acetyl-3'-aza-2'-chlorofolic acid di-tert-butylester (2), in a maximum decay corrected radiochemical yield of about 9% in ≥98% radiochemical purity and high specific activities of 35-127 GBq/µmol. Binding affinity to the FR was high (IC(50) = 0.8 ± 0.2 nM), and the radiotracer was stable in human plasma over 4 h at 37 °C. No degradation or defluorination was detected after incubation of the radiotracer for 1 h at 37 °C with human and murine liver microsomes and human S9-fraction. In vivo PET imaging and biodistribution studies with mice demonstrated a high and specific uptake in FR-positive KB tumor xenografts (12.59 ± 1.77% ID/g, 90 min p.i.). A high and specific accumulation of radioactivity was observed in the kidneys (57.33 ± 8.40% ID/g, 90 min p.i.) and salivary glands (14.09 ± 0.93% ID/g, 90 min p.i.), which are known to express the FR and nonspecific uptake found in the liver (10.31 ± 2.37% ID/g, 90 min p.i.). Preinjection of folic acid resulted in a >85% reduced uptake of [(18)F]6 in FR-positive tissues (xenografts, kidneys, and salivary glands). Furthermore, no radioactive metabolites were detected in the blood, urine, or tumor tissue, 30 min p.i. These characteristics indicate that this new (18)F-labeled 3'-azafolate is an appropriate tool for imaging FR-positive (malignant) tissue.

Hydrophilic acrylic intraocular lens as a drug delivery system: influence of the presoaking time and comparison to intracameral injection.

PURPOSE: To evaluate the influence of different intraocular lens (IOL) presoaking times in an antibiotic solution and to compare the results with intracameral antibiotic injection alone. METHODS: Part A: 45 IOLs were soaked in gatifloxacin, moxifloxacin, or prednisolone acetate for 10 min, 24 h, and 1 week and then placed in a vial with a balanced salt solution. The solutions were sampled 12 and 24 h later. Part B: 90 eyes of 45 rabbits were divided into three groups. Group A received intracameral injection of moxifloxacin after lens removal and nonpresoaked IOL implantation. Groups B and C were implanted with IOLs that were presoaked for 15 min in moxifloxacin (group B) or gatifloxacin (group C), after lens removal with no intracameral antibiotic injections. Aqueous humor samples were taken 2, 4, 6, 8, and 10 h after surgery for high-performance liquid chromatography. RESULTS: Part A: In comparison with the 24-h group, the 10-min group showed release of about 30% of the antibiotics amount; the 1-week group showed a longer release time of the antibiotics and an increase of 27% for gatifloxacin and 43% for moxifloxacin. No prednisolone acetate was found. Part B: The moxifloxacin concentrations in the intracameral injection group were higher after surgery, but with faster antibiotic decrease in comparison with both presoaked IOL groups. CONCLUSION: Intracameral antibiotic injection showed a high antibiotic concentration for a short time. Presoaked IOLs showed slower decrease rates of the antibiotic level.

Comparison of corneal and aqueous humor penetration of moxifloxacin, gatifloxacin and levofloxacin during keratoplasty.

INTRODUCTION: Achieving high antibiotic concentrations is important for preventing and treating postoperative infections. However, no study has simultaneously compared the achieved concentrations of moxifloxacin, gatifloxacin, and levofloxacin in the human cornea and aqueous humor. The authors therefore performed a randomized study to determine the concentrations of 0.5% moxifloxacin, 0.3% gatifloxacin, and 0.5% levofloxacin in the corneal tissue and aqueous humor after topical instillation in patients undergoing penetrating keratoplasty. METHODS: Patients who required penetrating keratoplasty were eligible for this study. The topical preparations of 0.5% moxifloxacin, 0.3% gatifloxacin, and 0.5% levofloxacin used in the study were preservative free (Japanese formulations). Patients were randomly assigned to one of three sequential drug groups, in which each drug was administered three times before surgery. In each administration cycle, the patients received two drops of each drug at 2-minute intervals. Samples of corneal tissue and aqueous humor were collected during surgery. The concentrations of each drug in the samples were determined by high-performance liquid chromatography. RESULTS: A total of 63 patients across eight centers in Japan were enrolled in the study. Overall, 61 corneal and 58 aqueous humor samples were evaluated. The concentration (mean±standard deviation) of moxifloxacin in corneal tissues was 12.66±8.93 µg/g, which was significantly higher than that of gatifloxacin (4.71±3.39 µg/g; P<0.0001) and levofloxacin (5.95±4.02 µg/g; P<0.0001). The mean concentration of moxifloxacin in aqueous humor samples was 1.40±1.17 µg/mL, which was significantly higher than that of gatifloxacin (0.65±0.80 µg/mL; P=0.0001) and levofloxacin (0.89±0.86 µg/mL; P<0.05). The sequence of drug administration did not significantly affect the results. CONCLUSION: These results show that 0.5% moxifloxacin achieved superior ocular concentration than both 0.3% gatifloxacin and 0.5% levofloxacin.

Penetration of moxifloxacin into liver tissue.

Moxifloxacin is considered for treatment of pyogenic liver abscesses as well as antibiotic prophylaxis in the case of hepatobiliary interventions. The aim of this study was to provide data on the pharmacokinetic (PK) profile of moxifloxacin in serum and liver tissue of patients undergoing liver resection due to primary or secondary tumours of the liver. Patients scheduled for liver resection (n=34) received moxifloxacin 400 mg at randomised time intervals prior to surgery. Blood and healthy liver tissue were sampled 1.5-26 h after administration of moxifloxacin. Immediately after centrifugation, plasma was separated, frozen and stored until analysis. In a subgroup of 19 patients, additional plasma specimens were obtained after 2, 4, 8, 12, 24, 36 and 48 h to assess the PK profile. PK parameters of moxifloxacin were calculated applying a two-compartment model. Median (interquartile range) PK parameters were as follows: peak concentration at the end of moxifloxacin infusion (C(max)), 6.0 mg/L (4.8-7.1 mg/L); area under the concentration-time curve extrapolated to infinity (AUC(0-∞)), 51.1 mgh/L (40.3-57.7 mgh/L); elimination half-life, 13.2h (11.0-14.1 h); volume of distribution at steady state (V(ss)), 138.7 L (102.7-168.5 L); and total body clearance (CL), 7.8 L/h (6.9-9.9L/h). Mean tissue concentrations were 9.13 mg/kg after 1.6-2.4 h, 7.62 mg/kg after 2.6-4.9h, 7.48 mg/kg after 5.6-10.0 h and 6.24 mg/kg after 22.9-26.5 h. Mean tissue:serum ratios were 2.9, 3.4, 5.0 and 12.3, respectively. The lowest tissue concentration found in the study at any time point was 2.8 mg/kg. In conclusion, moxifloxacin rapidly penetrates into the liver tissue where its concentration remains high following intravenous administration. Therefore, intravenously applied moxifloxacin might be used for the treatment of bacterial liver infections such as pyogenic liver abscess as well as in pre-operative prophylaxis.