LZ-106, a novel analog of enoxacin, inducing apoptosis via activation of ROS-dependent DNA damage response in NSCLCs.

Lung cancer, especially non-small-cell lung cancer (NSCLC), plays the leading role in cancer which is closely related to a myriad of fatal results. Unfortunately, current molecular mechanisms and clinical treatment of NSCLC still remain to be explored despite the fact that intensive investigations have been carried out in the last two decades. Recently, growing attention to finding exploitable sources of anticancer agents is refocused on quinolone compounds, an antibiotic with a long period of clinic application, for their remarkable cell-killing activity against not only bacteria, but eukaryotes as well. In this study, we found LZ-106, an analog of enoxacin, exhibiting potent inhibitory effects on NSCLC in both cultured cells and xenograft mouse model. We identified apoptosis-inducing action of LZ-106 in NSCLC cells through the mitochondrial and endoplasmic reticulum (ER)-stress apoptotic pathways via Annexin-V/PI double-staining assay, membrane potential detection, calcium level detection and the expression analysis of the key apoptotic proteins. Through comet assay, reactive oxygen species (ROS) detection, the expression analysis of DNA damage response (DDR) marker γ-H2AX and other DDR-related proteins, we also demonstrated that LZ-106 notably induced ROS overproduction and DDR. Interestingly, additional evidence in our findings revealed that DDR and apoptosis could be alleviated in the presence of ROS scavenger N-acetyl-cysteine (NAC), indicating ROS-dependent DDR involvement in LZ-106-induced apoptosis. Thus our data not only offered a new therapeutic candidate for NSCLC, but also put new insights into the pharmacological research of quinolones.

Effect of solvent composition during preparations on the characteristics of enoxacin microparticles.

We have studied the effect of the solvent system during preparation on the morphology, encapsulation efficiency, and release characteristics of enoxacin microparticles intended for localized delivery to the bone for the treatment of bone infections. Microparticles of enoxacin were formulated using poly(glycolic acid-co-DL-lactic acid) (PGLA) of different viscosity grades by the solvent-evaporation technique. Microparticles prepared with pure dichloromethane had smoother surfaces and less tendency to aggregate than microparticles prepared with dichloromethane-acetone solvent mixtures, which had porous surfaces. Approximately 65% of the microparticles prepared with pure dichloromethane were < 125 microm in diameter compared with 16% (approx.) of microparticles prepared with dichloromethane-acetone mixtures. Increasing the proportion of acetone from dichloromethane-acetone, 10:0, to dichloromethane-acetone, 1:1, resulted in an increase in encapsulation efficiency from 25 to 37%, and an increase in the yield of microparticles harvested from 39 to 51%. Although a further increase in the amount of acetone to dichloromethane-acetone, 1:9, had no significant effect on the yield, aggregation, or fraction of microparticles below 125 microm in diameter, the encapsulation efficiency increased to 56%. Approximately 55% of enoxacin was released in 24 h for microparticles prepared with dichloromethane-acetone, 1:9, compared with 100% release in 10h and 2h for microparticles of the same size range prepared with dichloromethane-acetone, 1:1, and dichloromethane-acetone, 10:0, respectively. The results suggest that the composition of the dichloromethane-acetone solvent system significantly influences the encapsulation efficiency and the rate of release of enoxacin from microparticles. This is important for the formulation of sustained-release enoxacin microparticles for the localized treatment of osteomyelitis.

Evaluation of transdermal iontophoresis of enoxacin from polymer formulations: in vitro skin permeation and in vivo microdialysis using Wistar rat as an animal model.

Polymers were used in vehicles to form hydrogel matrices in this study to evaluate the in vitro permeation and in vivo microdialysis of enoxacin. The highest transdermal delivery determined by area under flux-time curve (AUC) and intracutaneous enoxacin concentration were observed in methylcellulose (MC) and polyvinylpyrrolidone (PVP) hydrogels, respectively. To avoid the pH shift in vehicles during iontophoresis, buffer species were added to formulations to increase the buffer capacity. As expected, the permeability of enoxacin of anodal iontophoresis was larger than that of cathodal iontophoresis. Combination of benzalkonium chloride, a cationic surfactant as an enhancer, and iontophoresis exerted an enhancing effect for anionic enoxacin at pH 10.0. However, no effect or a negative effect was detected for cationic enoxacin in deionized water or pH 5.0 buffer, due to the shielding of the negative charge in the skin. The skin residue of enoxacin was slightly increased after the incorporation of Azone in PVP hydrogel. The result of in vivo microdialysis was in accordance with that of in vitro study. The effect of Azone on the intracutaneous enoxacin was more significant for in vivo microdialysis than in the in vitro study indicating the clinical feasibility of Azone for iontophoretic delivery. Microdialysis can be considered as a useful technique to investigate the pharmacokinetics of transdermal iontophoresis in vivo.

Oral enoxacin for infection prevention in adults with acute nonlymphocytic leukemia. The Enoxacin Prophylaxis Study Group.

A randomized, double-blind, placebo-controlled trial was conducted in eight hematologic units to determine the efficacy and safety of oral enoxacin for infection prevention in adult patients with acute nonlymphocytic leukemia. One hundred nineteen patients undergoing remission induction or consolidation chemotherapy were enrolled; 62 of them received enoxacin (400 mg orally every 12 h). Patients received antifungal prophylaxis with oral mycostatin (1,000,000 U four times daily) or clotrimazole (1 troche five times daily). Analysis was performed on an intent-to-treat basis. There was no significant difference between groups in race, age, or type and stage of leukemia, but there were more males in the placebo group (P = 0.073 [Fisher's exact test]). Fewer enoxacin patients had gram-negative bacteremia (1 versus 14 [P < 0.001]), gram-negative infection at any site (2 versus 19 [P < 0.001]), or bacterial and/or fungal infection (17 versus 26 [P = 0.056]). There was no significant difference in the number of patients with gram-positive infection at any site (12 versus 16), gram-positive bacteremia (9 versus 10), deep fungal infection (6 versus 2), death (2 versus 3), other antimicrobial therapy required (48 versus 48), therapy with amphotericin B (15 versus 7 [P = 0.105]), any adverse event (45 versus 36), or any study drug-associated adverse events (13 versus 6). Logistic regression confirmed (odds ratios and 95% confidence intervals are given in parentheses) that enoxacin reduced the risk of gram-negative infection (0.07; 0.01 to 0.30), especially gram-negative bacillary bacteremia (0.05; 0.01 to 0.37), without altering the risk of gram-positive bacterial (0.63; 0.26 to 1.5), deep fungal (2.57; 0.47 to 13.9), or Clostridium difficile (1.16; 0.3 to 4.56) infection. The median time to the onset of fever of more than or equal 102.8 F (39.3 degree C) was 32 days for the enoxacin group versus 15 days for patients receiving placebo (P=0.0007 [Wilcoxon test]). In patients with acute nonlymphocytic leukemia, oral enoxacin prevents gram-negative infections, delays the onset of fever, does not alter the incidence of gram-positive or proven deep fungal infections, and is well tolerated.

[Photosensitivity following enoxacin and xipamide: combined phototoxic and photo-allergic reaction to enoxacin, photo-allergic reaction to xipamide with subsequent transient light reaction]. / Photosensitivität nach Enoxacin und Xipamid: Kombinierte phototoxische und photoallergische Reaktion auf Enoxacin, photoallergische Reaktion auf Xipamid mit nachfolgender transienter Lichtreaktion.

In a 51-year-old female patient, we observed a combined phototoxic and photoallergic reaction to Enoxacin, a photoallergic reaction to Xipamide, as well as increased sensitivity to light after withdrawal of the drugs. This unusual diagnosis was based on the clinical picture, graded radiation with UV-A and UV-B, the irradiated intradermal assay, and histological findings. To the best of our knowledge, this is the first report on a photoallergic reaction to Xipamide associated with a combined phototoxic and photoallergic reaction to Enoxacin.

Single-dose enoxacin compared with 3-day treatment for urinary tract infection.

Oral treatment of simple urinary tract infections generally involves 5 to 7 days of antibiotic therapy. This study with enoxacin, a new antibacterial agent of the quinolone-azaquinolone class, investigated the efficacy of a single dose compared with 3 days of treatment. A total of 154 outpatients with symptoms of simple cystitis were treated in an open randomized study with enoxacin, either one 600-mg dose or 200 mg twice a day for 3 days. A urine sample was collected for culture before treatment, 7 to 10 days after treatment, and 4 to 6 weeks after treatment. Seventy-three patients had positive bacterial cultures from the pretreatment urine sample; the predominant pathogen was Escherichia coli, along with a number of other gram-negative organisms and Staphylococcus spp. Of these patients, 33 received a single dose of enoxacin and 40 were treated for 3 days. Follow-up examination at 7 to 10 days showed negative urine cultures in 76% of patients from the single-dose group and 89% from the multiple-dose group, a difference that was not statistically significant (P = 0.665, Fisher's exact test). A number of patients were lost to follow-up at 4 to 6 weeks. However, of those who did attend, only three patients were shown to have relapsed or become reinfected (two in the multiple-dose group and one in the single-dose group). Enoxacin was well tolerated in both groups of patients; the few adverse events were mostly mild.

[Enoxacin concentration in seminal fluid, in prostate secretions and in prostatic adenoma tissue following oral administration or intravenous infusion]. / Enoxacin-Konzentrationen in der Samenflüssigkeit, im Prostatasekret und im Prostataadenomgewebe nach oraler Gabe oder intravenöser Infusion.

In eleven volunteers and 39 patients undergoing transurethral resection of the prostate or bladder tumor, concentrations of enoxacin were measured in seminal fluid (volunteers), in prostatic fluid (volunteers, patients) and in prostatic adenoma tissue (patients) after oral (400 mg) administration and intravenous (428 mg) infusion (60 min) of enoxacin. Simultaneously 2.534 g of iothalamic acid was i.v. injected to identify possible urinary contamination. The concentrations of enoxacin in seminal fluid after 2-4 h and in prostatic tissue after about 1-4 h and 14-16 h exceeded plasma concentrations more than two-fold. The concentrations in prostatic fluid after 1-4 h were about half the plasma concentrations. Venous blood samples were taken after intravenous infusion at intervals of up to 24 h in a total of 14 patients. The mean plasma concentration of enoxacin decreased from its maximum of 6.9 mg/l at the end of infusion to 0.5 mg/l at 12 h after administration. A terminal half life of 6.65 h was calculated according to an open two-compartment model.

[Enoxacin concentrations in lung tissue]. / Enoxacin-Konzentrationen im Lungengewebe.

For successful treatment of bacterial lung infections the administered antibiotic must reach sufficiently high concentrations in lung tissue. Therefore, the concentrations of enoxacin in this tissue were measured in ten patients requiring pulmonary surgery. In order to prevent postoperative infection, the patients received 400 mg enoxacin b.i.d. for three days. Eight h after the final dose samples of venous blood were drawn and a sample of lung tissue was removed. Using a microbiological assay, we found the following concentrations (mean +/- S.D.):serum 2.36 (+/- 0.65) mg/l, lung 6.48 (+/- 1.54) mg/kg. With the HPLC-technique the corresponding values method were 2.37 (+/- 0.80) mg/l and 7.41 (+/- 3.01) mg/kg. Thus concentrations of enoxacin in lung tissue are about three times higher than the corresponding serum concentrations.

[Enoxacin concentration in human prostatic tissue after 3-day administration].

The penetration of enoxacin into prostatic tissue was examined Thirty-five patients with benign prostatic hypertrophy entered the study. Enoxacin was administered orally in a dose of 200 mg three times daily for 3 days preoperatively. Blood samples were taken simultaneously at the time of tissue sampling. The patients were divided into groups 1 and 2. In group 1, tissue sampling was done after about 17 hours of final administration of the drug. The mean concentration of enoxacin in prostatic tissue was 1.87 +/- 1.23 micrograms/g and 1.05 +/- 0.458 micrograms/ml in serum. In group 2, sampling was done after 5.5 hours of final administration. The mean concentration of enoxacin in prostatic tissue was 2.51 +/- 0.725 micrograms/g and 1.78 +/- 0.586 micrograms/ml in serum.

[Clinical studies on enoxacin in urinary tract infection].

Enoxacin was administered orally to 49 out-patients with urinary tract infections (UTI) at the doses of 600 mg/day and clinical effects were evaluated. Out of 13 patients with simple acute UTI evaluated by the UTI criteria, the results were excellent in 8 cases and good in 5 cases. Overall effectiveness rate was 100%. Out of 10 patients with simple acute UTI evaluated on over 5-day administration, the results were excellent in 9 cases and good in 1 case. Overall effectiveness rate was 100%. Out of 14 patients with simple acute UTI evaluated by our own criteria because their bacteriological response is unknown, the results were excellent in 7 cases and good in 7 cases. Overall effectiveness rate was 100%. Out of 12 patients with chronic complicated UTI evaluated by the UTI criteria, the results were excellent in 6 cases, good in 3 cases and poor in 3 cases. Overall effectiveness rate was 75.0%. Poor effective cases were mainly found in ones with mixed infection. Sensitivity test using discs did not always correspond to the bacteriological effect in cases with chronic complicated UTI. An adverse reaction was noted in 3 patients (6.1%). Two cases had gastrointestinal symptoms and 1 case had skin eruption. All symptoms were readily improved after discontinuing administration. From the above results, Enoxacin was considered to be a useful agent for urinary tract infection.