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PubMed2005

EPR, UV-vis, magnetic, spectral studies and electrochemical behaviour of mononuclear transition metal complexes derived from novel hexa-aza-macrotricyclic ligand.

Aza-macrocyclic complexes have gained importance because of their pharmacological properties. Hexa-aza-macrocycles containing glutarimide efficiently coordinate as hexa-dentate ligand, to give complexes of Cu(II) possessing tetragonal structure and Mn(II), Co(II) and Ni(II) metal ions that are essentially octahedral. Spectroscopic, and chemical characterizations of these systems are presented in this article. For Ni(II) complexes results on electron transfer processes measured by cyclic voltammetry and colourimetry have been studied.

Aza Compounds↗
PubMed2006

Theoretical studies on NMR chemical shifts in azacubanes.

Successive substitution of CH groups of cubane (CH)(8), by isoelectronic nitrogen atoms leads to a class of energy-rich azacubanes (CH)(8-alpha)N(alpha) (with alpha=1-8). In the present work, we systematically investigate how substitution of nitrogen in a cubanoid influence deshielding of carbon and manifest in the chemical shift in NMR spectra calculated using the second order Møller-Plesset (MP2) perturbation level of theory. PMR spectra predict a large downshift of delta(H)=7.9 ppm in heptaazacubane owing to the more number of nitrogen and the stronger C-H...N interactions. These chemical shifts are explained by the net atomic charges derived from the population analysis based on Hirshfeld partitioning scheme.

Aza Compounds↗
PubMed2004

Fluoroquinolone resistance in ophthalmology and the potential role for newer ophthalmic fluoroquinolones.

The three topical ophthalmic fluoroquinolones recently introduced into the U.S. market--levofloxacin, gatifloxacin, and moxifloxacin--offer several advantages over the previously available fluoroquinolones (norfloxacin 0.3%, ciprofloxacin 0.3%, and ofloxacin 0.3%). These include enhanced spectrum and potency for Gram-positive cocci and possibly atypical mycobacterial species, improved penetration into the anterior segment, and reduced propensity to promote the development of resistance. Although published data and clinical experience with these agents is quite limited given their relatively recent entry into the U.S. market, this perspective will attempt to provide an understanding of the potential role of these newer fluorquinolones in addressing the problem of increasing fluoroquinolone resistance amongst bacterial ocular isolates.

Anti-Infective Agents↗
PubMed2005

Ophthalmic infections and their anti-infective challenges.

This introduction provides an overview of the succeeding articles contained within this supplement on the new fourth-generation fluoroquinolone antibiotic product, moxifloxacin ophthalmic solution 0.5% (VIGAMOX, Alcon Laboratories, Inc., Fort Worth, TX). Moxifloxacin was developed specifically to address the increasing incidence of resistance to earlier-generation antibiotic molecules. Structural modifications to the moxifloxacin molecule have decreased the likelihood of the development of resistant organisms. This antibiotic has been shown to possess greater activity than previous-generation molecules against gram-positive bacteria while maintaining excellent potency against gram-negative organisms and nontuberculous (atypical) mycobacteria. Moxifloxacin ophthalmic solution 0.5% exhibits enhanced bioavailability due to a unique molecular structure that combines high lipophilicity for enhanced corneal penetration with high aqueous solubility at physiological pH. Numerous studies have shown that moxifloxacin ophthalmic solution 0.5% has high potency against a broad range of microbial species and a favorable profile in terms of safety and tolerability. The results presented in this supplement provide additional evidence for the potential benefits of moxifloxacin ophthalmic solution 0.5% in surgical prophylaxis and treatment of sight-threatening infections, such as bacterial conjunctivitis, endophthalmitis and keratitis.

Aza Compounds↗
PubMed2005

Overview of the potency of moxifloxacin ophthalmic solution 0.5% (VIGAMOX).

Antibiotics have been the mainstay of therapy for infectious diseases since their origins in the 1940s. As microorganisms changed and resistance developed, more advanced antibiotics were ultimately needed to provide adequate coverage and spectrum. By selecting optimal antibiotics and dosing regimens, clinicians can avoid treatment failures and adverse events and can help prevent the emergence of further antibiotic resistance. The fourth-generation ophthalmic fluoroquinolones include moxifloxacin (VIGAMOX, Alcon Laboratories, Inc., Fort Worth, TX) and gatifloxacin (Zymar, Allergan, Irvine, CA), and they are now approved for the treatment of bacterial conjunctivitis. This review highlights four scientific methods that compare and rank antibiotic potencies and predict their clinical efficacy and their propensity to develop resistance: 1) in vitro assay for minimum inhibitory concentrations, 2) in vivo models for pharmacokinetic and pharamacodynamic properties, 3) therapeutic index or inhibitory quotient, and 4) in vitro assay for mutant prevention concentration. The fourth-generation ophthalmic fluoroquinolones perform well in these assays. Both antibiotics have better in vitro activity against gram-positive bacteria than ciprofloxacin or ofloxacin. Moxifloxacin penetrates better into ocular tissues than gatifloxacin and older fluoroquinolones; in vitro activity of moxifloxacin and gatifloxacin against gram-negative bacteria is similar to that of older fluoroquinolones. Moxifloxacin also has better mutant prevention characteristics than other fluoroquinolones. These findings support the use of the newer fluoroquinolones for the prevention and treatment of serious ophthalmic infections (e.g., keratitis, endophthalmitis) caused by susceptible bacteria.

Animals↗
PubMed2005

Safety of moxifloxacin as shown in animal and in vitro studies.

Topical treatment of ocular bacterial infection is practiced widely, and the choice of the antibacterial agent depends on the nature of the infection, including the susceptibility of the organism, the tissue affected, and the safety profile of the agent. Moxifloxacin is a fourth-generation fluoroquinolone approved for ophthalmic use as moxifloxacin ophthalmic solution 0.5% (VIGAMOX, Alcon, Fort Worth, TX). Moxifloxacin ophthalmic solution 0.5% is self-preserved at a near-neutral pH of 6.8. In treating ocular infection, the three important aspects of therapeutic control are potency, penetration of the drug to the target site, and safety of the drug and the drug product. Moxifloxacin ophthalmic solution 0.5% provides antibacterial potency and high penetration of target ocular tissues. The ocular and systemic safety profile of moxifloxacin compares favorably with those of other fluoroquinolone antimicrobial agents, with a low risk of recognized quinolone-related toxicity. In vitro studies of fluoroquinolones with human or rabbit corneal epithelial cells or keratocytes suggest that moxifloxacin is similar in cytotoxicity potential to other drugs of this family. Specialized in vivo corneal wound-healing studies draw little distinction between moxifloxacin-treated eyes and those treated with other fluoroquinolones. Repeated-dose topical ocular studies in rabbits and monkeys, with high concentrations (up to 3%) of moxifloxacin and at treatment durations and regimens well in excess of label-prescribed use, demonstrated a high safety margin for ocular and extraocular tissues. Cornea, the tissue with highest exposure, was found to be unaffected by these high exposures, with slit-lamp biomicroscopy, corneal thickness measurement, intraocular pressure, and specular microscopy of the corneal endothelium (monkeys only), and histologic evaluation showing no effects, as compared with controls. Moxifloxacin ophthalmic solution 0.5% affords superior efficacy and ocular tissue penetration, with a favorable safety profile.

Animals↗
PubMed2005

Clinical safety of moxifloxacin ophthalmic solution 0.5% (VIGAMOX) in pediatric and nonpediatric patients with bacterial conjunctivitis.

Five independent, multicentered, double-masked, parallel, controlled studies were conducted to determine the safety of moxifloxacin ophthalmic solution 0.5% (VIGAMOX) in pediatric and nonpediatric patients with bacterial conjunctivitis. Patients were randomized into one of two treatment groups in each study and received either moxifloxacin ophthalmic solution 0.5% b.i.d. or t.i.d. or a comparator. A total of 1,978 patients (918 pediatric and 1,060 nonpediatric) was evaluable for safety. The most frequent adverse event in the overall safety population was transient ocular discomfort, occurring at an incidence of 2.8%, which was similar to that observed with the vehicle. No treatment-related changes in ocular signs or visual acuity were observed with moxifloxacin ophthalmic solution 0.5%, except for one clinically relevant change in visual acuity. Thus, based upon a review of adverse events and an assessment of ocular parameters, moxifloxacin ophthalmic solution 0.5% formulated without the preservative, benzalkonium chloride, is safe and well tolerated in pediatric (3 days-17 years of age) and nonpediatric (18-93 years) patients with bacterial conjunctivitis.

Adult↗
PubMed2005

Future of ophthalmic anti-infective therapy and the role of moxifloxacin ophthalmic solution 0.5% (VIGAMOX).

The vintage antibiotics that were available in the 1950s-1980s were sometimes toxic, had limited spectra, and were bacteriostatic agents, and they have been replaced by significantly broader-spectrum therapies. We ask more of our future antibiotic products for ophthalmology: they must be 1) broad spectrum, 2) convenient to use, 3) useful prophylactically, 4) effective therapeutically, 5) benzalkonium chloride-free, 6) comfortable, and 7) nontoxic. The emergence of antibiotic resistance has focused us on more potent agents effective against resistant strains of bacteria. Fluoroquinolones have become a dominant family of ophthalmic antibiotics. But even the older fluoroquinolones (e.g., ofloxacin, ciprofloxacin) have lost much of their effectiveness against some important ocular isolates. Considering all of the characteristics for an ideal ophthalmic antibiotic product available today, moxifloxacin ophthalmic solution 0.5% represents a primary antibiotic product of choice for treating and preventing ophthalmic infections.

Aza Compounds↗
PubMed2005

In vitro and in vivo potency of moxifloxacin and moxifloxacin ophthalmic solution 0.5%, a new topical fluoroquinolone.

Fluoroquinolones are a class of synthetic antibacterial agents that were approved for ocular therapy in 1991 and have become popular therapy for the treatment and prevention of various ocular infections. These agents are synthetic, broad-spectrum, rapidly bactericidal, and have good penetration into ocular tissues. Their main mechanism of action is the inhibition of bacterial enzymes needed for bacterial DNA synthesis. However, antibiotic resistance occurred swiftly to the earlier fluoroquinolones and better fluoroquinolones were needed. The fourth-generation fluoroquinolones, such as moxifloxacin and gatifloxacin, have enhanced activity against gram-positive bacteria while retaining potent activity against most gram-negative bacteria. These fourth-generation fluoroquinolones have improved penetration into the anterior chamber and have also demonstrated increased in vivo efficacy in several animal models of ocular infections. In addition, topical ophthalmic antibiotic products can deliver antibiotic concentrations directly to the eye that are thousands of times higher than their MICs. This article reviews published data describing the in vitro potency of moxifloxacin and its in vivo activity for treating and preventing experimental ocular infections.

Administration, Topical↗
PubMed2005

Ocular pharmacokinetics of moxifloxacin after topical treatment of animals and humans.

The ocular penetration and pharmacokinetics of moxifloxacin in comparison to other fluoroquinolones (ofloxacin, ciprofloxacin, gatifloxacin, norfloxacin, levofloxacin, and lomefloxacin) have been determined by in vitro and ex vivo techniques, as well as in animal and human studies. This article reviews the original pharmacokinetics work performed by Alcon and other studies reported in the ocular fluoroquinolone literature. The results consistently demonstrate higher maximum concentrations for moxifloxacin relative to the other fluoroquinolones in ocular tissues with levels well above its minimum inhibitory concentrations for relevant ocular pathogens. This superior performance is due to the unique structure of moxifloxacin that combines high lipophilicity for enhanced corneal penetration with high aqueous solubility at physiological pH. The latter property creates a high concentration gradient at the tear film/corneal epithelial interface providing a driving force for better ocular penetration for moxifloxacin. In addition, the higher concentration of moxifloxacin in VIGAMOX (i.e., 0.5% vs. 0.3%) allows more antibiotic to be available to ocular tissues. It is clear from the array of studies summarized in this report that moxifloxacin penetrates ocular tissues better (two- to three-fold) than gatifloxacin, ciprofloxacin, ofloxacin, or levofloxacin. This consistent, enhanced penetration of topical moxifloxacin offers powerful advantages for ophthalmic therapy.

Administration, Topical↗
PubMed2004

Targeting p53 by PTD-mediated transduction.

p53 is a major target for tumor therapy. Attempts have been made to restore or enhance p53 activity in tumor cells, including overexpression of exogenous p53 and small molecules that can rescue mutant p53. Notably, p53 peptides corresponding to the p53 carboxyl terminus can trigger a p53 response in both wild-type or mutant p53-containing cells. The recent protein transduction domain (PTD)-mediated cell entry might solve the obstacle of efficient delivery of peptides or large molecular biological cargos into cells. PTD-mediated transfer through the cell membrane occurs through a kind of endocytosis, macropinocytosis. Destabilization of macropinocytosomes by the influenza virus hemagglutinin protein (HA2) helps the escape of the PTD-cargo from macropinocytosomes and therefore significantly enhances the functional impact of transduced cargo.

Antineoplastic Agents↗
PubMed2004

In vitro antigenotoxic potential of acitretin in human lymphocytes treated with the antineoplastic alkylating agent ASE (NSC-71964).

Acitretin is widely used in the systemic treatment of severe forms of psoriasis and other skin disorders. ASE, namely 3beta-hydroxy-13alpha-amino-13,17-seco-5alpha-androstan-17-oic-13,17-lactam-p-bis(2-chloro-ethyl)amino phenylacetate (AzaSteroidalEster, NSC-71964), is an alkylating agent with antineoplastic activity and mutagenic properties. The aim of this study was to investigate the possible genotoxic and/or antigenotoxic effects of acitretin in human lymphocyte cultures in vitro, using sister chromatid exchange (SCE) and cytokinesis-blocked micronucleus (CBMN) assays. Micronucleus (MN) analysis was achieved in combination with fluorescence in situ hybridization (FISH), using an alpha-satellite DNA pancentromeric probe. It was found that acitretin alone demonstrated no clastogenic or aneugenic activity. However, simultaneous incubation of lymphocyte cultures with ASE and acitretin resulted in a reduction of ASE-induced SCEs. For MN analysis lymphocytes were treated with ASE and acitretin at 21 and 41 h after culture initiation, corresponding to G1 and G2 phases, respectively, and lasted until cell harvest. Acitretin caused a decrease in ASE-induced MN when treatment of cells started at 41 h, but exerted no effect on them when treatment started at 21 h. These findings suggest that acitretin exerts antigenotoxic effects in human lymphocyte cultures, the expression of which may be related to the cycle phase of the cells upon onset and duration of the treatment, at least as far as MN frequency is concerned.

Acitretin↗
PubMed2006

Pharmacokinetics and milk penetration of moxifloxacin after intravenous and subcutaneous administration to lactating goats.

The pharmacokinetics of moxifloxacin was studied following intravenous (IV) and subcutaneous (SC) administration of 5 mg/kg to healthy lactating goats (n = 6). Moxifloxacin concentrations were determined by high performance liquid chromatography assay with fluorescence detection. The moxifloxacin plasma concentration versus time data after IV administration could best be described by a two compartment open model. The disposition of SC administered moxifloxacin was best described by a one-compartment model. The plasma moxifloxacin clearance (Cl) for the IV route was 0.43 +/- 0.02 L/kg (mean +/- SE). The steady-state volume of distribution (Vss) was 0.79 +/- 0.08 L/kg. The terminal half-life (t1/2lambdaz) was 1.94 +/- 0.41 and 2.98 +/- 0.48 h after IV and SC administration, respectively. The absolute bioavailability was 96.87 +/- 10.27% after SC administration. Moxifloxacin penetration from blood to milk was quick for both routes of administration and the high AUCmilk/AUCplasma and Cmax-milk/Cmax-plasma ratios reached indicated a wide penetration of moxifloxacin into the milk. From these data, it appears that a 5 mg/kg SC dose of moxifloxacin would be effective in lactating goats against bacterial isolates with MIC < or = 0.20 microg/mL in plasma and MIC < or = 0.40 microg/mL in milk.

Animals↗
PubMed2005

Pharmacokinetics and milk penetration of moxifloxacin after intramuscular administration to lactating goats.

The pharmacokinetics of moxifloxacin was studied following intramuscular administration of 5mg/kg to healthy lactating goats (n=6). Moxifloxacin concentrations were determined by high performance liquid chromatography assay with fluorescence detection. The moxifloxacin plasma concentration versus time data could best be described by a one-compartment model. The plasma moxifloxacin clearance (Cl) was mean standard deviation (+/-SD) 0.49+/-0.14 L/h kg. The apparent volume of distribution (V(z)) was 0.83+/-0.20 L/kg. The terminal half-life (t(1/2 lambda z)) was 1.31+/-0.64 h. Moxifloxacin penetration from blood to milk was rapid and the high AUC(milk)/AUC(plasma) and C(max-milk)/C(max-plasma) ratios reached indicated a good penetration of moxifloxacin into the milk.

Animals↗
PubMed2006

Cardiovascular monkey telemetry: sensitivity to detect QT interval prolongation.

INTRODUCTION: Preclinical evaluation of delayed ventricular repolarization manifests electrocardiographically as QT interval prolongation and is routinely used as an indicator of potential risk for pro-arrhythmia (potential to cause Torsades de Pointes) of novel human pharmaceuticals. In accordance with ICH S7A and S7B guidelines we evaluated the sensitivity and validity of the monkey telemetry model as a preclinical predictor of QT interval prolongation in humans. METHODS: Cardiovascular monitoring was conducted for 2 h pre-dose and 24 h post-dosing with Moxifloxacin (MOX), with a toxicokinetic (TK) evaluation in a separate group of monkeys. In both studies, MOX was administered orally by gavage in 0.5% methylcellulose at 0, 10, 30, 100, 175 mg/kg. Each monkey received all 5 doses using a dose-escalation paradigm. Inherent variability of the model was assessed with administration of vehicle alone for 4 days in all 4 monkeys (0.5% methylcellulose in deionized water). RESULTS: MOX had no significant effect on mean arterial pressure, heart rate, PR or QRS intervals. MOX produced significant dose-related increases in QTc at doses of 30 (Cmax=5.5+/-0.6 microM), 100 (Cmax=16.5+/-1.6 microM), and 175 (Cmax=17.3+/-0.7 microM) mg/kg with peak increases of 22 (8%), 27 (10%), and 47 (18%) ms, respectively (p<or=0.05; compared to vehicle). DISCUSSION: In conclusion, we have developed a reproducible, sensitive and reliable primate telemetry model in rhesus monkeys, which exhibits low inherent intra-animal variability and high sensitivity to detect small but significant increases in QT/QTc interval (approximately 4%) with MOX in the same range of therapeutic plasma concentrations attained in humans. Therefore, the primate telemetry model should be considered an important preclinical predictor of QT prolongation of novel human pharmaceuticals.

Algorithms↗