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PubMed2006

Constrained azacyclic analogues of the immunomodulatory agent FTY720 as molecular probes for sphingosine 1-phosphate receptors.

Constrained azacyclic analogues of FTY720 were prepared starting with d- and l-pyroglutamic acids. One enantiomer was shown to be a substrate for sphingosine kinase 2, being phosphorylated 4-fold more efficiently than FTY720. Among the corresponding phosphates, two were found to have unusual specificity in binding to S1P receptors: while being inactive on S1P1 and S1P3, they acted as potent agonists on S1P4 and S1P5. The phosphates may be useful to explore the biology and binding site of these receptors.

Animals↗
PubMed2006

Synthesis and antibacterial activities of new quinolone derivatives utilizing 1-azabicyclo[1.1.0]butane.

The ring-opening reactions of 1-azabicyclo[1.1.0]butane 3 with thiols 6a-f gave 3-sulfenylazetidine derivatives 7a-f in 50-92% yields. Treatment of 3 with aromatic amines 11a-e and dibenzylamine 11f in the presence of Mg(ClO(4))(2) afforded the corresponding 3-aminoazetidine derivatives 12a-f in 24-53% yields. These azetidine derivatives were introduced into the C7 position of a quinolone nucleus 8 to afford the corresponding fluoroquinolones 9a-f and 13a-f in 21-83% yields. Some of them exhibited superior antibacterial activity against quinolone-susceptible MRSA in comparison with clinically used fluoroquinolones, such as levofloxacin, ciprofloxacin, and gatifloxacin.

Anti-Bacterial Agents↗
PubMed2004

Preliminary ecotoxicological characterization of a new energetic substance, CL-20.

A new energetic substance hexanitrohexaazaisowurtzitane (or CL-20) was tested for its toxicities to various ecological receptors. CL-20 (epsilon-polymorph) was amended to soil or deionized water to construct concentration gradients. Results of Microtox (15-min contact) and 96-h algae growth inhibition tests indicate that CL-20 showed no adverse effects on the bioluminescence of marine bacteria Vibrio fischeri and the cell density of freshwater green algae Selenastrum capricornutum respectively, up to its water solubility (ca. 3.6 mg l(-1)). CL-20 and its possible biotransformation products did not inhibit seed germination and early seedling (16-19 d) growth of alfalfa (Medicago sativa) and perennial ryegrass (Lolium perenne) up to 10,000 mg kg(-1) in a Sassafras sandy loam soil (SSL). Indigenous soil microorganisms in SSL and a garden soil were exposed to CL-20 for one or two weeks before dehydrogenase activity (DHA) or potential nitrification activity (PNA) were assayed. Results indicate that up to 10,000 mg kg(-1) soil of CL-20 had no statistically significant effects on microbial communities measured as DHA or on the ammonium oxidizing bacteria determined as PNA in both soils. Data indicates that CL-20 was not acutely toxic to the species or microbial communities tested and that further studies are required to address the potential long-term environmental impact of CL-20 and its possible degradation products.

Analysis of Variance↗
PubMed2004

Physico-chemical measurements of CL-20 for environmental applications. Comparison with RDX and HMX.

CL-20 is a polycyclic energetic nitramine, which may soon replace the monocyclic nitramines RDX and HMX, because of its superior explosive performance. Therefore, to predict its environmental fate, analytical and physico-chemical data must be made available. An HPLC technique was thus developed to measure CL-20 in soil samples based on the US Environmental Protection Agency method 8330. We found that the soil water content and aging (21 days) had no effect on the recoveries (>92%) of CL-20, provided that the extracts were kept acidic (pH 3). The aqueous solubility of CL-20 was poor (3.6 mg l(-1) at 25 degrees C) and increased with temperature to reach 18.5 mg l(-1) at 60 degrees C. The octanol-water partition coefficient of CL-20 (log KOW = 1.92) was higher than that of RDX (log KOW = 0.90) and HMX (log KOW = 0.16), indicating its higher affinity to organic matter. Finally, CL-20 was found to decompose in non-acidified water upon contact with glass containers to give NO2- (2 equiv.), N2O (2 equiv.), and HCOO- (2 equiv.). The experimental findings suggest that CL-20 should be less persistent in the environment than RDX and HMX.

Aza Compounds↗
PubMed2005

Ultrasound-assisted liquid-phase microextraction and high-performance liquid chromatographic determination of nitric oxide produced in PC12 cells using 1,3,5,7-tetramethyl-2,6-dicarbethoxy-8-(3',4'-diaminophenyl)-difluoroboradiaza-s-indacene.

To reveal the function of nitric oxide (NO) that has been reported as an intracellular second messenger and a diffusible intercellular messenger, a novel ultrasound-assisted liquid-phase microextraction (ULPME) and high-performance liquid chromatographic method for the determination of NO produced in PC12 cells has been developed. 1,3,5,7-Tetramethyl-2,6-dicarbethoxy-8-(3',4'-diaminophenyl)-difluoroboradiaza-s-indacene (DAMBO-CO(2)Et) has been used for NO trapping to form corresponding triazole (DAMBO-CO(2)Et-T). The enrichment factor of DAMBO-CO(2)Et-T reached 150 in 2.5 min with the proposed ULPME method. NO produced in (200+/-5) PC12 cells has been determined directly with the detection limit (S/N=3) of 2.5 x 10(-13)mol/L (5a mol), which was the lowest in HPLC determination of NO reported yet. The proposed method was sensitive, selective, convenient and rapid, which has great prospect in the qualitative and quantitative determination of NO in minimal biological samples.

Animals↗
PubMed2005

Acute interstitial nephritis associated with moxifloxacin use.

BACKGROUND: Moxifloxacin is a fluoroquinolone antimicrobial agent with proven efficacy against community-acquired respiratory pathogens. Common adverse effects associated with its use include gastro-intestinal symptoms, but nephrotoxicity has not yet been reported to the manufacturer or in the literature (based on a MEDLINE search [key words: fluoroquinolone, moxifloxacin, kidney, interstitial, and nephritis; years: 1970-2005]). OBJECTIVE: The purpose of this article was to describe a case of nephrotoxicity associated with moxifloxacin use. METHODS: A 68-year-old woman weighing 65 kg was referred to our nephrology clinic by her general practitioner because of an acute increase in serum creatinine concentration (SCC). In this patient, biopsyproven acute tubulointerstitial nephritis (ATIN) developed approximately 10 days after the end of moxifloxacin therapy for a nonspecific bronchial infection. The patient initially presented with nonspecific clinical symptoms, foaming of her urine, elevated erythrocyte sedimentation rate, and the acute increase in SCC. Urinalysis revealed signs of tubulointerstitial damage, including leukocyturia and proteinuria with a high concentration of alpha(1)-microglobulin. Oral corticosteroid therapy with prednisolone was started approximately 14 days after symptom development, beginning at 1 mg/kg body weight QD. RESULTS: After the initiation of therapy, renal function was gradually restored over 6 months, but mild proteinuria persisted. Although the exact pathogenesis of drug-induced ATIN remains unclear, an immune-mediated hypersensitivity reaction is the assumed mechanism. CONCLUSIONS: Fluoroquinolones might have a nephrotoxic effect. In this patient, ATIN was likely associated with moxifloxacin use. Because the course of ATIN is unpredictable and might lead to long-term dialysis, considering ATIN as a possible diagnosis in the scenario of systemic symptoms after moxifloxacin treatment is essential.

Acute Disease↗
PubMed2005

Clinical assessment of drug-induced QT prolongation in association with heart rate changes.

BACKGROUND: The formulas for heart rate (HR) correction of QT interval have been shown to overcorrect or undercorrect this interval with changes in HR. A Holter-monitoring method avoiding the need for any correction formulas is proposed as a means to assess drug-induced QT interval changes. METHODS: A thorough QT study included 2 single doses of the alpha1-adrenergic receptor blocker alfuzosin, placebo, and a QT-positive control arm (moxifloxacin) in 48 healthy subjects. Bazett, Fridericia, population-specific (QTcN), and subject-specific (QTcNi) correction formulas were applied to 12-lead electrocardio-graphic recording data. QT1000 (QT at RR = 1000 ms), QT largest bin (at the largest sample size bin), and QT average (average QT of all RR bins) were obtained from Holter recordings by use of custom software to perform rate-independent QT analysis. RESULTS: The 3 Holter end points provided similar results, as follows: Moxifloxacin-induced QT prolongation was 7.0 ms (95% confidence interval [CI], 4.4-9.6 ms) for QT1000, 6.9 ms (95% CI, 4.8-9.1 ms) for QT largest bin, and 6.6 ms (95% CI, 4.6-8.6 ms) for QT average. At the therapeutic dose (10 mg), alfuzosin did not induce significant change in the QT. The 40-mg dose of alfuzosin increased HR by 3.7 beats/min and induced a small QT1000 increase of 2.9 ms (95% CI, 0.3-5.5 ms) (QTcN, +4.6 ms [95% CI, 2.1-7.0 ms]; QTcNi, +4.7 ms [95% CI, 2.2-7.1 ms]). Data corrected by "universal" correction formulas still showed rate dependency and yielded larger QTc change estimations. The Holter method was able to show the drug-induced changes in QT rate dependence. CONCLUSIONS: The direct Holter-based QT interval measurement method provides an alternative approach to measure rate-independent estimates of QT interval changes during treatment.

Adrenergic alpha-Antagonists↗
PubMed2006

Increased polymorphonuclear leukocyte respiratory burst function in type 2 diabetes.

The predisposition to infection and chronic inflammation in diabetes may in part be related to the effects of hyperglycemia or other metabolic abnormality on polymorphonuclear leukocytes (PMN). We evaluated oxidative respiratory burst activity (superoxide production) in non-stimulated and stimulated PMN from 70 stable type 2 Hispanic diabetic patients, as compared to 70 healthy Hispanic individuals without diabetes. The influences of protein kinase C (PKC) inhibitors and certain antibiotics on superoxide production were examined. Both resting and stimulated (PMA, zymosan) PMN from diabetic individuals produced more superoxide than PMN from controls. Inhibitors of PKC, a possible mediator of the augmented respiratory burst activity, decreased superoxide production in all (resting and stimulated) diabetic and control PMN. Azithromycin, which is markedly concentrated by PMN, profoundly inhibited superoxide generation in all groups of diabetic and control cells. PMN from Hispanic diabetic patients produced greater quantities of superoxide than non-diabetic controls. This increased oxidative respiratory burst activity may predispose to infection and chronic inflammation in diabetes. PKC inhibitors and azithromycin inhibited this respiratory burst response. The possible role of PKC (especially PKC beta) as the mediator of this augmented respiratory burst response requires further evaluation, and may lead to therapeutic studies with appropriate inhibitors.

Anti-Bacterial Agents↗
PubMed2004

Susceptibility testing of Singapore strains of Mycoplasma hominis to tetracycline, gatifloxacin, moxifloxacin, ciprofloxacin, clindamycin, and azithromycin by the Etest method.

The minimal inhibitory concentrations of tetracycline, gatifloxacin, moxifloxacin, ciprofloxacin, clindamycin and azithromycin for 28 Singapore clinical Mycoplasma hominis strains were studied using the Etest method. Different incubation conditions did not affect susceptibility categories, except for tetracycline intermediate-susceptibility strains. Tetracycline-susceptibility was only 35.7%. All strains were susceptible to the fluoroquinolones and clindamycin but resistant to azithromycin.

Anti-Bacterial Agents↗
PubMed2004

Concentrations of moxifloxacin in serum and synovial fluid, and ex vivo bactericidal activity against arthritis-causing pathogens.

Three doses of moxifloxacin 400 mg qd were administered orally to 20 candidates for knee arthroscopy (mean age, 71.2 years). The procedure was scheduled at four different points of time after the last dose: 2, 6, 12, and 24 h. Five patients were studied at each point of time. Drug levels were determined by the bioassay method. Bactericidal activity against four bacterial pathogens (two strains of each) was studied on serum and synovial fluid samples obtained during arthroscopy using the NCCLS guidelines. Mean (+/-S.D.) peak serum and synovial fluid concentrations were 3.46 +/- 0.78 mg/L and 3.42 +/- 0.51 mg/L, respectively. Levels above 1.0 mg/L were detected as long as 24 h. The peak bactericidal titers were (in serum and synovial fluid, respectively) 1:18.3 and 1:32 against Staphylococcus aureus, 1:18.3 and 1:22.6 against Streptococcus pyogenes, 1:45.2 and 1:64.0 against Klebsiella pneumoniae, and 1:2.3 and 1:1.7 against Pseudomonas aeruginosa. Bactericidal titers >1:2 were documented against the first three pathogens up to 24 h after dosing. On the basis of its pharmacokinetic and pharmacodynamic characteristics, moxifloxacin seems to be an excellent candidate for the treatment of joint infections, except those caused by P. aeruginosa.

Administration, Oral↗
PubMed2005

Changing patterns of fluoroquinolone resistance among Bacteroides fragilis group organisms over a 6-year period (1997-2002).

The evolution of susceptibility to the newer fluoroquinolones, moxifloxacin and trovafloxacin, of Bacteroides fragilis group organisms isolated in our hospital from 1997 to 2002 was studied. A total of 927 strains were included in the study. Trovafloxacin was more active than moxifloxacin against the various species of the group. During the study period, an increase in resistance to both quinolones was observed. Rates of resistance to moxifloxacin at a breakpoint of 8 microg/mL remained stable at around 6% during the period 1997-1998 and increased to 11.4% in 2000 and to 16.5% in 2001-2002 (P<0.005). Resistance to trovafloxacin rose significantly from 0.6% in 1998 to 6.8% in 1999 (P<0.05) and did not change appreciably over the last 3 years studied. This study confirms the increasing resistance of B. fragilis group organisms to trovafloxacin and moxifloxacin and emphasizes the need to perform periodic antimicrobial susceptibility tests to guide the selection of appropriate antimicrobial therapy.

Anti-Infective Agents↗
PubMed2004

In vivo experimental approach for the risk assessment of fluoroquinolone antibacterial agents-induced long QT syndrome.

The proarrhythmic effects of fluoroquinolone antibacterial agents, sitafloxacin, gatifloxacin and moxifloxacin, were compared using three in vivo models. In the halothane-anesthetized dogs (n=5), intravenous 10-min infusion of gatifloxacin and moxifloxacin (1-3 mg/kg) prolonged the ventricular effective refractory period and the repolarization period to a similar extent, whereas sitafloxacin (1-3 mg/kg) prolonged the former only. No significant change was detected in other cardiovascular parameters. In the chronic complete atrioventricular block dogs (n=4), oral administration of 100 mg/kg of gatifloxacin (2 of 4) and moxifloxacin (3 of 4) induced torsades de pointes, which was not observed by sitafloxacin. In the alpha-chloralose-anesthetized rabbits (n=5), intravenous 20-min infusion of 60 mg/kg of gatifloxacin induced torsades de pointes (1 of 5) in the presence of methoxamine infusion, which was not observed by sitafloxacin or moxifloxacin. Thus, the halothane-anesthetized model is suitable for assessing QT prolongation, whereas the chronic complete atrioventricular block model is sensitive for detecting torsadogenic action of drugs. The alpha-chloralose-anesthetized model is the simplest and least expensive method, but its sensitivity to detect proarrhythmic action may be less great.

Administration, Oral↗
PubMed2005

Permeability of pig urinary bladder wall: the effect of chitosan and the role of calcium.

Chitosan is a cationic polysaccharide widely employed as an absorption enhancer. The aim of this work was to examine the effect of chitosan on the permeability of isolated pig urinary bladder wall as well as to determine the role of calcium ions in this process. Besides permeability studies, scanning electron microscopy and fluorescent microscopy were applied to get an insight into the mechanism by which chitosan increases the permeability of urinary bladder wall. Additionally, the obtained findings were compared to the mechanism proposed for Caco-2 cells. The results show that 0.5% (w/v) chitosan increases the permeability of urinary bladder wall by causing the desquamation of the urothelium. Calcium ions, when applied to the luminal surface of the urinary bladder at the same time as chitosan, decreases the effect of chitosan on permeation of the model drug moxifloxacin into the bladder wall in concentration dependent way. The desquamation of urothelium cells caused by chitosan was reduced in the presence of calcium, but not to such extent as it would be expected from the permeability studies. When present, calcium obviously interferes directly in the interactions between chitosan and the surface of urothelium.

Animals↗
PubMed2005

Synthetic studies on heterocyclic natural products.

This article reviews past and ongoing research in the author's laboratory directed toward the synthesis of natural products displaying an azaspirocyclic framework, or incorporating a medium-ring nitrogen heterocycle. New synthetic technologies were devised in order to address the synthetic problems posed by the target molecules. Thus, efforts in the area of azaspirocyclic substances have relied on an oxidative amidation of phenols promoted by iodobenzene diacetate, whereas access to medium-ring nitrogen heterocycles has been secured by means of a ring expansion sequence that relies on the fragmentation of an aziridine triggered by a homo-Brook transposition. Details of the development of these technologies are presented, together with applications to the total synthesis of FR-901483, TAN-1251C, cylindricines, and mitomycinoids.

Aza Compounds↗
PubMed2006

Optimisation and evaluation of 1,2-indanedione for use as a fingermark reagent and its application to real samples.

1,2-indanedione is an emerging fingermark reagent used on porous surfaces. The general consensus is that this reagent is at least as sensitive as DFO, with some research showing higher sensitivity for 1,2-indanedione as opposed to DFO. However, a number of discrepancies existed in the literature as to which formulation and which development procedure produces optimal results. This project set out to investigate the best formulation and development procedure under Australian conditions, encompassing all published recommendations as well as some novel approaches. 1,2-indanedione formulations were compared with respect to initial colour, fluorescence, concentration of reagent, acetic acid concentration, and the effect of different carrier solvents. Numerous development conditions were investigated, including a conventional oven, a heat press and humidity. Further enhancement using metal salt treatment and liquid nitrogen was also evaluated. The heat press set at 165 degrees C for 10s proved to give the best initial colour and most intense luminescence. Secondary metal salt treatment improved initial colour and luminescence. The Polilight, the VSC 2000, and the Condor Chemical Imaging macroscope have been used to detect the fingerprints developed with 1,2-indanedione on a variety of high- and low-quality porous and semi-porous surfaces, with impressive results overall. Laboratory and field tests were conducted to compare 1,2-indanedione with DFO and ninhydrin as well as to investigate the position of 1,2-indanedione in the sequence of reagents for fingermark detection on porous surfaces. Overall, 1,2-indanedione proved to be a viable alternative to traditional methods for the detection of fingermarks on porous surfaces, with more fingermarks being developed using this reagent on real samples than both DFO and ninhydrin and a combination of the two reagents.

Adult↗
PubMedDate not supplied

Campylobacter jejuni pancolitis mimicking idiopathic ulcerative colitis.

Campylobacter jejuni is the most common cause of community-acquired acute bacterial diarrhea. Campylobacter diarrhea is usually accompanied by fever and abdominal pain. Campylobacter diarrhea is usually watery. Nausea, vomiting, headache, and myalgias may also be present. Tenesmus is a common feature. The majority of patients with Campylobacter diarrhea have some component of segmental colitis, usually beginning in the small bowel and progressing distally to the cecum and colon. C. jejuni is a rare cause of pancolitis. Community-acquired colitis may be caused by C. jejuni or other enteric pathogens, for example, Shigella, Entamoeba, Yersinia, Escherichia coli 0157:H7, Clostridium difficile colitis, ischemic colitis, or idiopathic ulcerative colitis. We present a case of C. jejuni pancolitis in an elderly woman. Differential diagnosis is included in the discussion. The patient's C. jejuni pancolitis was successfully treated with a 7-day course of oral moxifloxacin.

Aged↗
PubMed2003

Disposition and intracellular levels of moxifloxacin in human THP-1 monocytes in unstimulated and stimulated conditions.

Moxifloxacin uptake by human THP-1 monocytes was passive and initially linear and reached equilibrium after approximately 4 h. High intracellular concentrations were achieved and intracellular/extracellular [I/E] ratios were between 1925 and 4575 for the lowest concentration of 0.004 microg/ml at pH 7.4 and 6.9. The uptake of moxifloxacin was reduced by sodium fluoride, -azide, -cyanide, low temperature and low pH. However, the uptake was not affected by any of the ion channel blockers. Adenosine demonstrated marginal competition with moxifloxacin for uptake suggesting a nucleoside transporter may be involved. The sodium-ATPase pump when blocked, also retarded moxifloxacin uptake at 2 and 4 h. This I/E ratio was high compared with other macrolides and indicateed that the monocyte may contain sufficient moxifloxacin levels to conduct the antibiotic throughout systemic circulation to infection sites. Efflux from THP-monocytes was essentially complete after 2 h indicating no long term sequestering of the antibiotic occurred. Disposition of the antibiotic within the THP-1 monocytes showed large amounts present in the nucleus and cytoplasm in stimulated and unstimulated cells. Increased amounts of the drug were found in the THP-1 monocytes as well as the endoplasmic reticulum and the isolated phagosomes after stimulation by zymogen A, Staphylococcus aureus or Streptococcus pneumoniae.

Anti-Bacterial Agents↗