In vitro activities of the oxazolidinone antibiotics U-100592 and U-100766 against Staphylococcus aureus and coagulase-negative Staphylococcus species

U-100592 and U-100766 are closely related antibiotics of the oxazolidinone class. Their in vitro activities were determined against 100 isolates of Staphylococcus aureus and 100 isolates of coagulase-negative Staphylococcus species by broth and agar dilution test methods. The MICs of both compounds by either test method at which 50 and 90% of isolates are inhibited were 2 and 4 micrograms/ml, respectively, for S. aureus and 1 to 2 micrograms/ml for coagulase-negative staphylococci. Time-kill assay with selected strains indicated a primarily bacteriostatic effect against staphylococci.     

Activities of RPR 106972 (a new oral streptogramin), cefditoren (a new oral cephalosporin), two new oxazolidinones (U-100592 and U-100766), and other oral and parenteral agents against 203 penicillin-susceptible and -resistant pneumococci

Agar dilution was used to determine the MICs of RPR 106972 (a new oral streptogramin), cefditoren (a new oral cephalosporin), two new oxazolidinones (U-100592 and U-100766), and other oral and parenteral agents for 203 penicillin-susceptible and -resistant pneumococci. All pneumococci were inhibited by RPR 106972 at < or = 0.5 microgram/ml. Cefditoren was very active against all pneumococcal groups, with MICs of < or = 2.0 micrograms/ml. Amoxicillin with or without clavulanate was the next most active oral beta-lactam, followed by cefdinir, cefuroxime, cefpodoxime, and cefprozil. U-100592 and U-100766 were very active against all classes of pneumococci, with all MICs < or = 1.0 microgram/ml.     

Non-natural aglycones of glycopeptide antibiotics of the vancomycin group. Synthesis and antibacterial activity

A new approach for the modification of the heptapeptide core of glycopeptide antibiotics was proposed based on the replacement of amino acid residues in positions 1 and 3 in teicoplanin aglycone and in position 1 in the eremomycin aglycone. Six novel nonnatural aglycones of the vancomycin type were obtained. Compounds derived from the teicoplanin aglycone exhibited in vitro activity against Gram-positive bacteria, and two of them were also active against the vancomycin-resistant enterococci.     

Synthesis,characteristics, and antibacterial activity of a rare-earth samarium/silver/titanium dioxide inorganic nanomaterials

An inorganic nanomaterials combination of Sm, Ag, and TiO2 was synthesized using supercritical fluid drying （SCFD） combined with solgel techniques. The structure, photocatalysis and bacteriostatic activity of the materials were characterized by X-ray diffraction （XRD）, transmission electron microscopy （TEM）, X-ray photoelectron spectroscopy （XRPS）, photocatalytic performance, and antibacterial activity experiments. The XRD results showed that the average particle diameter of Sm/Ag/TiO2 was 14.62 nm and Ag and Sm ions were dispersed on the surface of TiO2 in a highly dispersed, amorphous form. The TEM image showed that the size of the particle was 12 nm using the scherer formula. The XPS result showed that the element Sm was doped and Ag was loaded inorganic nanomaterials successfully. Sm/Ag/TiO2 exhibited optimal photocatalytic properties at 600 oC, the photocatalytic optimal proportion of Sm/Ag/TiO2 was 2：2：100. When the molar ratio was 2：2：100, the bacteriostatic circle diameter was 16 mm for Staphylococcus aureus, the minimum bacteriostatic concentration was 200μg/mL for white beads coccus, and the minimum bactericidal concentration was 2×10^4μg/mL for white beads coccus. The SEM results showed that the antibacterial material attached to the candida albicans cell surface, cells appeared fold deformation. Therefore the inorganic nanomaterials Sm/Ag/TiO2 had high temperature resistance, good photocatalytic and antibacterial characteristics in visible light.     

The synthesis and antibacterial activity of two pyoverdin-ampicillin conjugates, entering Pseudomonas aeruginosa via the pyoverdin-mediated iron uptake pathway

Two pyoverdin-ampicillin conjugates were synthesized and their structures were confirmed by mass spectrometry and NMR spectroscopy. In contrast to ampicillin, the conjugates exhibited high antibacterial activity against Pseudomonas aeruginosa ATCC 15692 and ATCC 27853, effective only against the strain which is using the parent pyoverdin for iron uptake. This suggests that the conjugates enter the bacterial cell via the ferripyoverdin uptake pathway. Growth stimulation studies with conjugates hydrolysed at the beta-lactam ring of the ampicillin moiety supported this view.     

Synthesis and pharmacological activity of two derivatives of the amide of valproic acid

Valproic acid (VPA), a synthetic branched-chain fatty acid, and its pro-drug the primary amide (VPD) are effective and widely used anti-epileptic agents. Although the use of VPA has grown in recent years, major side effects are still associated with this drug. We presume that it is possible, without loosing the VPD pharmacological profile, to obtain new compounds by undertaking substitutions in the CONH group. N,N'-bis-(2-propylpentanoyl)- 1,2-ethanediamine (3) and N,N'-bis-(2-propylpentanoyl)-1,3-propanediamine (4) were obtained from VPA (1) using a method reported in the literature. The chemical structures of the new compounds were demonstrated by elemental analysis, IR, and 1H NMR spectroscopy. Both compounds are less toxic and more effective in protecting the animals from death caused by PTZ than VPD after intraperitoneal administration to mice.     

Efficacy and tolerability of brodimoprim od versus norfloxacin bid in the treatment of bacterial urinary tract infections

The efficacy and tolerability of brodimoprim OD versus norfloxacin BID were studied in patients affected by bacterial urinary tract infections. The study was performed in 203 patients divided into two parallel randomized groups orally given either brodimoprim 400 mg OD on the first day followed by 200 mg OD for 2 days, or norfloxacin 400 mg BID respectively. The efficacy of treatment was evaluated by the bacterial cultures, tolerability, analysis of signs and symptoms, a complete physical examination and from laboratory data. The results showed that brodimoprim and norfloxacin in the majority of patients resulted in a reduction of fever and symptoms caused by the infective process. Of the 103 patients enrolled in the brodimoprim OD group, 99 had a complete course of therapy with a positive outcome. There was only one case of failed treatment and 3 cases which could not be evaluated because of voluntary interruption of treatment. Of the 100 patients treated with norfloxacin BID, 94 completed therapy with a positive clinical outcome and there were 4 cases of treatment failure. Thus the efficacy of brodimoprim OD appears comparable to that of norfloxacin BID in the treatment of urinary tract infections.     

Pyridoxal isonicotinoyl hydrazone and its analogs: potential orally effective iron-chelating agents for the treatment of iron overload disease

At present, the only iron (Fe) chelator in clinical use for the treatment of Fe overload disease is the tris-hydroxamate deferoxamine (DFO). However, DFO suffers from a number of disadvantages, including the need for subcutaneous infusion (12 to 24 hours a day, 5 or 6 times per week), its poor intestinal absorption, and high cost. Therefore, there is an urgent need for an efficient, economical, and orally effective Fe chelator. Pyridoxal isonicotinoyl hydrazone (PIH) is a tridentate Fe-chelating agent that shows high Fe chelation efficacy both in vitro in cell culture models and also in vivo in rats and mice. In addition, this chelator is relatively nontoxic, economical to synthesize, and orally effective, and it shows high selectivity and affinity for Fe. However, over the last 10 years the development of PIH and its analogs has largely been ignored because of justifiable interest in other ligands such as 1,2-dimethyl-3-hydroxypyrid-4-one (L1). Unfortunately, recent clinical trials have shown that significant complications occur with L1 therapy, and it is controversial whether this chelator is effective at reducing hepatic Fe levels in patients. Because of the current lack of a clinically useful Fe chelator to replace DFO, PIH and its analogs appear to be potential candidate compounds that warrant further investigation. In this review we will discuss the studies that have been performed to characterize these chelators at the chemical and biologic levels as effective agents for treating Fe overload. The evidence from the literature suggests that these ligands deserve further careful investigation as potential orally effective Fe chelators.     

Canadian pyrrhotite treatment: the history,inventory and potential for tailings processing

Canadian nickel-copper ore deposits have been a major source of nickel, copper, cobalt and precious metals for more than 120 years. The two main minerals of interest, pentlandite (Pn, (Ni,Fe)9S8) and chalcopyrite (Cp, CuFeS2), are usually accompanied by large quantities of pyrrhotite (Po, Fe1-xS). Until the 1950s, Po containing small amounts of nickel was routinely smelted as part of the valuable Ni concentrate. The rapid growth in Ni demand following World War II created impetus to treat the Po separately. This action would liberate a valuable smelting capacity for higher value Pn and recover Ni, Fe, S and energy. The Ni industry would then have a more sustainable process. Both Inco (now Vale) and Falconbridge (now Glencore) developed processes and built large industrial plants for this purpose that operated with some success. But technical issues and tenuous economics were continual challenges. By the early 1980s, these industrial operations were closed and Po containing up to 1%Ni became a waste material reporting to the tailings stream. As part of a major study on possible processing methods of Po for both value recovery and waste remediation, this paper presents a historical perspective on Canadian Po tailings with regard to their inventory.     

Synthesis and evaluation of a novel series of phosphodiesterase IV inhibitors. A potential treatment for asthma

The synthesis and pharmacological profile of a novel series of potent and selective phosphodiesterase type IV (PDE IV) inhibitors is described.     

Structural and functional characterisation of two proteolytic fragments of the bacterial protein toxin, pneumolysin

Proteolytic cleavage of the bacterial protein toxin pneumolysin with protease K creates two fragments of 37 and 15 kDa. This paper describes the purification of these two fragments and their subsequent physical and biological characterisation. The larger fragment is directly involved in the cytolytic mechanism of this pore-forming protein, via membrane binding and self-association. The smaller fragment lacks ordered structure or discernible activity.     

Biology and potential strategies for the treatment of GM2 gangliosidoses

The GM2 gangliosidoses are a group of heritable neurodegenerative disorders caused by excessive accumulation of the ganglioside GM2 owing to deficiency in beta-hexosaminidase activity. Tay-Sachs and Sandhoff diseases have similar clinical phenotypes resulting from a deficiency in human hexosaminidase alpha and beta subunits, respectively. The lack of treatment for GM2 gangliosidoses stimulated interest in developing animal models to understand the molecular mechanisms underlying the various forms of this disease and to test new potential therapies. In this review, we discuss the molecular biology of GM2 gangliosidoses and the different strategies that have been tested in animal models for the treatment of this genetic disorder, including gene transfer and cell engraftment of neural stem cells engineered to express the hexosaminidase isoenzymes.     

A short-term assessment of tumor-promotion activity in the livers of rats treated with two genotoxic methylating agents: dimethylnitrosamine and methylnitrosourea

Induction of replicative DNA synthesis (RDS) and mitoinhibitory effects were studied in the hepatocytes of F344 rats exposed in vivo to the methylating agents dimethylnitrosamine (DMN, hepatocarcinogen) and methylnitrosourea (MNU, non-hepatocarcinogen). Cytotoxicity and chromosome aberrations (CA) in rat liver were also investigated to clarify the cause of changes in RDS and mitoinhibitory effects, respectively. The animals were killed at different intervals (up to 14 days) after a single oral dose, or 1 day after 7 or 14 days of repeated oral doses. The hepatocytes were isolated and cultured with Williams' medium E to assess their RDS, mitoinhibitory effects and CA. Mitoinhibitory effects were investigated by monitoring their effect on epidermal growth factor-induced replicative DNA synthesis (EGF-induced RDS) in rat hepatocytes. Hepatotoxic effects were assessed by measuring aspartate transaminase and alanine transaminase in the plasma and by histopathological examination. In the single-dose study, DMN (20 mg/kg body weight (bw)) induced both RDS and hepatotoxicity. MNU (50 mg/kg bw) induced RDS without causing hepatotoxicity, and thus was classified as a mitogen. In the repeated-dose study, DMN (4 mg/kg bw) induced both RDS and hepatotoxicity, but MNU (10 mg/kg bw) induced neither. Both inhibition of EGF-induced RDS and induction of CA were observed in the hepatocytes of rats treated with DMN, but were not observed with MNU in both single and repeated dose studies. The mitoinhibitory effect of DMN persisted for 14 days after the single dose and time dependently increased for 14 days after repeated administration. This mitoinhibitory effect correlated positively with CA. The mitoinhibitory effect was thought to be attributable to the DNA-damaging effect that induces CA. We concluded that the differences which we found in this study between DMN and MNU contribute to the differences in their hepatocarcinogenicity. Our findings suggested that both cell proliferative and mitoinhibitory properties play an important role in tumor promotion, and measuring them may provide an ancillary index that is useful in predicting hepatocarcinogenicity.     

Retinoic acid conjugates as potential antitumor agents: synthesis and biological activity of conjugates with Ara-A, Ara-C, 3(2H)-furanone, and aniline mustard moieties

In a dual targeting approach, to explore the ability of tretinoin (all-trans-retinoic acid) to behave as a covalent carrier for cytotoxic entities, conjugates of retinoic acid with a few representative molecules, being important examples of antitumor pharmacophores (i.e., nucleoside analogues and alkylating agents), have been synthesized and tested for their cytostatic and differentiating activity. All compounds were stable to in vitro hydrolysis in human plasma and more lipophilic than the parent compounds, thus consenting enhanced uptake into the cells. Among the nucleoside analogues the Ara-C derivatives 3 and 6 and the Ara-A derivative 7 proved the most cytostatic (IC50 < 0.32 microgram/mL) resulting from 25- to > 144-fold more active (Ara-A derivatives) or at least as equally active (Ara-C derivatives) as compared to the parent nucleosides. Compound 3, endowed with a highly lipophilic silyl moiety at the 3' and 5' positions, showed the highest differentiating activity (54% and 44% differentiated HL-60 cells at 0.2 and 0.05 microgram/mL respectively). With regard to the retinoic acid conjugates of alkylating agents, compound 10 was the most cytostatic agent (IC50 < 0.32 microgram/mL) and the most potent differentiating agent (33-34% at 0.32 and 0.08 microgram/mL). These structures may also be regarded as analogs of either retinoic acid or the cytotoxic compound.     

Gemcitabine and other new chemotherapeutic agents for the treatment of metastatic bladder cancer

An improved quality of life secondary to reduced chemotherapy toxicity is an important end point in the treatment of all patients with metastatic cancer. In this review, we have demonstrated that gemcitabine and gemcitabine/cisplatin combinations appear to have a reduced toxicity profile compared with MVAC. Phase II studies with gemcitabine and cisplatin have shown good response rates that are possibly equivalent to MVAC, and a Phase III trial is now completed. Similar data have been reported for the paclitaxel/carboplatin combination and a Phase III trial comparing that combination with MVAC is planned. For patients with TCC who are in mild renal failure or who have significant underlying medical conditions, gemcitabine can also be considered as a reasonable single agent therapy. Complete responses can be seen, even in patients who are older than the age of 70. Moore et al., for example, demonstrated near complete responses to gemcitabine monotherapy in 4 patients older than 80 years of age. In conclusion, chemotherapy options for patients with metastatic bladder cancer have changed significantly with the addition of gemcitabine and other drugs to the armentarium. The integration of gemcitabine into the initial chemotherapy plan for these patients is still being developed. It is clear that this agent should be included in the management discussions of all patients with metastatic bladder cancer.     

Synthesis and properties of 2-S-(N,N-dialkylamino)ethyl)thio-1,3,2-dioxaphosphorinane 2-oxide and of the corresponding quaternary derivatives as potential nontoxic antiglaucoma agents

A new series of cyclic organophosphorus esters, 2-S-[2'-N,N-dialkylamino)ethyl]thio-1,3,2-dioxaphosphorinane 2-oxide and their quaternary derivatives, was synthesized and studied as potential antiglaucoma agents. Thes compounds inhibit acetylcholinesterase (E.C.3.1.1.7)at a bimoecular rate constant (ki) in the range of 10(3)-10(4) M-1 min-1. Values of the affinity (K) and phosphorylation (k') rate constants for this enzyme indicate that k' is responsible for the relatively low values of ki as compared with similar data for the open-chain analogues, O,O-diethyl phosphorothiolates (10(6) M-1 min-1). The mammalian toxicity of the new compounds in terms of acute LD50 values in mice is 1-3 x 10(3) less than that of phospholine, an open-chain analogue. In an initial clinical trial, one member of the new series (alkyl = C2H5) caused a significant decrease of intraocular pressure in aphakic glaucoma, while phospholine proved to be ineffective.     

Synthesis of [(2'S, 3'S)-bis(hydroxylmethyl)pyrrolidin-1-yl] purine and pyrimidine nucleosides as potential antiviral agents

The enantiomerically pure synthesis of [(2'S, 3'S)-bis(hydroxymethyl)pyrrolidin-1-yl] thymine 17 and -adenine 20 was achieved via construction of the base on the 1-amino-pyrrolidine 15, and their anti-HSV-1 and -2, and anti-HIV-1 activities were evaluated.     

Comparative antimicrobial activity of RP 59,500 (quinupristin-dalfopristin), the first semisynthetic injectable streptgramin, against gram-positive cocci and other recent clinical pathogens

RP 59,500 (Quinupristin-Dalfopristin) is the first semisynthetic injectable streptogramin antimicrobial agent, which is a combination of quinupristin and dalfopristin in a 30:70 ratio. The components of RP 59,500 act synergically to provide bactericidal activity through action at different sites on bacterial ribosomes. In the present study, the antimicrobial activity of RP 59,500 was compared with those of four macrolides (erythromycin, clarithromycin, azithromycin, roxithromycin). Susceptibility testing was carried out by microdilution method on 303 strains of 10 species, especially antibiotic-resistant Gram-positive cocci. RP 59,500 was active against a wide range of Gram-positive cocci including methicillin-resistant Staphylococci and penicillin-resistant Streptococcus pneumoniae. The MICs90 of RP 59,500 against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis were both 0.25 microgram/ml, although those of four macrolides were higher than 32 micrograms/ml. The MICs90 of RP 59,500 against penicillin-sensitive, -intermediate and -resistant S. pneumoniae were all 0.5 microgram/ml, although those of four macrolides against penicillin-resistant S. pneumoniae were higher than 32 micrograms/ml. RP 59,500 also exhibited equivalent activities to the four macrolides against strains of Streptococcus pyogenes. Streptococcus agalactiae and Moraxella catarrhalis. RP 59,500 exhibited the highest activities against Enterococcus faecalis, Enterococcus faecium and Enterococcus avium strains which are intrinsically resistant to most antimicrobial agents. No cross-resistance was observed between RP 59,500 and the four macrolides, which will merit attention in future clinical trials of the agent. The effect of human serum on the MIC of RP 59,500 was studied with strains of S. aureus, S. epidermidis and E. faecalis. The presence of 20% (V/V) serum had little or no effect on the MIC, although 50% (V/V) serum increased MICs by 4-8 folds. Laboratory-induced resistance to RP 59,500 occurred in a stepwise fashion in broth cultures of S. aureus, S. epidermidis and E. facalis strains and the induction rate was slow and no more than four fold increases were observed. Population analysis was performed on RP 59,500 and the reference macrolides against S. aureus ATCC 25,923 strain. Although low frequencies (less than 0.01%) of resistant sub-population were detected with EM, CAM, AZM and RXM, no RP 59,500-resistant sub-population was detected in this study.