4-Methyltetrahydropyran as a Convenient Alternative Solvent for Olefin Metathesis Reaction: Model Studies and Medicinal Chemistry Applications.

A number of metathesis reactions were successfully conducted in 4-methyltetrahydropyran, including both standard model dienes, as well as more complex substrates, such as analogues of biologically active compounds and active pharmaceutical ingredients. To place this solvent in a context of pharmaceutical R + D, larger-scale syntheses of SUAM 1221, a prolyl endopeptidase inhibitor with potential application in Alzheimer disease treatment, and a derivative of sildenafil, an analogue of the popular Viagra drug, were executed. In the latter case, despite all the setup being made in air, the metathesis reaction at a 33 g scale proceeded very well with relatively low catalyst loading and without need of aqueous workup or column chromatography.

Large-Scale Synthesis of a Niche Olefin Metathesis Catalyst Bearing an Unsymmetrical N-Heterocyclic Carbene (NHC) Ligand and its Application in a Green Pharmaceutical Context.

A large-scale synthesis of known Ru olefin metathesis catalyst VII featuring an unsymmetrical N-heterocyclic carbene (NHC) ligand with one 2,5-diisopropylphenyl (DIPP) and one thiophenylmethylene N-substituent is reported. The optimised procedure does not require column chromatography in any step and allows for preparation of up to 0.5 kg batches of the catalyst from simple precursors. The application profile of the obtained catalyst was studied in environmentally friendly dimethyl carbonate (DMC). Although VII exhibited low efficiency in cross-metathesis (CM) with electron-deficient partners, good to excellent results were noted for substrates featuring easy to isomerise C-C double bonds. This includes polyfunctional substrates of medicinal chemistry interest, such as analogues of psychoactive 5F-PB-22 and NM-2201 and two PDE5 inhibitors-Sildenafil and Vardenafil. Finally, a larger scale ring-closing metathesis (RCM) of a Vardenafil derivative was conducted in DMC, allowing for straightforward isolation of the expected product (23 g) in high yield and with low Ru contamination level (7.7 ppm).

Tuberculosis among the homeless and inmates kept in custody and in penitentiary institutions in the Silesia region.

INTRODUCTION: There are more than 10 million prisoners in the world. Tuberculosis incidence is 10-100 times higher in prisoners than in the general population. Inmates have close contact with other prisoners and with prison workers and visitors, so tubercle bacilli may be easily spread. Most of the inmates come back to normal life and contact with the general population. The aim of the study was to assess active tuberculosis incidence among prisoners and homeless persons in the Silesia region. MATERIAL AND METHODS: In total 897 people entered the study, of whom 720 were Silesian penitentiary system inmates, and 177 were homeless. BACTEC MGIT fast TB detection system and GenoType Mycobacteria Direct test were used. Drug susceptibility testing was done using SIRE KIT and PZA KIT. RESULTS: Tuberculosis was diagnosed in 13 out of 897 persons (1.45%): in 11 out of 720 inmates (1.53%) and in 2 out of 177 homeless persons (1.13%). Data concerning drug susceptibility were obtained for 11 persons. M. tuberculosis strains isolated from eight persons were susceptible to four first-line antituberculosis drugs (streptomycin, isoniazid, rifampin, ethambutol), while M. tuberculosis strains isolated from three persons were drug-resistant. One out of three isolated strains was resistant to ethambutol, but susceptible to streptomycin, isoniazid, rifampin, and pirazynamide. The second strain was resistant to streptomycin and pyrazinamide but susceptible to isoniazid, rifampin, and ethambutol. The third strain was susceptible to rifampin but resistant to the other four tested drugs. According to the obtained data, culture-positive pulmonary tuberculosis was 100 times more frequent in the examined population than in the general population of the Silesia region in the same period of time. CONCLUSIONS: The health project enabled effective detection of tuberculosis in risk groups and should be continued in the following years. The set of the applied diagnostic methods allowed the detection of in the studied subpopulations people suffering from tuberculosis. Patients were treated with antituberculosis drugs that would stop them from spreading the disease to other people.

Occurrence of Clostridium difficile PCR-ribotype 027 and it's closely related PCR-ribotype 176 in hospitals in Poland in 2008-2010.

Since 2003, a rising incidence of Clostridium difficile infection (CDI) in North America and Europe has coincided with outbreaks of C. difficile PCR ribotype 027. This ribotype was not observed in Poland until 2008. In the period 2008-2010, outbreaks of antibiotic-associated diarrhoea occurred in three different hospitals in Poland. Of 30 C. difficile isolates available for microbiological characterisation, 17 (56%) were positive for binary toxin genes and belonged to PCR ribotype 027 (n = 7) and its closely related PCR ribotype 176 (n = 10). All 17 binary toxin-positive C. difficile strains demonstrated high-level resistance to fluoroquinolones (minimum inhibitory concentration (MIC) ≥ 32 mg/L), including ciprofloxacin, gatifloxacin, and moxifloxacin, as well as erythromycin and clindamycin (MIC ≥ 256 mg/L for both). Of 14 patients from whom clinical information was available, 50% had a severe form of CDI, defined by fever (>38.5 °C), decreased kidney function, and high leucocyte count. We conclude that outbreaks of CDI associated with hypervirulent strains belonging to PCR ribotypes 027 and 176 occurred in hospitals in Poland. Further studies evaluating the clinical impact of type 176 are urgently needed.

[Assessment of antagonistic activity in vitro Lactobacillus spp. strains againts Clostridum difficile strains isolated from gastrointestinal tract of patients hospitalized in three hospitals in region Mazovia]. / Ocena antagonistycznego dzialania w warunkach in vitro szczepów z rodzaju Lactobacillus wobec toksynotwórczych szczepów Clostridium difficile wyhodowanych z przewodu pokarmowego pacjentów leczonych w szpitalach na terenie województwa mazowieckiego.

INTRODUCTION: The aim of this study was to evaluate the antagonistic activity of Lactobacillus strains against clinical C. difficile strains isolated from faecal samples of adults patients with diarrhea. A total 61 strains of C. difficile randomly selected isolated in the period 2007-2008 from the gastrointestinal tract of hospitalized patients in three hospitals province Mazovia, Poland. To determination of antagonistic activity ofprobiotic Lactobacillus spp. strains used four reference strains: Lactobacillus plantarum 2017405, Lactobacillus fermentum 353, Lactobacillus acidophilus DSM 21007 and Lactobacillus rhamnosus GG. METHODS: Isolation of C. difficile was performed on selective Columbia agar supplemented with cycloserine/cefoxitine and amphothericin B (CLO medium, bioMérieux, France). The plates were incubated in an anaerobic chamber for 48 h at 37 degrees C. Isolates were identified as C. difficile by the characteristic morphology of the colonies and horse-like odour, green yellow fluorescence under UV. Toxigenicity of of C. difficile strains was determined in PCR to detection of fragments of genes encoding toxin A (tcdA), toxin B (tcdB) and binary toxin (cdtA and cdtB). The study of antagonistic activity four Lactobacillus spp. strains against 61 clinical C. difficile strains was performed according to standard methods. Lactobacillus strains were inoculated on MRS medium and incubated in oxygen-free atmosphere and cut the bars of MRS agar and applied to the plate with cultures of C. difficile strains. RESULTS: Assessment of antagonist activity of Lactobacillus spp. strains was performed by measuring the zone of inhibition of grown of C. difficile strains. The study shows that of probiotic Lactobacillus spp. strains interacted antagonistically in vitro against all toxigenic (A+B+CDT- and A+B+CDT+) of C. difficile strains. CONCLUSIONS: The differences in the antagonistic activity of Lactobacillus spp. strains against different toxigenic clinical C. difficile strains were not observed.

[Assessment of susceptibility of strictly anaerobic bacteria originated from different sources to fluoroquinolones and other antimicrobial drugs]. / Ocena wrazliwosci szczepów bezwzglednych beztlenowców pochodzacych z róznych zródel na fluorochinolony oraz inne leki stosowane w lecznictwie szpitalnym.

INTRODUCTION: During the past 20 years, several studies at a national level in different countries followed resistance trends for Bacteroides sp. and Clostridium difficile. This study analysed antimicrobial susceptibility 73 anaerobic bacteria strains of Bacteroides fragilis group (BFG) and C. difficile to fluoroquinolones and other antimicrobial drugs. METHODS: The strictly anaerobes strains isolated in different hospitals were sent to the Department of Medical Microbiology, Medical Uniwersity of Warsaw, where species determination was carried out with the API20 ANA (bioMerieux SA, Marcy-l'Etoile, France) system. Susceptibility to antimicrobials was determined using E-test. RESULTS: The rates of high resistance to ciprofloxacin and moxifloxacin of BFG was respectively 84% and 31% and among of C. difficile strains respectively 92% and 36%). The percentage of BFG strains resistant to erythromycin and clindamycin were respectively 84% and 46%. The percentage of C. difficile strains resistant to erythromycin and clindamycin was 52%. Reduced level of susceptibility of BFG strains to amoxicillin/clavulanic acid (8%) was confirmed. Resistance to cefoxitin was 16% of BFG strains. All tested strains as well as BFG and C. difficile were susceptible to metronidazole. Was observed reduced leve (EUCAST) of susceptibility of C. difficile strains to vancomycin (13%). CONCLUSIONS. Increasing resistance to various antimicrobial agents is a significant problem in Poland. This demonstrate the need to continue with antibiotic resistance testing and surveys in anaerobic bacteria.

Antimicrobial resistance of Helicobacter pylori in Poland: a multicentre study.

The resistance of Helicobacter pylori to antimicrobials, known to be increasing in many countries, is an important factor compromising the efficacy of eradication therapy. Therefore, our study aimed at analysing the current susceptibility status of H. pylori in Poland. A total of 337 H. pylori isolates were cultured from children (N=179) and adults (N=158) from various regions of the country from January 2001 to December 2004. All strains were susceptible to amoxicillin and tetracycline. The overall resistance to clarithromycin (CL) was 28%, but there were significant differences between the centres (ranging from 0% to 33%) and between child and adult isolates (28% versus 15%, respectively; P=0.01) for primary a resistance. Altogether, 46% of H. pylori isolates were resistant to metronidazole (MTZ) and 20% of isolates were simultaneously resistant to CL and MTZ.

The ability of new sugar-modified derivatives of antitumor anthracycline, daunorubicin, to stimulate NAD(P)H oxidation in different cellular oxidoreductase systems: NADH dehydrogenase, NADPH cytochrome P450 reductase, and xanthine oxidase.

Numerous data indicate that cellular oxidoreductases may be responsible for the cardiotoxic effects of antitumor anthracycline drugs as a consequence of the mediation by these agents of one-electron transfer from reduced nucleotides to atmospheric oxygen. This process is catalyzed primarily by NADH dehydrogenase, NADPH cytochrome P450 reductase, and xanthine oxidase and leads to the formation of reactive oxygen species (ROS). In this work the data on the ability of new amino sugar derivatives of daunorubicin to stimulate NAD(P)H oxidation in the above oxidoreductase systems are presented. They represent analogues of daunorubicin in which the amino sugar nitrogen is bounded to an unsubsituted, or amino- or nitro-substituted benzyl group. It was found that the ability of examined sugar-modified derivatives of daunorubicin to stimulate NAD(P)H oxidation differs considerably depending on the subsituent in the phenyl ring. It was also determined that this ability was not identical in the three enzymatic systems studied, showing that these derivatives have different affinities for the enzymes examined. More similarities were observed in their interaction with NADH dehydrogenase and NADPH cytochrome P450 reductase than with xanthine oxidase.

[ESBL-positive strains of the Bacteroides fragilis group isolated from patients at the regional hospital center in Plock (Poland)]. / ESBL-dodatnie szczepy z grupy Bacteroides fragilis wyizolowane od pacjentów wojewódzkiego szpitala zespolonego w Plocku.

The aim of this study was to confirm a presumptive qualification of clinical B. fragilis group strains isolated in Plock as ESBL-positive strains and to determine some properties of these strains. Twenty four clinical strains belonging to the B. fragilis group, isolated first of all from surgical patients, were received for testing. Identification of strains was performed in the automatic ATB Expression system (bioMerieux sa, France) using biochemical API 20 A strips. Strains were tested for the production of catalase (ID Color Catalase test, bioMerieux sa) and beta-lactamase (Cefinase, BBL, Becton Dickinson, USA). Susceptibility of strains to four antimicrobial agents: clindamycin, metronidazole, amoxicillin/clavulanic acid and imipenem was determined by Etest (AB Biodisk, Sweden). ESBLs were detected with the use of two disc diffusion methods: the double-disc synergy test (DDST) according to Jarlier et al. and the diagnostic disc (DD) test according to Appleton. Seventeen of examined strains belonged to the species Bacteroides fragilis, three--to B. ovatus/thetaiotaomicron, two--to B. distasonis, one--to B. uniformis and one--to B. stercoris/eggerthii. One strain (B. uniformis) did not produce catalase, whereas all strains produced beta-lactamases. Examined strains were susceptible in vitro to metronidazole, amoxicillin/clavulanic acid and imipenem. One clindamycin-resistant strain was detected (B. fragilis). Occurrence of ESBL-type enzymes was confirmed in 22 strains of following species: B. fragilis (17 strains), B. ovatus/thetaiotaomicron (3), B. distasonis (1) and B. uniformis (1). Clinical strains of the B. fragilis group with a new mechanism of resistance to beta-lactam antibiotics appeared during last years in Poland. They produce extended-spectrum beta-lactamases (ESBLs), so they are resistant to penicillins, cephalosporins and monobactams. Monitoring of infections caused by these threatening strains in hospital patients is very important.

Differential ability of cytostatics from anthraquinone group to generate free radicals in three enzymatic systems: NADH dehydrogenase, NADPH cytochrome P450 reductase, and xanthine oxidase.

The antitumor drugs of the anthraquinone group are widely used agents in the treatment of a variety of human neoplasms. However, their clinical effectiveness is limited by several factors, among which dose-dependent cardiotoxicity is of great importance. Numerous data indicate that the cardiac effects of these drugs are the consequence of one-electron transfer from reduced nucleotides to atmospheric oxygen. This process is catalyzed primarily by NADH dehydrogenase, NADPH cytochrome P450 reductase, and xanthine oxidase, and leads to the formation of reactive oxygen species. In our previous studies we have shown that the NADH dehydrogenase catalyzed electron transfer phenomenon is correlated with the affinity of anthraquinone drugs to the enzyme. In this work data are presented on the ability of compounds belonging to several structural types of anthraquinone cytostatics (sugar- and quinone-modified derivatives of DR and ADR, and anthracenedione compounds) to stimulate free radical formation in the above three enzymatic systems. It has been shown that the three oxidoreductases exhibit different structural requirements with respect to their substrate properties for anthraquinones. Therefore, evaluation of the structural factors determining the ability of anthraquinone compounds to generate active oxygen species cannot be limited to a single oxidoreductase system but must include all types of enzymatic systems involved in the catalysis of one-electron transfer reactions.