Toward New Antileishmanial Compounds: Molecular Targets for Leishmaniasis Treatment

The leishmaniases are a group of diseases caused by protozoan parasites—Leishmania sp. Leishmaniasis is classified among the 20 neglected diseases by WHO. Although the disease has been known for more than 120 years, the number of drugs used for the treatment is still limited to 5–6. The first-line drugs against leishmaniasis are pentavalent antimonials, which were introduced to the treatment 70 years ago—despite all their side effects. Molecular targets are becoming increasingly important for efficacy and selectivity in postgenomic drug research studies. In this chapter, we have discussed potential therapeutic targets of antileishmanial drug discovery such as pteridine reductase (PTR1), trypanothione reductase (TR), N-myristoyltransferase (NMT), trypanothione synthetase (TryS), IU-nucleoside hydrolase, and topoisomerases, enzymes and their inhibitors reported in the literature

Fused Pyridine Derivatives: Synthesis and Biological Activities

Five-membered heteroaromatic ring fused pyridine derivatives are of increasing interest in drug design and medicinal chemistry. The structural similarity of many drugs (especially antiviral and anticancer ones) with DNA bases such as adenine and guanine is a key factor to explain their effectiveness. Apart from these, it is also found in the structures of substances with antituberculosis, antibacterial, antifungal, anti-inflammatory, and antimalarial activities. Another advantage of this group of compounds is their positive contribution to solubility, polarity, lipophilicity, and hydrogen bonding capacity properties of the compounds they are incorporated into. In this chapter, various bioactivities of fused pyridine derivatives will be categorized and summarized

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Synthesis, Biological Evaluation and Molecular Docking Study of Hydrazone-Containing Pyridinium Salts as Cholinesterase Inhibitors

WOS: 000382352700006PubMed ID: 27581632A series of pyridinium salts bearing alkylphenyl groups at 1 position and hydrazone structure at 4 position of the pyridinium ring were synthesized and evaluated for the inhibition of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. The cholinesterase (ChE) inhibitory activity studies were carried out by using the Ellman's colorimetric method. All compounds displayed considerable AChE and BuChE inhibitory activity and some of the compounds manifested remarkable anti-AChE activity compared to the reference compound, galantamine. Among the title compounds, the series including benzofuran aromatic ring exhibited the best inhibitory activity both on AChE and BuChE enzymes. Compound 3b, 4-[2-(1-(benzofuran-2-yl)ethylidene)hydrazinyl]-1-(3-Phenylpropyl)pyridinium bromide, was the most active compound with IC50 value of 0.23 (0.24) mu m against enantiomeric excess (ee)AChE (human (h)AChE) while compound 3a, 4-[2-(1-(benzofuran-2-yl)ethylidene)hydrazinyl]-1-phenethylpyridinium bromide, was the most active compound with IC50 value of 0.95 mu m against BuChE. Moreover, 3a and b exhibited higher activity than the reference compound galantamine (eeAChE (hAChE) IC50 0.43 (0.52) mu m; BuChE IC50 14.92 mu m). Molecular docking studies were carried out on 3b having highest inhibitory activity against AChE.Research Grants from Ege University [13/Ecz/026]This study was supported by Research Grants from Ege University (Project Number: 13/Ecz/026). The authors would like to thank the Pharmaceutical Sciences Research Centre (FABAL) at Ege University Faculty of Pharmacy for spectral analyses of the compounds

Evaluation of Teicoplanin Resistance Detected by Automated System in Coagulase Negative Staphylococci: A Comparison with Gradient Test and Broth Microdilution Methods

Upon the observation of an increase in teicoplanin resistance rates in coagulase negative staphylococci (CoNS) isolates determined by the automated system, we aimed to compare the automated system and gradient test methods with the gold standard broth microdilution method. In addition, the effect of standard antimicrobial susceptibility guidelines on teicoplanin susceptibility test results in CoNS was investigated. A total of 81 CoNS isolates, 52 resistant and 29 susceptible to teicoplanin determined by automated system (Phoenix, Becton Dickinson, USA), were tested. The minimum inhibitory concentration (MIC) values were determined by gradient test (M.I.C. Evaluators, OXOID, UK) and broth microdilution methods. Susceptibility categories were determined according to EUCAST and CLSI criteria and the results were compared. Among 29 isolates found to be susceptible by automated system, one isolate was found resistant by gradient and broth microdilution tests. Of the 52 resistant isolates determined by automated system, 12 (23%) were found to be resistant by gradient test and 22 (42.3%) were resistant by broth microdilution. According to CLSI criteria, no resistant isolates were detected by broth microdilution and six isolates were intermediately susceptible while, two isolates were detected to be resistant and five isolates were found to be intermediately susceptible by the gradient test. In conclusion, compared to microdilution, teicoplanin resistance was detected at a higher rate in CoNS isolates by the automated system used. On the other hand, the gradient test method which is frequently used for confirmation was not reliable in MIC values close to the EUCAST breakpoint values (4 mu g/mL). In addition, lower resistance rates were observed when the CLSI breakpoints were used in gradient test and broth microdilution methods

Design, synthesis, in vitro- In vivo biological evaluation of novel thiazolopyrimidine compounds as antileishmanial agent with PTR1 inhibition

The leishmaniasis are a group of vector-borne diseases caused by a protozoan parasite from the genus Leish-mania. In this study, a series of thiazolopyrimidine derivatives were designed and synthesized as novel anti-leishmanial agents with LmPTR1 inhibitory activity. The final compounds were evaluated for their in vitro antipromastigote activity, LmPTR1 and hDHFR enzyme inhibitory activities, and cytotoxicity on RAW264.7 and L929 cell lines. Based on the bioactivity results, three compounds, namely L24f, L24h and L25c, were selected for evaluation of their in vivo efficacy on CL and VL models in BALB/c mice. Among them, two promising compounds, L24h and L25c, showed in vitro antipromastigote activity against L. tropica with the IC50 values of 0.04 mu g/ml and 6.68 mu g/ml; against L. infantum with the IC50 values of 0.042 mu g/ml and 6.77 mu g/ml, respec-tively. Moreover, the title compounds were found to have low in vitro cytotoxicity on L929 and RAW264.7 cell lines with the IC50 14.08 mu g/ml and 21.03 mu g/ml, and IC50 15.02 mu g/ml and 8.75 mu g/ml, respectively. LmPTR1 enzyme inhibitory activity of these compounds was determined as 257.40 mu g/ml and 59.12 mu g/ml and their selectivity index (SI) over hDHFR was reported as 42.62 and 7.02, respectively. In vivo studies presented that L24h and L25c have a significant antileishmanial activity against footpad lesion development of CL and at weight measurement of VL group in comparison to the reference compound, Glucantime (R). Also, docking studies were carried out with selected compounds and other potential Leishmania targets to detect the putative targets of the title compounds. Taken together, all these findings provide an important novel lead structure for the anti-leishmanial drug development.We would like to thank Parasite Bank of Medical School of Manisa Celal Bayar University and Prof. W. N. Hunter (University of Dundee, UK) for the Lm PTR1 construct. The authors extend their appreciation to the Scientific and Technological Research Council of Turkey (TUBITAK) , project no: SBAG-117-S-041 and Izmir Katip Celebi University Scientific Research Coordinatorship, grant no: 2018-ODL-ECZF-0018. This work was partially supported by ARRS (Slovenian Research Agency) pro-gramme grant P1-0201.Scientific and Technological Research Council of Turkey; Izmir Katip Celebi University Scientific Research Coordinatorship [2018-ODL-ECZF-0018]; ARRS (Slovenian Research Agency) programme; [SBAG-117-S-041]; [P1-0201

VERMIAN FOSSA - AN ANATOMICAL STUDY

Objective: Vermian fossa (VF) is a shallow fossa of varying size which may occasionally be found on dorsal aspect of foramen magnum. Our aim was to find out frequency of VF and to measure length and width of the determined VF's and to classify them according to their shapes