Target fishing reveals PfPYK-1 and PfRab6 as potential targets of an antiplasmodial 4-anilino-2-trichloromethylquinazoline hit compound.

We present investigations about the mechanism of action of a previously reported 4-anilino-2-trichloromethylquinazoline antiplasmodial hit-compound (Hit A), which did not share a common mechanism of action with established commercial antimalarials and presented a stage-specific effect on the erythrocytic cycle of P. falciparum at 8 < t < 16 h. The target of Hit A was searched by immobilising the molecule on a solid support via a linker and performing affinity chromatography on a plasmodial lysate. Several anchoring positions of the linker (6,7 and 3') and PEG-type linkers were assessed, to obtain a linked-hit molecule displaying in vitro antiplasmodial activity similar to that of unmodified Hit A. This allowed us to identify the PfPYK-1 kinase and the PfRab6 GTP-ase as potential targets of Hit A.

Compounding and quality control of two pediatric topiramate pharmaceutical preparations.

In pediatric wards, topiramate is prescribed as an antiepileptic at non-licensed dosages. Compounding is the best way to obtain topiramate drug adapted to pediatric patients, but this practice requires to control the quality of batches and to manage a stability study to establish a beyond-use-date. With this objective, 6 mg. mL 1 topiramate oral suspension and 9 mg capsules were realized, and our laboratory was mandated for their quality control. Previously described dosing methods did not allow us to determine topiramate content in prescribed preparations. An original HPLC-UV derivatization dosing method of topiramate was validated and was proved to be stability indicating. This derivatization methodology, but also total aerobic microbial count (TAMC) and total combined yeasts and mold count (TYMC) allowed the quality control of topiramate capsules and topiramate suspension. Beyond-use-dates can be attributed with regards to United States Pharmacopoeia recommendations, and a stability study was performed on 6 mg. mL-1 topiramate suspension to confirm empirical data. Topiramate pediatric suspension was found to be stable for two months at +2/+8 °C, one month after opening and one day at ambient temperature.

Stability Studies of Antipyocyanic Beta-Lactam Antibiotics Used in Continuous Infusion.

In intensive care, beta-lactams can be reconstituted in 50 mL polypropylene syringes with NaCl 0.9 % and administered for 8 to 12 h at various concentrations with motor-operated syringe pumps. The feasibility and/or the stability of these antibiotic therapies are often poorly known by clinicians. The purpose of this study was to determine the stability of seven antipyocyanic beta-lactam antibiotics and cilastatin under real-life conditions. Stability indicating HPLC methods allowing quantification in pharmaceutical preparations and subsequent stability studies were performed. The stability studies showed that continuous infusion of piperacillin/tazobactam 80/10 mg/mL, of cefepime 20 and 40 mg/mL and of aztreonam 40 and 120 mg/mL can be used over 12 h. Moreover, continuous infusion of cefepime 120 mg/mL can be used over 10 h, whereas meropenem 10 and 20 mg/mL and ceftazidime 40 mg/mL remained stable only over 8 h, and meropenem 40 mg/mL was significantly degraded after 6 h. Finally, imipenem/cilastatin 5/5 mg/mL and piperacillin/tazobactam 320/40 mg/mL should not be used as continuous infusion. These data allow the establishment of protocols of administration of antipyocyanic beta-lactams by continuous infusion. Some of them are not appropriate to this mode of administration (imipenem/cilastatin, piperacillin/ tazobactam 320/40 mg/mL) or must be avoided if possible (ceftazidime 40 mg/mL).

Methods to control anticancer chemotherapy preparations ranked by risk analysis.

The observed increase in cancer led to a continuous rise in anticancer drug preparations in Hospital Centres. The quality and security of these preparations are essential to ensure the efficacy and to limit the risk of iatrogenic toxicity. Several methods have been described to secure the process of preparation (i.e. non-analytical methods for the control during the fabrication; analytical methods for the final product evaluation). These different methods have been presented in many studies, in particular in descriptive studies, but in practice, selecting a method is difficult and related to needs and hospital priorities. Therefore, we decided to conduct this present review focused on various existing methods allowing enhancement in security of anti-cancer drugs preparation process. A proactive hazard analysis method was applied, considering preparation and control steps, to discuss the choice of a method in terms of quality and security and to identify potential risks of failure. The results show that none method is perfect. Methods with the lowest criticality score are the robotization closely followed by Drugcam® in the case of re-labelling of all containers. According to these elements a University Hospital Centre could consider these risk indexesimplementing control methods.

[City-hospital network and quality control of officinal preparations]. / Interactions ville­hôpital et contrôle qualité des préparations magistrales réalisées à l'officine.

OBJECTIVES: In a hospital environment, the quality control of the hospital preparations allows to release homogeneous batches in a secure way. These controls are totally integrated into the process of production and can also, in certain cases, be realized for high-alert magistral preparations. In community pharmacy, these controls were not required, but the Agence régionale de santé (ARS) recently incited compounding community pharmacies to realize this type of analyses. This decision motivated the creation of a collaboration between the pharmacy department of a French teaching hospital and a society including around thirty community pharmacies having a preparatory. METHODS: Twenty community pharmacies distributed on all the territory have submitted one of their pediatric preparation, capsules of captopril 2mg, to the pharmacopoeia controls usually realized in the industry or hospital. RESULTS: All the analyzed batches were in agreement with European Pharmacopeia specifications. CONCLUSIONS: We shall present the rational of this work, the results as well as the numerous perspectives offered by this new type of collaboration joining completely the logic of a network city-hospital allowing the improvement of security of the medication circuit in France.

Stability studies of five anti-infectious eye drops under exhaustive storage conditions.

Several ocular infections require anti-infectious eye drops prepared by hospital pharmacy. Stability of these preparations is described in the literature, but studies do not always adequately consider physico-chemical parameters or storage conditions. We describe herein a complete study conducted on five anti-infectious eye drops containing vancomycin, gentamicin, ceftazidime, amphotericin B and voriconazole. We looked for significant changes in active pharmaceutical ingredient content, pH, osmolality and subvisible particles. Our study was designed to monitor stability at ambient temperature, at 2-8 °C, and also at 2-8 °C after various freezing periods. Under ambient storage conditions, eye drops were stable for 15 days, except for ceftazidime, which was stable for less than 1 day only. Under refrigeration conditions (2-8 °C), amphotericin B and voriconazole were stable for 60 days, vancomycin and gentamicin were stable for 30 days while ceftazidime was only stable for 15 days. After 90 days freezing and thawing, voriconazole remained stable at 2-8 °C for 60 days, vancomycin and amphotericin B for 30 days and gentamicin only for 21 days. Ceftazidime eye drops were stable for only 7 days at 2-8 °C after 60 days freezing. Our results are compared to the most relevant publications. Results of this study allow the compounding of large batches of harmonized anti-infectious eye drops.

Preventing the contamination of hospital personnel by cytotoxic agents: evaluation and training of the para-professional healthcare workers in oncology units.

This study was specifically focused on para-professional healthcare workers (PHCWs) who handle cytotoxic drugs and contaminated wastes at the Public Teaching Hospitals of Marseille (AP-HM), France. It first aimed at evaluating the knowledge and professional practice of the PHCWs who belong to a personnel category among the less informed and protected in hospitals. In a second time, this study also proposed to raise awareness, educate and train the staff on protective measures to minimise the exposure of the PHCWs to the potential toxicity of anticancer chemotherapy agents (or metabolites) when cleaning and handling both cytotoxic drugs and wastes. Among the 11 oncology units evaluated, 82% completed an assessment survey, 63% of which were PHCWs. Out of nine oncology units assessed, 89% reported limited knowledge of the general risk and of the safe handling of cytotoxic drugs, 89% reported using vinyl gloves which are the less protective ones. Forty-four per cent of the units used wet sweeping techniques for cleaning the floors, and 11% of the units did not have specific procedures for cleaning the equipments used for collecting contaminated excreta. Protective outer apparel was not always worn and chemotherapy wastes were not managed consistently between all units. Standardized procedures and guidelines to prevent occupational exposure were not used by PHCWs. More education and training are needed to improve safety.

Meningococcal vaccines: Current state and future outlook.

Neisseria meningitidis infections are a major public health problem worldwide. Although conventional approaches have not led to development of a serogroup B meningococcal vaccine, a new technique based on genome sequencing has created new perspectives. Recently, a universal serogroup B meningococcal vaccine, Bexsero(®), was licensed in Europe, Australia and United States, following several clinical studies demonstrating its immunogenicity and safety. Availability of this vaccine could contribute positively to human health, by significantly reducing the incidence of meningococcal infections. However, unfavorable cost-effectiveness analysis means that routine vaccination is not currently recommended. Another serogroup meningococcal vaccine, Trumemba(®), was also recently licensed in United States. Like any drug, Bexsero(®) and Trumemba(®) will require close observation to assess their impact on meningococcal epidemiology.

Pathophysiology and treatment of typical and atypical hemolytic uremic syndrome.

Hemolytic uremic syndrome is a rare disease, frequently responsible for renal insufficiency in children. Recent findings have led to renewed interest in this pathology. The discovery of new gene mutations in the atypical form of HUS and the experimental data suggesting the involvement of the complement pathway in the typical form, open new perspectives for treatment. This review summarizes the current state of knowledge on both typical and atypical hemolytic uremic syndrome pathophysiology and examines new perspectives for treatment.

Development of metronidazole-resistant lines of Blastocystis sp.

Metronidazole (MTR) is frequently used for the treatment of Blastocystis infections, but with variable effectiveness, and often with treatment failures as a possible result of drug resistance. We have developed two Blastocystis MTR-resistant (MTR(R)) subtype 4 WR1 lines (WR1-M4 and WR1-M5), with variable susceptibility to a panel of anti-protozoal agents including various 5-nitroimidazoles, nitazoxanide and furazolidone. WR1-M4 and WR1-M5 were developed and assessed over an 18-month period and displayed persistent MTR resistance, being more than 2.5-fold less susceptible to MTR than the parent isolate. The MTR(R) lines grew with a similar g time to WR1, but were morphologically less consistent with a mixture of size. All Blastocystis isolates and the MTR(R) lines were most susceptible to the 5-nitroimidazole drug ronidazole. WR1-M5 was apparently cross-resistant to satranidazole and furazolidone, and WR1-M4 was cross-resistant to nitazoxanide. These MTR(R) lines now provide a valuable tool for the continued assessment of the efficacy and mechanism of action of new and established drugs against a range of Blastocystis sp. subtypes, in order to identify a universally effective drug and to facilitate understanding of the mechanisms of drug action and resistance in Blastocystis.

Influence of silver nanoparticles on 2,3-bis(chloromethyl)anthracene-1,4,9,10-tetraone.

Size effect of silver nano particles on the photophysical properties of 2,3-bis(chloromethyl)anthracene-1,4,9,10-tetraone (BCMAT) have been investigated using optical absorption and fluorescence emission techniques. Silver NPs of different sizes have been prepared by two different methods. Quenching of fluorescence of BCMAT has been found to increase with decrease in the size of the silver NPs. Stern-Volmer quenching constants have also been calculated.

Stockpiled N95 respirator/surgical mask release beyond manufacturer-designated shelf-life: a French experience.

BACKGROUND: To reduce the shortage of N95 respirators and surgical masks during the COVID-19 pandemic, stockpiled equipment beyond its expiry date could be released. AIM: Centralized testing of batches of expired surgical masks and N95 for safe distribution to hospital departments saving users time. METHODS: Tests of compliance with health authority directives were developed and carried out on 175 batches of N95 masks and 31 batches of surgical masks from 12th March 2020 to 16 April 2020. Five quality-control tests were performed on batch samples to check: packaging integrity, mask appearance, breaking strength of elastic ties and strength of nose clip test, and face-fit. FINDINGS: Forty-nine per cent of FFP2 mask batches were compliant with directives, 32% of batches were compliant but with some concerns and 19% of batches were non-compliant. For surgical masks, 58% of batches were compliant, 39% of batches compliant but with concerns and 3% of batches were non-compliant. CONCLUSION: The main areas of non-compliance were the breaking strength of the elastic ties and the nose clip but these alone were not considered to make the masks unacceptable. Only mask appearance and face-fit results were decisive non-compliance criteria.

Preferential solvation of 1,4-dimethoxy-2,3-dimethyl-9,10-anthraquinone--a spectrophotometric and fluorometric study.

Electronic absorption and fluorescence emission spectra of DMDMAQ (1,4-dimethoxy-2,3-dimethyl-9,10-anthraquinone) have been studied as a function of solvent composition in some binary mixtures and in different neat solvents. The binary mixtures consist CCl(4) (Carbon tetrachloride)-DMSO (Dimethylsulfoxide), EtOH (Ethanol)-DMSO, and CCl(4)-EtOH combination of single solvents. The wavelength maxima of the absorption band for DMDMAQ are quite solvent sensitive in aprotic solvents. But, in protic solvent, there is no marked shift in absorption and emission maximum which shows the absence of specific interaction. Excited state shows increasing shift with increasing solvent polarity compared to ground state. The ratio of dipole moment in the excited state to that in the ground state was calculated. Different criteria were considered to analyse preferential solvation characteristics in different binary mixtures, viz., local mole fraction (X(2)(L)), solvation index (delta(S2)) and exchange constant (K(12)).

Antitumoral activity of quinoxaline derivatives: A systematic review.

Cancer is a leading cause of death and a major health problem worldwide. While many effective anticancer agents are available, the majority of drugs currently on the market are not specific, raising issues like the common side effects of chemotherapy. However, recent research hold promise for the development of more efficient and safer anticancer drugs. Quinoxaline and its derivatives are becoming recognized as a novel class of chemotherapeutic agents with activity against different tumors. The present review compiles and discusses studies concerning the therapeutic potential of the anticancer activity of quinoxaline derivatives, covering articles published between July 2013 and July 2018.

Solvatochromism and preferential solvation of 1,4-dihydroxy-2,3-dimethyl-9,10-anthraquinone by UV-vis absorption and laser-induced fluorescence measurements.

Solvation characteristics of 1,4-dihydroxy-2,3-dimethyl-9,10-anthraquinone (1) in pure and binary solvent mixtures have been studied by UV-vis absorption spectroscopy and laser-induced fluorescence techniques. The binary solvent mixtures used as CCl(4) (tetrachloromethane)-DMF (N,N-dimethylformamide), AN (acetonitrile)-DMSO (dimethylsulfoxide), CHCl(3) (chloroform)-DMSO, CHCl(3)-MeOH (methanol), and MeOH-DMSO. The longest wavelength band of 1 has been studied in pure solvents as well as in binary solvent mixtures as a function of the bulk mole fraction. The Vis absorption band maxima show an unusual blue shift with increasing solvent polarity. The emission maxima of 1 show changes with varying the pure solvents and the composition in the case of binary solvent mixtures. Non-ideal solvation characteristics are observed in all binary solvent mixtures. It has been observed that the quantity [nu (12)-(X(1)nu (1)+X(2)nu (2))] serves as a measure of the extent of preferential solvation, where nu and X are the position of band maximum in wavenumbers (cm(-1)) and the bulk mole fraction values, respectively. The preferential solvation parameters local mole fraction (X(2)(L)), solvation index (delta(s2)), and exchange constant (k(12)) are evaluated.

[TDAE strategy applied to drug-candidate synthesis]. / Stratégie TDAE appliquée à la synthèse de candidats-médicaments.

Research, developed at the Laboratory of Organic Pharmaceutical Chemistry of the School of Pharmacy, UMR-CNRS 6517, is centred on the synthesis of novel therapeutic compounds using monoelectronic transfer reactions. Tetrakis(dimethylamino)ethylene (TDAE) is a powerful electron donor which has the specific property of activating the carbon-halogen bond leading to the formation of a stable electrophilic radical and a stable neutrophilic anion. Since 2002, our team has developed a program using monoelectronic transfer reactions initiated by TDAE of nitroaromatic, nitroheterocyclic and quinonic bioreducible alkylating agents. The goal is to synthesize new therapeutic compounds for use as anti-infectious agents, anticancer agents, and agents active on the central nervous system. In this context, we present the first pharmacochemical tools obtained with this strategy during reactions between diverse electrophilic compounds (aldehydes, ketones, alpha-keto-esters, ketomalonates, alpha-ketolactames, ...) and benzylic anions formed in situ by the action of TDAE. We illustrate the usefulness of this strategy by describing the preparation of new compounds of biological interest and the associated pharmacomodulation work.

Rapid synthesis of sulfone derivatives as potential anti-infectious agents.

An original one-pot microwave reaction was developed for the synthesis of sulfone derivatives as new potent antimicrobial agents. This eco-friendly methodology conducted in 30min led to desired products with good yields. The sulfones (4a and 4b) were obtained via the reaction of 3a with the corresponding halo-derivatives in the presence of sodium hydride. All compounds were tested for their antibacterial and antifungal activities against four bacterial strains (two gram positive, and two gram negative ones) and two yeasts. The disk diffusion method has shown an interesting antibacterial activity for seven compounds (3b-g and 4b) against Staphylococcus aureus. Among these seven compounds, five derivatives (3b-e and 3g) showed activity against Candida tropicalis.

Surface Enhanced Raman Spectroscopic investigations of 2-bromo-3-methylamino-1,4-naphthoquinone on silver nanoparticles.

Surface Enhanced Raman Spectroscopic technique has been employed to investigate the orientation of 2-bromo-3-methylamino-1,4-naphthoquinone (BMANQ) on silver nanoparticles. Silver nanoparticles have been prepared by solution combustion method with citric acid as fuel. Silver nanoparticles were characterized by X-ray Diffraction (XRD), High Resolution Transmission Electron Microscopy (HRTEM) and Scanning Electron Microscopy (SEM). XRD and morphological results confirmed the nanocrystalline nature of the prepared silver nanoparticles. The observed intense CO stretching, CBr stretching and NH2 vibration suggests that the BMANQ molecule may be adsorbed in a 'stand-on' orientation to the silver surface. The calculated highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy show that charge transfer occurs within the molecule.

Surface enhanced Raman spectral studies of 2-bromo-1,4-naphthoquinone.

Silver nanoparticles have been synthesized by a simple and inexpensive solution combustion method with urea as fuel. The structural and morphology of the silver nanoparticles were investigated through X-ray powder diffraction (XRD), Field Emission Scanning Electron Microscopy (FESEM) and Energy Dispersion Spectra (EDS) techniques. Structural and morphological results confirmed the nanocrystalline nature of the silver nanoparticles. Density Functional Theory (DFT) calculations were also performed to study the ground and excited state behavior of 2-bromo-1,4-naphthoquinone (2-BrNQ) and 2-BrNQ on silver nanoparticles. Surface-Enhanced Raman Scattering (SERS) spectra of 2-BrNQ adsorbed on silver nanoparticles were investigated. The CO, CH in-plane bending and CBr stretching modes were enhanced in SERS spectrum with respect to normal Raman spectrum. The spectral analysis reveals that the 2-BrNQ adsorbed 'stand-on' orientation on the silver surface. Density Functional Theory (DFT) calculations are also performed to study the vibrational features of 2-BrNQ molecule and 2-BrNQ molecule on silver surface.

Adsorption of N-(1-(2-bromophenyl)-2-(2-nitrophenyl)ethyl)-4-methylbenzenesulfonamide on silver nanoparticles: SERS investigation.

SERS provides essential data regarding the interaction of molecules in drugs with DNA. In the present study silver nanoparticles were synthesized using a solution combustion method with urea as fuel. The prepared silver nanoparticles are rod like structure. Surface-enhanced Raman scattering (SERS) of N-(1-2-bromophenyl)-2-(2-nitrophenyl)ethyl)-4-methylbenzenesulfonamide (BrS) adsorbed on the silver nanoparticle was studied. The nRs and Raman spectral analysis reveal that the BrS adsorbed tilted orientation on the silver surface. Vibrational modes of nRs along with HF calculations are also performed to study the HOMO and LUMO behavior and vibrational features of BrS.