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.

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.

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.

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.

Two new pyridine monoterpene alkaloids by chemical conversion of a commercial extract of harpagophytum procumbens

The treatment of harpagide (1), harpagoside (2), or 8-O-p-coumaroylharpagide (3), the main iridoids of Harpagophytum procumbens and Harpagophytum zeyheri, with NH3 and HCl led to aucubinine B(4), a pyridine monoterpene alkaloid (PMTA). A similar procedure applied to a commercial extract of H. procumbens yielded 4 and two new PMTAs named beatrine A (5) and beatrine B (6). The structures of these new PMTAs were established using ESIMS and 2D NMR. Their semisynthesis was analyzed in terms of reaction mechanisms.

Implication of nitro group reduction in the mutagenic and chromosome damaging activities of 22 new 5-nitroisoquinolines by the Salmonella mutagenicity test and the cytokinesis-blocked micronucleus assay.

The mutagenic (MUT) and chromosome-damaging (CHR) activities of 22 potential antimalarial drugs (5-nitroisoquinoline derivatives) were evaluated by the Salmonella test and the cytokinesis-blocked micronucleus assay (CBMN). The Salmonella mutagenicity test was performed with and without metabolic activation (S9 mix) in S. typhimurium strains TA100 and YG1042 (an overproducing nitroreductase and O-acetyltransferase TA100 strain). The CBMN was carried out on human lymphocytes without metabolic activation. Four concentrations were tested: 1, 10, 100 and 1000 ng/ml. MUT was expressed as minimal mutagenic concentrations (MMC, microM) and CHR was expressed as minimal chromosome-damaging concentrations (MCDC, nM) to compare both activities. All the 5-nitroisoquinoline compounds were mutagenic in TA100. MMC ranged from 0.1 to 52.9 microM in TA100. A statistically significant decrease in MMC was observed in YG1042 (8 x 10(-3) to 3.5 microM), implicating reduction of the nitro group. Modulation of MUT by S9 mix was not significant in TA100 and YG1042. CHR was detected in 13 products for at least one concentration. Among the chromosome-damaging compounds, the MCDC ranged from 2.9 x 10(-3) to 3.6 nM. No relationship was found between MUT and CHR, suggesting two distinct pathways of DNA damage.

[Electron transfer reactions: from electrons to drugs]. / Les réactions de transfert monoélectronique: de l'électron au médicament.

Electron transfer reactions have been at the heart of great advances in organic and inorganic chemistry and biology since the early work in 1954 by H. Taube (Nobel Chemistry Prize in 1983) and R. Marcus (Nobel Chemistry Prize in 1991). In organic chemistry, a new kind of chain substitution reaction with paramagnetic species was defined and identified as S(RN)1 (substitution, radial-nucleophilic, unimolecular). In our laboratory, choosing more or less complex molecules which possess electron-withdrawing groups and correctly disposed alkylation sites has enabled us to extend this concept to the heterocyclic (S(RN)1 HET) and quinonic (S(RN)1 QUI) series. These studies led us to prepare, under mild operating conditions, highly branched molecules hard to obtain via other pathways and which possess high pharmacological activity in various fields. We have discovered new reaction mechanisms such as LD-S(RN)1 (long-distance S(RN)1) E(RC)1 (elimination radical chain, unimolecular), bis-S(RN)1 and poly-S(RN)1. Moreover, we have developed a new technology using microwaves which increases the interest of electron transfer reactions in medicinal chemistry for drugs synthesis.

Albumin-bound paclitaxel: the benefit of this new formulation in the treatment of various cancers.

Paclitaxel and docetaxel are established as the standards of care, either as monotherapy or in combination with other cytotoxic agents in metastasic breast cancer. In order to improve the efficiency of solvent-based paclitaxel and to overcome its drawbacks in terms of safety, a solvent-free formulation has been developed. This work is a review of the albumin-bound paclitaxel data relative to its pharmacodynamic and pharmacokinetic profiles, its therapeutic efficiency and its safety of use. The activity of albumin-bound paclitaxel in phase II and III trials indicates its significant clinical efficiency in the treatment of metastatic breast cancer. In lung and pancreatic cancer and in melanoma, the use of albumin-bound paclitaxel leads to interesting results which require further investigations. Preclinical and clinical studies have shown that albumin-bound paclitaxel is associated with a better tolerance compared to standard paclitaxel.

[Semi-concentrated radiation of cerebral metastases of bronchial cancer]. / L'irradiation semi-concentrée des métastases cérébrales des cancers bronchiques.

Results of radiotherapy in 49 patients with cerebral metastases are reported, overall treatment including anti-edema therapy based on Synacthene and radiotherapy of the whole brain by delivering 17.5 grays in 5 days. Tolerance to treatment was good. Total, durable (more than 2 months) neurological remission was obtained in 50 p. cent of cases, duration of remission being a mean of 120 days in patients responding to therapy. Concentrated irradiation is therefore effective and useful in the treatment of cerebral metastases from bronchial cancer as it improves survival conditions.

[Radiotherapy of localized inoperable bronchial squamous cell carcinoma (author's transl)]. / Radiothérapie et radiochimiothérapie des carcinomes bronchiques épidermoïdes localisés inopérables.

Authors have shown that in some favorable cases radiotherapy of localized bronchial carcinoma could give very good results. The study on the cases from 1960 to 1969 shows that authors have 8% of three years survival upon 105 patients who have been treated by 50 Grays or more in 5 weeks. The survival was better for the small cancers T2 than for the large ones. The study on the cases from 1970 to 1977 shows that to obtain 101 cases of squamous cell carcinoma (T2,4 -N0,2 -M0) authors were obliged to study 564 cases. The three years survival was 3,1% for carcinoma receiving more than 40 Grays/4 weeks. The survival is better for small cancer and for the cases without radiological mediastinal nodes. In conclusion, radiotherapy is the best treatment after surgery, limited disease can be cure, and iterative radiotherapy increases our results.