Ethyl 2-[4-(4-meth-oxy-benz-yl)-3-methyl-6-oxopyridazin-1-yl]acetate.

In the title mol-ecule, C17H20N2O4, the inner part of the ester substituent is nearly perpendicular to the di-hydro-pyridazine ring, forming a dihedral angle of 83.21 (7)°. In the crystal, inversion dimers are formed by pairwise C-H⋯O inter-actions with the dimers connected into chains extending along the b-axis direction by C-H⋯π(ring) inter-actions. The chains are connected by π-stacking inter-actions to give corrugated layers parallel to the ab plane. The terminal ethyl group is disordered over two two sets of sites with the major component having a site occupancy factor of 0.715 (10).

Crystal structure and Hirshfeld surface analysis of (E)-3-benzyl-idene-4-oxo-penta-noic acid.

The asymmetric unit of the title mol-ecule, C12H12O3, contains two independent mol-ecules having opposite conformations and each forming self-dimers through complementary O-H⋯O hydrogen bonds. These dimers are linked by weak C-H⋯π inter-actions and C-H⋯O hydrogen bonds into a three-dimensional structure in which one can discern layers parallel to the bc plane. A Hirshfeld surface analysis of the inter-molecular inter-actions is included.

Design, synthesis, structural and molecular characterization, toxicity, psychotropic activity and molecular docking evaluation of a novel phenytoin derivative: 3-decyl-5,5-diphenylimidazolidine-2,4-dione.

The hydantoin scaffold is of substantial importance and it is commonly used in drug discovery. Herein, we report the synthesis of a novel phenytoine (a hydantoin derivative) with high yield by the reaction of phenytoin with 1-bromodecyl agent. Namely, 3-decyl-5,5- diphenylimidazolidine-2,4-dione (3DDID). The optimized geometry of the compound was calculated using density functional theory (DFT) method by B3LYP with 6-311++G(d,p) basis set. For this calculation, the X-ray data were used as initial values. Molecular electrostatic potential (MEP) surface and Frontier molecular orbitals (FOMs) were prepared for the compound. The crystal structure of the title compound contains intermolecular N-H···O, C-H···O hydrogen bonds and weak C-H···π interactions. Hirshfeld surface analysis and 2D fingerprint plots of the molecule aid comparison of intermolecular interactions and these analysis reveals that two close contacts are associated with intermolecular hydrogen bonds. The psychotropic activity evaluation of the synthesized compound was further explored using hole bored test for exploratory behaviors, dark//light box test for anxiolytic activity and Rota-road, traction, chimney testes were used to assess the myrelaxant effect. In addition, molecular modeling study was also conducted to rationalize the potential as neurotherapeutic drugs of our synthesized compound by predicting their binding modes, binding affinities and optimal orientation at the active site of the GABA-A receptor and Na+ channel. Finally, in silico ADMET predictions was also examined. HighlightsSynthesis, structural, and molecular characterization of a novel phenytoin derivative.DFT, XRD, and the Hirshfeld surface analysis of crystal structure was studied.Acute toxicity and psychotropic activity evaluation of 3-decyl-5,5 diphenylimidazolidine-2,4-dione (3DDID).Molecular modeling studies have been conducted to rationalize the obtained data and to determine the probable binding mode.Communicated by Ramaswamy H. Sarma.

Impact of clinical pharmacy services in a hematology/oncology ward in Morocco.

BACKGROUND: Clinical pharmacists are contributing to safe medication use by providing comprehensive management to patients and medical staff. The aim of this study is to document and evaluate the role of clinical pharmacy services in oncology department. PATIENTS AND METHODS: A prospective, descriptive, observational study was carried out from July 2018 through June 2019 at the Department of Medical Oncology at the National Institute of Oncology, Morocco. Medication reviews concerning hospitalized adult cancer patients were performed every day by the clinical pharmacist assigned to the department. RESULTS: A total of 3542 prescriptions of 526 adult cancer patients were analyzed. The pharmacist identified 450 drug-related problems (12.7% of the prescriptions) primarily related to the analgesics (31.5%). Medication problems included mostly untreated indications (31.3%), overdosing (17.1%), drug-drug interactions (12.4%), underdosing (11.1%), administration omissions (6.7%), drug not indicated (6.0%), and contraindication (5.3%). Interventions (n = 450) led to drug additions (30.7%), drug dosing adjustments (27.1%), treatment discontinuations (20.0%), recall of the treatment (6.2%), replacement of a drug with another one (5.1%), administration optimization (4.0%), therapeutic drug monitoring (3.1%), alternate routes of administration (2.5%), and extension of treatment duration (1.3%). Most (98%) of the interventions were accepted and implemented by the medical staff-172 (38.2%) having a significant clinical impact on the patient, 88 (19.6%) as having a very significant clinical impact, and 71(15.8%) as having a potential vital impact. CONCLUSION: This work highlights the positive clinical relevance of pharmacists' interventions in oncology and the importance of medicopharmaceutical collaboration to prevent medication error.

Assessment of the medical expenditure of the basic health insurance in Morocco.

INTRODUCTION: The health care consumption for the population insured by the Basic Health Insurance in Morocco are paid directly to the care providers for the health care or health products from the health insurance funds. The level of expenditure recorded is changing at an accelerated rate than the financial resources. The objective of this study is to evaluate the health care consumption care by the insured population under the Basic Health Insurance. METHODS: This is a cross-sectional study analysis of the economic data collected by the National Moroccan Health Insurance Agency Related to the expenditures from the health insurance fund for both public and private sectors to identify the behavior of the consumption of health care by the insured population under the Basic Health Insurance. RESULTS: The medical expenditure of the covered population by the basic Health Insurance in Morocco has almost doubled from 354800 to 652500 US Dollars between 2009 and 2014 with significant increase in the public sector than the private sector. The share of expenditures in the public ambulatory care sector under Basic Health Insurance is higher relative to the hospital care. Although in the private sector the share of expenditures for both types of care varies. In 2014, the drug item expenditure accounted for 33% of Health Insurance expenses for both sectors. The level of health care consumption among the population in Long-Term Illness (LTI) represents 49,29% of the total expenditure by the Health Insurance whereas its insured covered population does not exceed 2,78%. CONCLUSION: Controlling the medical expenditure of the health insurance requires strengthening and the development of regulatory measures that contribute to the health reforms. For chronic diseases, it is necessary to put in place prevention actions.

Virtual docking screening and QSAR studies to explore AKT and mTOR inhibitors acting on PI3K in cancers.

The phosphoinositide 3-kinase (PI3K) pathway is an important regulator of cell proliferation and metabolism. PI3K activation initiates a signal transduction cascade, of which the major effectors are the kinases AKT and mTOR. Aberrant activation of the PI3K/AKT/mTOR pathway is frequently observed in many human malignancies and the combination of compounds simultaneously targeting different related molecules in the PI3K/AKT/mTOR pathway leads to synergistic activity. To explore the competing common ATP inhibitors PI3K/AKT and PI3K/mTOR we developed a model PI3K-SAR 2D which made it possible to predict the bioactivity of inhibitors of AKT and mTOR towards PI3K; the interaction of the best inhibitors was evaluated by docking analysis and compared to that of dactolisib and pictilisib. A PI3K-SAR model with a correlation coefficient (R2) of 0.81706 and an RMSE of 0.16029 was obtained, which was validated and evaluated by a cross-validation method, LOO. The most predicted AKT and mTOR inhibitors present respectively pIC50 activities between 9.26-9.93 and 9.59-9.87. After docking and several comparisons, inhibitors with better predictions showed better affinity and interaction with PI3K compared to pictilisib and dactolisib, so we found that 4 inhibitors of AKT and 14 mTOR inhibitors met the criteria of Lipinski and Veber and could be future drugs.

[Analysis of the infectious risk around the patient in the hemodialysis unit of Ibn Sina Rabat hospital using the failure modes, effects and criticality analysis method]. / Analyse du risque infectieux autour du patient dans l'unité d'hémodialyse de l'hôpital Ibn Sina de Rabat par application de la méthode d'analyse des modes de défaillance, de leurs effets et de leur criticité.

INTRODUCTION: Hemodialysis is a technique of extra-renal purification associated with high level of risk. The objective is to assess infectious risk during a hemodialysis session on hygiene around the patient in hospital. METHODS: An a priori risk assessment by Failure Modes, Effects and Criticality Analysis method (FMECA) was carried out from May to August 2018, in order to overview infectious risk during the process of hemodialysis in the Ibn Sina Hospital (Rabat, Morocco). RESULTS: Twenty eight failure modes were identified during the hemodialysis process around the patient: fourteen criticality level 1, ten level 2, and four level 3. A prevention plan has been drafted. Three of the four level 3 failure modes were reduced to level 1 and one to level 2. DISCUSSION: FMECA have enabled us to identify the potential risks, to reconsider certain procedures and to suggest measure matrix for the coverage of the most critical risks. CONCLUSION: This analysis makes it possible, through periodic evaluations, to enter a real quality approach, which reinforces the satisfaction of the patients as well as all the actors of the hemodialysis center.

[Corrigendum: The characteristics of the population covered by Compulsory Health Insurance (CMI) in Morocco]. / Corrigendum: Les caractéristiques de la population couverte par le régime de l'assurance maladie obligatoire au Maroc.

[This corrects the article DOI: 10.11604/pamj.2018.30.266.13209.][This corrects the article DOI: 10.11604/pamj.2018.30.266.13209.].

[Medical assistance in middle-income countries needs regulation to ensure its sustainability: Case of Morocco]. / Réguler l'aide médicale des pays à revenu intermédiaire : le cas du Maroc.

INTRODUCTION: The sustainability of medical assistance, considered necessary in middle-income countries, requires permanent regulation. In Morocco, the medical assistance scheme (MAS) is confronted with the lack of regulation tools and the difficulty of affixing these tools effectively in the absence of a regulator. In this sense, the shortcomings of the current practice of its regulation should be identified in order to recommend actions and tools to improve its implementation and guarantee its continuity. METHODS: The analysis and the proposed recommendations are based on the review of the available literature, the review of the legal texts framing the basic medical coverage and the analysis of the current practice of regulation of the MAS. RESULTS: The regulation of the MAS was not treated in the same way as the compulsory health insurance. There is no proper regulator as the case of the compulsory health insurance. In substance, the planned measures remain very insufficient and scattered between several actors and sometimes difficult to apply. Based on a reference framework designed along four axes (resources, expenditures, health care offer and population), the analysis identified fifteen actions and tools to correct deficiencies and support its sustainability. CONCLUSION: The proposed recommendations need a durable commitment from all the actors who must trigger as quickly as possible urgent actions to optimize the implementation of the medical assistance scheme and improve its perception in the citizen.

Reactive Oxygen Species-Mediated Apoptosis and Cytotoxicity of Newly Synthesized Pyridazin-3-Ones In P815 (Murin Mastocytoma) Cell Line.

BACKGROUND: In cancer cells, the intracellular antioxidant capacity and the redox homeostasis are mainly maintained by the glutathione- and thioredoxin-dependent systems which are considered as promising targets for anticancer drugs. Pyridazinones constitute an interesting source of heterocyclic compounds for drug discovery. The present investigation focused on studying the in-vitro antitumor activity of newly synthesized Pyridazin-3(2h)-ones derivatives against P815 (Murin mastocytoma) cell line. METHODS: The in-vitro cytotoxic activities were investigated toward the P815 cell line using tetrazolium-based MTT assay. Lipid peroxidation and the specific activities of antioxidant enzymes were also determined. RESULTS: The newly compounds had a selective dose-dependent cytotoxic effect without affecting normal cells (PBMCs). Apoptosis was further confirmed through the characteristic apoptotic morphological changes and DNA fragmentation. Two compounds (6F: and 7H: ) were highly cytotoxic and were submitted to extend biological testing to determine the likely mechanisms of their cytotoxicity. Results showed that these molecules may induce cytotoxicity via disturbing the redox homeostasis. Importantly, the anticancer activity of 6F: and 7H: could be due to the intracellular reactive oxygen species hypergeneration through significant loss of glutathione reductase and thioredoxin reductase activities. This eventually leads to oxidative stress-mediated P815 cell apoptosis. Furthermore, the co-administration of 6F: or 7H: with Methotrexate exhibited a synergistic cytotoxic effect. CONCLUSIONS: considering their significant anticancer activity and chemosensitivity, 6F: and 7H: may improve the therapeutic efficacy of the current treatment for cancer.

Ethyl 2-(4-benzyl-3-methyl-6-oxo-1,6-dihydropyridazin-1-yl)acetate: crystal structure and Hirshfeld surface analysis.

The title compound, C16H18N2O3, is constructed about a central oxopyridazinyl ring (r.m.s. deviation = 0.0047 Å), which is connected to an ethyl-acetate group at the N atom closest to the carbonyl group, and benzyl and methyl groups second furthest and furthest from the carbonyl group, respectively. An approximately orthogonal relationship exists between the oxopyridazinyl ring and the best plane through the ethyl-acetate group [dihedral angle = 77.48 (3)°]; the latter lies to one side of the central plane [the Nr-Nr-Cm-Cc (r = ring, m = methyl-ene, c = carbon-yl) torsion angle being 104.34 (9)°]. In the crystal, both H atoms of the N-bound methyl-ene group form methyl-ene-C-H⋯O(ring carbon-yl) or N(pyridazin-yl) inter-actions, resulting in the formation of a supra-molecular tape along the a-axis direction. The tapes are assembled into a three-dimensional architecture by methyl- and phenyl-C-H⋯O(ring carbon-yl) and phenyl-C-H⋯O(ester carbon-yl) inter-actions. The analysis of the calculated Hirshfeld surface indicates the dominance of H⋯H contacts to the overall surface (i.e. 52.2%). Reflecting other identified points of contact between mol-ecules noted above, O⋯H/H⋯O (23.3%), C⋯H/H⋯C (14.7%) and N⋯H/H⋯N (6.6%) contacts also make significant contributions to the surface.

[Corrigendum: The characteristics of the population covered by Compulsory Health Insurance (CMI) in Morocco]. / Corrigendum: Les caractéristiques de la population couverte par le régime de l'assurance maladie obligatoire au Maroc.

[This corrects the article DOI: 10.11604/pamj.2018.30.266.13209.][This corrects the article DOI: 10.11604/pamj.2018.30.266.13209.].

Cytotoxicity of new pyridazin-3(2H)-one derivatives orchestrating oxidative stress in human triple-negative breast cancer (MDA-MB-468).

Triple-negative breast cancer (TNBC) is a complex and aggressive subtype of breast cancer characterized by high morbidity and mortality. In the absence of targeted therapy, only chemotherapy is available in this case of cancer. The current study investigated the antitumor effect of new pyridazin-3(2H)-one derivatives on the human TNBC cell line, MD-MB-468. The in vitro cytotoxic activities were investigated using the tetrazolium-based MTT assay. Lipid peroxidation, H2 O2 content, and the specific activities of antioxidant enzymes were also determined. Two molecules, 6f and 7h, were found to be selectively highly active against tumor cells with IC50 values of 3.12 and 4.9 µM, respectively. Furthermore, cells exposed to 6f showed a significant increase in H2 O2 and lipid peroxidation levels, accompanied by a decrease in the enzyme activities of glutathione reductase (GR) and thioredoxin reductase (TrxR). The cytotoxicity of the compound 6f may improve the therapeutic efficacy of the current treatment for TNBC via the inhibition of GR and TrxR activities.

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review.

Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug rimonabant, difenamizole, an analgesic, betazole, a H2-receptor agonist and the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety. Owing to this diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This review highlights the different synthesis methods and the pharmacological properties of pyrazole derivatives. Studies on the synthesis and biological activity of pyrazole derivatives developed by many scientists around the globe are reported.

[The characteristics of the population covered by Compulsory Health Insurance (CMI) in Morocco]. / Les caractéristiques de la population couverte par le régime de l'assurance maladie obligatoire au Maroc.

Introduction: in Morocco, Compulsory Medical Insurance (CMI) entered into force in 2005. Insurance first covered health expenses of employees in public and private sectors, then of students. It was gradually expanded to independent workers. This study aims to determine the profile of the population covered by CMI in Morocco. Methods: We conducted a descriptive study of the population covered by CMI based on data collected from the National Health Insurance Agency in Morocco and from the Health Insurance funds. Results: A total of 8.428.218 persons were covered by CMI at the end of 2014, reflecting a rate of 34% of the general population. People having long duration disease (LDD) did not exceed 2.78% of the population covered by CMI. Active insured accounted for 81% of the population covered. In the private sector, gross salary of active affiliates ranged, on average, between $ 140 and $ 500 per month while gross salary pensions was less $280 per month. In the public sector, gross salary of active affiliates ranged, on average, between $ 280 and $ 825 per month while gross salary pensions ranged between $ 140 and $ 500 per month. Conclusion: Knowledge of the characteristics of the population covered by Compulsory Health Insurance in Morocco is necessary to ensure regulation and sustainability in the insurance sector.

[For sustainable financing of the Medical Assistance scheme in Morocco]. / Pour un financement pérenne du Régime d'assistance médicale au Maroc

INTRODUCTION: Five years after its implementation, the Medical Assistance scheme (Ramed) has been able to cover more than eleven million people. Nevertheless, its financing remains the main challenge. Its initial financial structure was exceeded after its implementation. A reconfiguration of the financial package has become a necessity in order to guarantee sustainable financing. METHODS: A review of the literature and a situational analysis through disseminated reports and documents made it possible to identify the initial financial package and its limits in order to design a new financial package. RESULTS: The current financing is out of step with the regulations, which has a negative impact on it. Funds are insufficient to cover needs and do not even exceed half of the planned funding, set at three billion dirhams, due to a partial collection of resources. In order to meet the needs of the beneficiaries and follow their growing rhythm, at least 4 billion dirhams annually must be collected. This amount can only be ensured with a revision of the contributions of the State and local authorities. CONCLUSION: The current funds do not meet the needs, which undermines the social acceptability of the regime and threatens its sustainability. It is essential to improve its funding through a diversity of resources and more commitment from stakeholders to ensure sustainable funding managed according to the principles of good governance.

New Pyrazole-Hydrazone Derivatives: X-ray Analysis, Molecular Structure Investigation via Density Functional Theory (DFT) and Their High In-Situ Catecholase Activity.

The development of low-cost catalytic systems that mimic the activity of tyrosinase enzymes (Catechol oxidase) is of great promise for future biochemistry technologic demands. Herein, we report the synthesis of new biomolecules systems based on hydrazone derivatives containing a pyrazole moiety (L1-L6) with superior catecholase activity. Crystal structures of L1 and L2 biomolecules were determined by X-ray single crystal diffraction (XRD). Optimized geometrical parameters were calculated by density functional theory (DFT) at B3LYP/6-31G (d, p) level and were found to be in good agreement with single crystal XRD data. Copper (II) complexes of the compounds (L1-L6), generated in-situ, were investigated for their catalytic activities towards the oxidation reaction of catechol to ortho-quinone with the atmospheric dioxygen, in an attempt to model the activity of the copper containing enzyme tyrosinase. The studies showed that the activities depend on four parameters: the nature of the ligand, the nature of counter anion, the nature of solvent and the concentration of ligand. The Cu(II)-ligands, given here, present the highest catalytic activity (72.920 µmol·L-1·min-1) among the catalysts recently reported in the existing literature.

Docking analysis of verteporfin with YAP WW domain.

The YAP oncogene is a known cancer target. Therefore, it is of interest to understand the molecular docking interaction of verteporfin (a derivative of benzo-porphyrin) with the WW domain of YAP (clinically used for photo-dynamic therapy in macular degeneration) as a potential WW domain-ligand modulator by inhibition. A homology protein SWISS MODEL of the human YAP protein was constructed to dock (using AutoDock vina) with the PubChem verteporfin structure for interaction analysis. The docking result shows the possibilities of verteporfin interaction with the oncogenic transcription cofactor YAP having WW1 and WW2 domains. Thus, the ability of verteporfin to bind with the YAP WW domain having modulator activity is implied in this analysis.

Assessment of iodine concentration in dietary salt at household level in Morocco.

BACKGROUND: Following WHO recommendations, Morocco adopted in 1995 the universal salt iodization (USI) as a strategy to prevent and control iodine deficiency disorders. In 2009, the standard salt iodine concentration was adjusted to 15-40 mg/kg. The success of USI for the control of iodine deficiency disorders requires an evaluation of iodine concentration in salt prior to assessing the iodine nutritional status of a population. METHODS: In our study we refer to the anterior studies that were made in Morocco in 1993 and 1998. 178 salt samples from households were tested for iodine using spot-testing kits. The iodometric titration method was used to analyze accurately the concentration of iodine in the 178 household salt samples. An empiric polling method was adopted, using a non-probability sampling method; across the different twelve regions in the country. RESULTS: The median and interquartile range iodine concentration in salt was 2.9 mg/kg (IQR: 2.4-3.7). The results show that only 25 % of households use iodized salt. The recommended iodine concentration in salt of 15-40 mg/kg was met only in 4.5 % of salt samples. The bulk salt is used by 8 % of households. All samples of this bulk salt were found in rural areas. According to nonparametric appropriate tests used, there is no significant difference in iodine concentrations between regions, between urban and rural areas and between packaged and bulk salt. CONCLUSIONS: Two decades since introducing legislation on Universal Salt Iodization, our survey shows that generalization of iodized salt is far from being reached. In 2015, only a quarter of Moroccan households use the iodized salt and only 4.5 % of salt is in conformity with regulations. The use of bulk salt by households in rural areas constitutes a major obstacle to the success of USI. The National Iodine Deficiency Disorders Control Program can only be achieved if an internal follow-up and a control of external quality of program is put in place.

[Legislation on the pharmaceutical industry in Morocco during the French protectorate 1912 - 1956]. / La législation sur l'industrie pharmaceutique au Maroc durant le Protectorat français 1912-1956.

In Morocco, the pharmaceutical industry was born with the French protectorate. She knew a great evolution: from a limited production for local needs, it became an important activity, organized to export pharmaceutical patent medicines. This article revisits the birth and history of this industry during the protectorate. It refers to the situation at the time by listing some examples of active establishments and some specialities marketed. It also aims to increase knowledge about the industry and provides an overview of the situation of practitioners remembering the texts governing the profession. Based on the available literature, we examined and analyzed the arrangements related to the establishment, organization and evolution of the pharmaceutical industry.