Identification of the new progress on Pyrazole Derivatives Molecules as Antimicrobial and Antifungal Agents.

Microbial infections remain a worldwide leading cause of death, despite the evolution of a large number of new antibiotics every year. Currently, several bacteria have developed resistance against antibiotics drugs which remain a major issue in antibiotics drug discovery. This review provides detailed information about antimicrobial and antifungal agent synthesis belonging to the pyrazoles scaffold. We reassemble the results obtained from several studies to characterize the importance of heteroatom nuclei in many synthetic products. Additionally, several compounds based on pyrazole derivatives such as benzimidazole, benzothiazole, indole, acridine, oxadiazole, imidazole, isoxazole, pyrazole, triazole, quinoline and quinazoline including other pyrazole containing drugs such as pyridazine, pyridine and pyrimidine are highlighted. Furthermore, you will find in this review 134 best promise structures collected from recent studies, relating the pyrazoles structures to the relevant biological activities, in particular, antimicrobial and antifungal one.

Les infections microbiennes restent une des principales causes de décès dans le monde, malgré l'évolution d'un grand nombre de nouveaux antibiotiques chaque année. Actuellement, plusieurs bactéries ont développé une résistance aux médicaments antibiotiques, ce qui reste un problème majeur dans la découverte de médicaments antibiotiques. Cette revue fournit des informations détaillées sur la synthèse d'agents antimicrobiens et antifongiques appartenant à l'échafaudage des pyrazoles. Nous rassemblons les résultats obtenus à partir de plusieurs études pour caractériser l'importance des noyaux d'hétéroatomes dans de nombreux produits synthétiques. En outre, plusieurs composés basés sur des dérivés du pyrazole tels que le benzimidazole, le benzothiazole, l'indole, l'acridine, l'oxadiazole, l'imidazole, l'isoxazole, le pyrazole, le triazole, la quinoléine et la quinazoline, ainsi que d'autres médicaments contenant du pyrazole comme la pyridazine, la pyridine et la pyrimidine, sont mis en évidence. En outre, vous trouverez dans cette revue 134 structures les plus prometteuses recueillies dans des études récentes, mettant en relation les structures des pyrazoles avec les activités biologiques pertinentes, en particulier antimicrobiennes et antifongiques. Mots-clés: Dérivés de pyrazoles ; antibiotiques ; activité antifongique; résistance microbienne, azote hétérocyclique.

Identification Des Nouveaux Progrès Sur Les Molécules Dérivées Du Pyrazole Comme AgentsAntimicrobiens Et Antifongiques

Microbial infections remain a worldwide leading cause of death,despite the evolution of a large number of new antibiotics everyyear. Currently, several bacteria have developed resistanceagainst antibiotics drugs which remain a major issue inantibiotics drug discovery. This review provides detailedinformation about antimicrobial and antifungal agent synthesisbelonging to the pyrazoles scaffold. We reassemble the resultsobtained from several studies to characterize the importance ofheteroatom nuclei in many synthetic products. Additionally,several compounds based on pyrazole derivatives such asbenzimidazole, benzothiazole, indole, acridine, oxadiazole,imidazole, isoxazole, pyrazole, triazole, quinoline and quinazolineincluding other pyrazole containing drugs such as pyridazine,pyridine and pyrimidine are highlighted. Furthermore, you willfind in this review 134 best promise structures collected fromrecent studies, relating the pyrazoles structures to the relevantbiological activities, in particular, antimicrobial and antifungalone.

[Moroccan pharmacy students' knowledge and perceptions about pharmacovigilance]. / Connaissances et perception de la pharmacovigilance par les futurs pharmaciens marocains.

OBJECTIVE: The aim of this study was to evaluate the impact of an educational work groups on the knowledge and perception of 2nd year pharmacist students towards pharmacovigilance in a moroccan faculty of medicine and pharmacy. METHOD: A descriptive study conducted in pharmacology laboratory of the faculty of medicine and pharmacy of Rabat on 2nd year pharmacist students, to assess their knowledge and perception towards PV via questionnaire before and after an educational work groups. RESULTS: Among the 122 invited students, 108 responded to the questionnaire distributed before working group with a participation rate of 88,5 %. This rate increased to 95,9 % (n=117) after work groups sessions. Pre-work groups, students showed an overall low knowledge, where only 27.7 % knew the ADRs reporting sheet. In addition, most students were not well prepared to report ADR in their future practice (n=82, 75.92 %). Work groups partially offsetting this deficit, and helped to better explain to the students the reporting system. Resulting in only 28 participants maintained their declaration of inability to report ADR in their future practice (25.92 %). On the other hand, students showed a favorable perception. CONCLUSION: In this study, students expressed the desire to learn more about PV during their university education. This result led to the introduction of a system of PV working groups for 3rd and 4th year pharmacy students for the 2018-2019 academic year.

Réévaluation clinico-biologique de l'antibiothérapie probabiliste en réanimation des brules.

Bacterial resistance is a major concern and the proper use of antibiotics is a global public health priority. Inappropriate use of antibiotic therapy can have serious ecological and pharmaco-economic consequences. The objective of our work was to study the reevaluation of probabilistic antibiotherapy in the burns intensive care unit. A prospective study concerning the clinical-biological reassessment of antibiotic therapy was set up in the burns intensive care unit at the Military Hospital Instruction Mohammed V of Rabat. The data was collected over a period of 6 months, from June 1, 2017 to November 30, 2017. During the study period, 142 patients received an antibiotic prescription. Only 68 serious hospitalized septic patients were included in our study. The population was predominantly male (75%). The average age of our patients was 36 years, ranging from 15 to 56 years old. The average length of hospitalization in intensive care was 10 days. Of the 68 antibiotic regimens implemented, the reassessment rate was 72.06%, with 75% justified treatment rates, and 25% not justified. Therapeutic de-escalation was performed in 8 cases (11.76%), when it could have been performed 25 times (36.76%). This is justified by the nosocomial context of the burns intensive care unit with a bacterial ecosystem of BMR type (Klebsiella pneumoniae, Acinetobacter baumanii, Escherichia coli and Staphylococcus coagulase negative), which restricts the choice of antibiotic therapy to some molecules. Clinico-biological re-evaluation of antibiotic therapy is essential to fight the misuse of antibiotics. This study allowed us to evaluate the re-evaluation practices of antibiotic therapy at 48-72h in burns resuscitation. Subsequently, several actions were carried out: the appointment of a pharmacist in antibiotherapy within the Pole Pharmacy of the Mohammed V Military Hospital in Rabat, the activation of an Anti-Infectious Committee and the dispensing of antibiotics via Pyxis MedStation.

Analysis of the drug formulary and the purchasing process at a Moroccan university medical center.

AIM: To give an overview of the pharmaceutical policy in the largest medical center in Morocco, a developing country in socio-economic transition. METHODS: This is an analytical descriptive study of the drug formulary and the purchasing process carried out at the Ibn Sina University Medical Center. RESULTS: Our formulary included 830 drugs belonging to 14 classes according to the Anatomical, Therapeutic and Chemical (ATC) Classification System. There was a respective predominance of class N (21.8%), class B (13.5%), and class J (12.6%). Injectable route was dominant (46%). Drugs had a significant actual benefit in 70% (according to the French Data), reimbursable in 42.8%, essential in 29.2% according to World Health Organization (WHO) list, and in 36.9% according to the Moroccan list. The calls for tenders included 542 drugs representing 65% of the formulary, and the attribution rate was 71%. The main reason for non-attribution was the lack of offers. Generics accounted for 45% by volume and 26.5% by value. CONCLUSION: With this first study, we were able to identify key indicators on drugs used in the largest medical center in Morocco. The current challenge is to introduce pharmacoeconomics in decision making concerning the updates of the drug formulary.

Multivariate statistical process control in product quality review assessment - A case study.

According to the Food and Drug Administration and the European Good Manufacturing Practices (GMP) guidelines, Annual Product Review (APR) is a mandatory requirement in GMP. It consists of evaluating a large collection of qualitative or quantitative data in order to verify the consistency of an existing process. According to the Code of Federal Regulation Part 11 (21 CFR 211.180), all finished products should be reviewed annually for the quality standards to determine the need of any change in specification or manufacturing of drug products. Conventional Statistical Process Control (SPC) evaluates the pharmaceutical production process by examining only the effect of a single factor at the time using a Shewhart's chart. It neglects to take into account the interaction between the variables. In order to overcome this issue, Multivariate Statistical Process Control (MSPC) can be used. Our case study concerns an APR assessment, where 164 historical batches containing six active ingredients, manufactured in Morocco, were collected during one year. Each batch has been checked by assaying the six active ingredients by High Performance Liquid Chromatography according to European Pharmacopoeia monographs. The data matrix was evaluated both by SPC and MSPC. The SPC indicated that all batches are under control, while the MSPC, based on Principal Component Analysis (PCA), for the data being either autoscaled or robust scaled, showed four and seven batches, respectively, out of the Hotelling T2 95% ellipse. Also, an improvement of the capability of the process is observed without the most extreme batches. The MSPC can be used for monitoring subtle changes in the manufacturing process during an APR assessment.

Azithromycin assay in drug formulations: Validation of a HPTLC method with a quadratic polynomial calibration model using the accuracy profile approach.

Many different assaying high performance thin layer chromatography (HPTLC) methods have been developed and validated in order to be used in routine analysis in different analytical fields. Validation often starts by the evaluation of the linearity of the calibration curve. Frequently, if the correlation coefficient is close to one, the linear calibration curve model is considered to be proper to predict the unknown concentration in the sample. But is this simple model effective to assess the behavior of the response of an HPTLC method as a function of concentration. To answer this question, a method for the determination of azithromycin by HPTLC has been developed and validated following both the classical approach and that based on the accuracy profile. Silica gel plates with fluorescence indicator F254 and chloroform - ethanol - 25% ammonia 6:14:0.2 (v/v/v) as mobile phase were used. Analysis was carried out in reflectance mode at 483nm. The RF of azithromycin was 0.53. The validation based on the classical approach, shows that the behavior is not linear, even though r2=0.999 because the lack of fit test is significant (P<0.05). Validation based on the accuracy profile approach considering both the straight line and the quadratic regression model, show that the former results is a ß-expectation tolerance interval outside the acceptance limits, while with the latter, this interval is within the limits of ±5% acceptability for a range which extends from 0.2 to 1.0µg/zone. With the quadratic model, the method showed to be precise and accurate.

Synthesis, antioxidant and analgesic activities of Schiff bases of 4-amino-1,2,4-triazole derivatives containing a pyrazole moiety.

A series of Schiff bases of 4-amino-1,2,4-triazole derivatives containing pyrazole (5a-h) were synthesized from condensation of 4-amino-5-(5-methyl-1H-pyrazol-3-yl)-4H-1,2,4-triazole-3-thiol (3) derivative with various aromatic aldehydes (4a-h). The structures of the synthesized compounds were elucidated by IR, 1H NMR, 13C NMR, and mass spectrometry. All the synthesized compounds (5a-h) were screened for their in vivo analgesic and in vitro antioxidant activities revealing significant analgesic and antioxidant properties.

[Fluoride content in well water in rural areas in Morocco]. / Teneur en fluorures des eaux de puits des régions rurales au Maroc.

The aim of our study was to determine fluorides (F-) content in the well water consumed as drinking water by some Moroccan populations in rural areas. All samples were collected between April and October 2011. Measurements were performed by an ion selective electrode. Thirty wells spread to cover most of the country and locally chosen based on the number of inhabitants who consume its water. All wells were in rural areas. The mean (+/- SD) of F- was 1.84 +/- 1.6 mg/L with a range from 0.42 to 8.95 mg/L Concentrations of F- in phosphate regions were higher than those found in other regions. More than half of the samples exceeded the current standard. Our study showed that water of some Moroccan regions is naturally rich in F-exposing people who consume it at high risk of fluorosis.

Development and validation of a reversed-phase HPLC method for simultaneous analysis of butylhydroxyanisol, simvastatin and its impurities in tablet dosage forms.

A simple, rapid, and sensitive RP-HPLC method using photodiode array detection was developed and validated for the simultaneous determination of butylhydroxyanisol and simvastatin with its impurities in tablet forms. Chromatographic separation was achieved on a Phenomenex Hypersil (250×4.6 mm, 5 µm) column using the mobile phase acetonitrile-sodium acetate (12 mM) buffered to 4.2 with glacial acetic acid. The flow rate was 1.7 mL/min, and the UV detection were made at 238 nm for simvastatin and its impurities and at 290 nm for butylhydroxyanisol. The system suitability solution used for peak impurity identification was generated in-situ without use of any impurity reference standard. The method was validated according to ICH Q2(R1) guidelines, and the acceptance criteria for accuracy, precision, linearity, specificity, robustness, LOD, and LOQ, were met in all cases. Moreover, the reproducibility results obtained by 22 Official Medicines Control Laboratories (OMCL) of European Directorate were satisfactory. The compounds selected for impurity validation were based on those found during long term and accelerate stability studies carried out on several formulation tablets from Moroccan and other markets. The described method was robust and successfully applied in quality control laboratories for routine analysis to determine the butylhydroxyanisol and simvastatin with its impurities content in tablet dosage forms.

[In vitro comparative study of plasma protein binding of 99mTc-DTPA used in renal scintigraphy]. / Étude comparative de l'estimation in vitro de la fixation plasmatique du 99mTc-DTPA utilisé en scintigraphie rénale.

The radiopharmaceutical (99m)Tc-DTPA (diethylene-triamine-pentaacetic acid) is a tracer widely used in renal scintigraphy to assess glomerular filtration rate. The estimation of protein binding is very important due to its impact on clinical parameters biodistribution since only the free fraction is filtered by the kidney. A number of laboratory techniques have been developed to study protein binding. Precipitation and ultrafiltration are the mostly used techniques in pharmacology for studies of the binding between proteins and small molecules. The aim of this work is to apply and compare those two analytical methods in (99m)Tc-DTPA protein binding determination in vitro before in vivo application. The results obtained by precipitation with trichloroacetic acid are not enough reproducible, while those obtained by ultrafiltration seem more consistent and reproducible.

[Medicines and breastfeeding: assessing the risk of medicines to infants]. / Médicaments et allaitement maternel: evaluation du risque médicamenteux chez le nourrisson.

Milk, in addition to its undeniable nutritional and immunological benefits, is an important element for the development of the infant. Warnings, sometimes exaggerated, may prevent the mother and child from enjoying the benefits of both breastfeeding and appropriate medication. This approach is justified by the total absence of investigations on the excretion of drugs in breast milk during clinical trials. The actual risk was evaluated by several classifications; an estimate of the passage of drugs into milk and estimation of infant exposure to the drug are possible and can provide a reliable indicator to better judge the risk to the infant. Generally we are faced with two different situations: a new treatment during lactation or maintenance treatment already prescribed during pregnancy. If treatment needs to be prescribed for a long period of breastfeeding, a strategic approach is required.

Medicines and breastfeeding: assessing the risk of medicines to infants

Milk, in addition to its undeniable nutritional and immunological benefits, is an important element for the development of the infant. Warnings, sometimes exaggerated, may prevent the mother and child from enjoying the benefits of both breastfeeding and appropriate medication. This approach is justified by the total absence of investigations on the excretion of drugs in breast milk during clinical trials. The actual risk was evaluated by several classifications; an estimate of the passage of drugs into milk and estimation of infant exposure to the drug are possible and can provide a reliable indicator to better judge the risk to the infant generally we are faced with two different situations: a new treatment during lactation or maintenance treatment already prescribed during pregnancy. If treatment needs to be prescribed for a long period of breastfeeding, a strategic approach is required

[Determination of fluoride in toothpastes marketed in Morocco using a fluoride-selective electrode]. / Détermination des teneurs en fluor dans les pâtes dentifrices commercialisées au Maroc par électrode sélective au fluor.

INTRODUCTION: Dental caries represents a problem of public health in Morocco and the reduction of this pathology is a priority of the Ministry of Health. The use of fluoride toothpastes is, at present, recognized as being an effective means for the prevention of dental caries. MATERIAL AND METHODS: [corrected] The aim of our study was to verify the correspondence of the information marked on packagings with the international standards, but also to determine using potentiometry the quantity of fluorine presents in toothpastes marketed in Morocco from three origins: pharmacies, hypermarkets and ambulant sellers. RESULTS: The study concerned 56 toothpastes, 73.2% of toothpastes respect the standards of the concerning WHO dates of manufacturing and lapsing. The type of fluoride was specified only on 67.8% of packagings and the used concentration of fluoride was indicated only in 62.5% of the tested samples. For 56 studied toothpastes, the results revealed that if we take into account standards recommended by the WHO and the European Union, only 57.1% of toothpastes could have an effect dental caries. CONCLUSION: The results of this study show that there is a real need of quality control of fluoride toothpastes sold in Morocco especially those of the itinerant market.

Trends in antihypertensives use among Moroccan patients.

PURPOSE: In this study, we analyzed the consumption trends of antihypertensives in Morocco during the 1991-2010 period and the impacts after the institution of Mandatory Health Insurance and the marketing of generic drugs. METHODS: We used sales data from the Moroccan subsidiary of IMS Health "Intercontinental Marketing Service". The consumption volumes were converted into defined daily doses (DDDs). RESULTS: Between 1991 and 2010, outpatient consumption of antihypertensives went from 4.37 to 23.14 DDD/1000 inhabitants/day, a 5.30-fold increase. In 2010, calcium channel blockers (CCBs) and angiotensin converting enzyme inhibitors (ACEI) were the most consumed (4.97 DDD/1000 inhabitants/day) for each one, followed by diuretics (4.20 DDD/1000 inhabitants/day). The most consumed products were amlodipine (4.27 DDD/1000 inhabitants/day) followed by ramipril (3.18 DDD/1000 inhabitants /day) and indapamide (1.72 DDD/1000inhabitants/day). Between 1991 and 2010, the consumption of generic antihypertensives went from 2% to 46%. CONCLUSION: Antihypertensive consumption increased between 1991 and 2010. However, despite the increase of generic drugs consumption, the levels of antihypertensive consumption remain lower than the needs of hypertensive patients.

[Anti-inflammatory activity of aqueous and ethanolic extracts of Zygophyllum gaetulum]. / Activité anti-inflammatoire des extraits aqueux et éthanolique de Zygophyllum gaetulum.

Zygophylle or Zygophyllum gaetulum Emberger and. Maire is a Moroccan medicinal plant which has been used as an anti-inflammatory, antidiabetic, antispasmodic and antidiarrheic. The present study was carried out to study and compare the anti-inflammatory effect of ethanolic extract with aqueous extract of Z. gaetulum. Organic extract of Z. gaetulum was obtained in soxhlet apparatus. Aqueous extract was obtained by infusion. The Wistar albinos rats of either sex weighing 200-300 g aged 2-3 months were used for this experiment. The rats were housed under standard environmental conditions. The anti-inflammatory activity was estimated by measuring the oedema induced by carragenin according to the method of Winter and al. Ethanolic extract of Z. gaetulum reduced the increase of the paw volume with a percentage of inhibition of 46% (p<0.01), this percentage was 47.48% (p<0.01) with aqueous extract. The inhibition decrease in time, it arrived to 39% (p<0.01) at the sixth hour while the activity of aqueous extract decrease a lot. In conclusion, Z. gaetulum is an interesting plant which the aqueous and éthanolic extracts could be used scientifically in the treatment of inflammation.

[Pharmacoepidemiolgy: regulatory basis, methodological approaches and scope]. / La pharmacoépidémiologie: bases réglementaires, approches méthodologiques et champ d'application.

Pharmacoepidemiology is a discipline that studies the use of drugs and evaluation of their beneficial or adverse effects on large populations. It requires compliance with laws and maintaining a regulatory approach in order to ensure confidentiality and protection of personal data. It also requires good knowledge of drugs and diseases and the use of the different available data sources. Pharmacoepidemiology incorporates epidemiological methods (cohort, case-control and cross-sectional studies) where the exposure is drug intake. These methods must be applied at the conception of the pharmacoepidemiological study in order to minimize the effect of bias hich can lead to false conclusions. This paper reviews the regulatory basis, methodological approaches and scope of pharmacoepidemiology.

Pharmacoepidemiology: regulatory basis, methodological approaches and scope

Pharmacoepidemiology is a discipline that studies the use of drugs and evaluation of their beneficial or adverse effects on large populations. It requires compliance with laws and maintaining a regulatory approach in order to ensure confidentiality and protection of personal data. It also requires good knowledge of drugs and diseases and the use of the different available data sources. Pharmacoepidemiology incorporates epidemiological methods [cohort, case-control and cross-sectional studies] where the exposure is drug intake. These methods must be applied at the conception of the pharmacoepidemiological study in order to minimize the effect of bias hich can lead to false conclusions. This paper reviews the regulatory basis, methodological approaches and scope of pharmacoepidemiology

Quality of chloroquine tablets available in Africa.

Malaria is the biggest killer of African children, yet it is cheaply preventable and curable with insecticides spraying, impregnated bednets and effective drugs. This study aimed to evaluate the quality of Chloroquine (CQ) tablets available in selected African countries. Twenty-six samples of antimalarial CQ tablet of 100, 150 and 250 mg were collected from 12 African countries and evaluated for their quality in the Drugs Quality Control Laboratory of Rabat, Morocco. The identification and dosage of active pharmaceutical ingredients in the tablets, dissolution rate, hardness and the friability of CQ tablets were performed according to the United States Pharmacopeia (USP) and European Pharmacopoeia (Eur.Ph.) recommended methods. The results showed that 7·7% of the sampled CQ tablets available in Burkina Faso were of low quality. Failure in dissolution profile was found in 50% of CQ tablets sampled from Benin, Burkina Faso, Comoros Union, Mali and Senegal. The findings showed poor quality of CQ tablets available in the African market. This problem may affect the efforts to control malaria in Africa. Efficient regulatory systems of drugs quality control should be implemented.

Determination of binary polymorphic mixtures of fluconazole using near infrared spectroscopy and X-ray powder diffraction: a comparative study based on the pre-validation stage results.

The aim of the present study was to develop near infrared (NIR) and X-ray powder diffraction methods (XRPD) able to determine pure crystalline form II of fluconazole in a binary polymorphic mixtures containing forms II and III. In order to give a first performance estimation of both methods, these latters were pre-validated using accuracy profiles, a statistical approach based on ß-expectation tolerance intervals. Both methods showed a good trueness, precision and accuracy and their ß-expectation tolerance intervals were fully included within the acceptance limits. The comparative study was carried out using statistical analysis based on the work of Bland and Altman. A good agreement between the two methods was demonstrated indicating the interchangeability of NIR method with XRPD method.