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Ultratrail running is a sport with growing number of adherents. To complete ultratrail despite physical issues such as joint and muscle pain, many runners use nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. Studies asking participants about their consumption of drugs during ultratrail revealed a prevalence of NSAIDs and acetaminophen up to 70% and 25%, respectively. The aims of the present study were to determine the prevalence of NSAIDs and acetaminophen for 81 runners during the 2021 Ultratrail du Mont Blanc® (UTMB®) using direct analysis of dried blood spots (DBS) and oral fluid (OF) and to compare results with the declaration of consumption by runners; this is to identify the most relevant method to study the prevalence of drugs. Our results show a prevalence of NSAIDs of 46.6% using DBS, 18.5% using OF, and 13.8% based on a questionnaire. Prevalence of acetaminophen were 30.1%, 30.9%, and 22.5% using DBS, OF, and questionnaire, respectively. From this study, we conclude that the analysis of drugs directly in DBS is the most relevant tool to determine the prevalence in ultratrail events.

The aim of this study was to investigate the molecular features and the antibiotic resistance profile of 98 clinical Staphylococcus aureus isolates collected during 6 months in two hospitals of Kabul, Afghanistan. For all isolates, antimicrobial resistance patterns were determined by the disc diffusion method (including methicillin resistance which was detected using cefoxitin). The presence of the mecA/mecC genes was detected by PCR. Strains were then extensively characterized using microarray analysis. Of the 98 S. aureus isolates, methicillin-resistant S. aureus (MRSA) prevalence was high at 66.3%. Antibiotic susceptibility testing also revealed a high resistance rate to penicillin (100%), erythromycin (66.3%), ciprofloxacin (55.1%), and cotrimoxazole (40.8%). Resistance to tobramycin was detected in 25.5%, to gentamicin in 16.3%, to chloramphenicol in 34.7%, and to doxycycline in 23.5% of the isolates. All the MRSA isolates were mecA-positive and none of them harbored mecC. Isolates were grouped into twelve clonal complexes and twenty-seven distinct clones. The most frequently detected clones were the Southwest Pacific clone (CC30-MRSA-IV PVL+) (21/65 MRSA, 32.3%), the CC22-MRSA-IV TSST-1+ clone (11/65 MRSA, 16.9%), and the Bengal Bay clone (ST772-MRSA-V PVL+) (11/65 MRSA, 16.9%). The PVL genes were found in 59.2% (46/65 MRSA and 12/33 methicillin-susceptible S. aureus, MSSA) and tst1 gene in 16.3% of isolates. This molecular study highlights the high prevalence of MRSA and the large genetic diversity of the S. aureus isolates circulating and detected in two hospitals of Kabul, with the presence of multiple virulence and antibiotic resistance genes.

The different branches of kynurenine pathways of tryptophan metabolism are the important mechanism to elucidate various neurological and immunological disorders. There is a substantial body of evidence indicating the involvement of kynurenine pathway (KP) in the pathophysiology of some neuropsychiatric and neurodegenerative perturbation. This pathway generates neuro-active compounds, those can interact with neurotransmitters receptors in the central nervous system (CNS). According to some recent studies, there are a strong relation between KP’s related enzymes such as indoleamine 2,3 dioxygenase (IDO) and tryptophan 2,3 dioxygenase (TDO) activation and neurological disease. In this review article, we focus on the level/ratios of different metabolites and precursors such as tryptophan (TRP), 5-hydroxytryptamine (5-HT), kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QUIN) in order to find the link with the KP-induced neuropathologies. Kynurenine metabolism is hypothesized to be one of the key mechanisms that link inflammation and depression. Some factors such as exercise (through PGC-1α), inflammation, stress, and some medication have the remarkable effects on KP. We highlight the role of different causes such as inflammation and stress, Tryptophan-kynurenine pathway with the whole biochemical and organ-specific biochemistry, and the neuropathomechanism of related pathologies. Here, we discuss the relations, the changes, and the mutual effects of KP with major depressive disorders, bipolar disorders, schizophrenia, Parkinson’s, and Alzheimer’s disease.

The aim of this study was to investigate the molecular features and the antibiotic resistance profile of 98 clinical Staphylococcus aureus isolates collected during 6 months in two hospitals of Kabul, Afghanistan. For all isolates, antimicrobial resistance patterns were determined by the disc diffusion method (including methicillin resistance which was detected using cefoxitin). The presence of the mecA/mecC genes was detected by PCR. Strains were then extensively characterized using microarray analysis. Of the 98 S. aureus isolates, methicillin-resistant S. aureus (MRSA) prevalence was high at 66.3%. Antibiotic susceptibility testing also revealed a high resistance rate to penicillin (100%), erythromycin (66.3%), ciprofloxacin (55.1%), and cotrimoxazole (40.8%). Resistance to tobramycin was detected in 25.5%, to gentamicin in 16.3%, to chloramphenicol in 34.7%, and to doxycycline in 23.5% of the isolates. All the MRSA isolates were mecA-positive and none of them harbored mecC. Isolates were grouped into twelve clonal complexes and twenty-seven distinct clones. The most frequently detected clones were the Southwest Pacific clone (CC30-MRSA-IV PVL+) (21/65 MRSA, 32.3%), the CC22-MRSA-IV TSST-1+ clone (11/65 MRSA, 16.9%), and the Bengal Bay clone (ST772-MRSA-V PVL+) (11/65 MRSA, 16.9%). The PVL genes were found in 59.2% (46/65 MRSA and 12/33 methicillin-susceptible S. aureus, MSSA) and tst1 gene in 16.3% of isolates. This molecular study highlights the high prevalence of MRSA and the large genetic diversity of the S. aureus isolates circulating and detected in two hospitals of Kabul, with the presence of multiple virulence and antibiotic resistance genes.

Aim Fluoxetine, one of the first newer SSRI antidepressant, is an extremely popular treatment for depression that could improve mental health problems. Many recent studies have suggested that SSRI have potential beneficial effects on skeletal muscle tissue. Main method We evaluated the potential beneficial effects of oral fluoxetine (18 mg/kg/day for 6 weeks) on muscle performance, after 6 weeks of physical exercise on treadmill. Male mice were randomly assigned to four groups (n = 12 per group) for treatment. Each group received treatment with following specifications: 1) no exercise with vehicle treatment (SED-S); 2) no exercise with fluoxetine treatment (SED-F); 3) exercise with vehicle treatment (EX-S); and 4) exercise with fluoxetine treatment (EX-F). Exercise performances were assessed based on the exhaustive running time and forelimb grip strength, anxious behavior by elevated plus-maze and open-field tests. Mitochondrial enzymes activity and ROS production were measured in the gastrocnemius and soleus muscles. Key finding Fluoxetine treatment had a significant effect on maximal aerobic capacity in mice without exercise, but more significant effects on gripping strength and anxiety when combined with exercise training, e.g. increased strength and decreased anxiety. Significance Fluoxetine treatment and exercise stimulation also had synergistic effects on strength and increased mitochondrial activity, cellular oxidative and antioxidant capacity in two different muscles.

Indomethacin has a high anti-inflammatory potential and an acceptable efficiency for external application. However, indomethacin can cause several side effects. It is crucial to reduce the employed indomethacin dosage and accordingly associated side effects. Therefore, topical delivery of indomethacin is as an interesting strategy. Thus, we designed poly (e-caprolactone) based nanoparticles loaded with the Nigella Sativa L. Seeds Essential Oil (NSSEO) and indomethacin to enhance analgesic and anti-inflammatory effects of indomethacin. Nanoparticles were prepared by nanoprecipitation method. Prepared nanoparticles pre-stability study was also carried out. Nanoparticles size was ranged between 230 nm and 260 nm and zeta potential of nanoparticles was between – 20 mV and – 30 mV at pH around 6. Encapsulation efficiency of indomethacin and NSSEO within nanoparticles was respectively 70% and 84% while drug loading of indomethacin and NSSEO were 14% and 5.63% respectively. The size and zeta potential of nanoparticles was not changed significantly within 30 days of pre-stability investigation. Nanoparticles had a size in nano scale with round shape and a proper stability. Indomethacin and NSSEO were successfully encapsulated that would boost the anti-inflammatory and analgesic effects of indomethacin.

This work focused on the preparation of polycaprolactone based nanoparticles containing indomethacin to provide topical analgesic and anti-inflammatory effect for symptomatic treatment of inflammatory diseases. Indomethacin loaded nanoparticles are prepared for topical application to decrease indomethacin side effects and administration frequency. Oppositely to already reported works, in this research non-invasive method has been used for the enhancement of indomethacin dermal drug penetration. Ex-vivo skin penetration study was carried out on fresh human skin. Nanoprecipitation was used to prepare nanoparticles. Nanoparticles were characterized using numerous techniques; dynamic light scattering, SEM, TEM, DSC and FTIR. Regarding ex-vivo skin penetration of nanoparticles, confocal laser scanning microscopy has been used. The results showed that NPs hydrodynamic size was between 220 to 245 nm and the zeta potential value ranges from −19 to −13 mV at pH 5 and 1 mM NaCl. The encapsulation efficiency was around 70% and the drug loading was about 14 to 17%. SEM and TEM images confirmed that the obtained nanoparticles were spherical with smooth surface. The prepared nanoparticles dispersions were stable for a period of 30 days under three temperatures of 4°C, 25°C and 40°C. In addition, CLSM images proved that obtained NPs can penetrate the skin as well. The prepared nanoparticles are submicron in nature, with good colloidal stability and penetrate the stratum corneum layer of the skin. This formulation potentiates IND skin penetration and as a promising strategy would be able to decline the side effects of IND.

Solvent displacement in comparison with other polymeric particles preparation technique provides certain crucial advantages such as water, time and energy lower consumption, procedure and set-up simplicity in nanoparticles preparation. The objective of this study was optimization of formulation in terms of the particle size, size distribution, zeta potential and morphology. In this study polycaprolactone based nanoparticles were prepared by solvent displacement or nanoprecipitation method. To prepare nanoparticles firstly, polycaprolactone was dissolved in acetone that form organic phase, secondly, for aqueous phase preparation, Tween ® 80 and polyvinyl alcohol as stabilizer of the system, were dissolved in the water. Consecutively, under magnetic agitation organic phase was injected through a syringe to the aqueous phase. Acetone was removed under reduced pressure by rotavapor. Furthermore, different formulation and process related variables such as evaporation technique, organic phase injection method and rate, stabilizer nature, polymer concentration, Tween ® 80 and polyvinyl alcohol concentration, stirring speed, organic and aqueous phases volume, were studied. To conclude, systematic study is indispensable before investigation of any drug encapsulation.

Curcumin, a polyphenolic compound extracted from Curcuma longa, has several pharmacological activities such as anticancer, anti-inflammatory, and antioxidant effects. The purpose of this study was to investigate the protective effects of curcumin and THERACURMIN, a highly bioavailable curcumin, against sodium nitroprusside (SNP)-induced oxidative damage in primary striatal cell culture. THERACURMIN as well as curcumin significantly prevented SNP-induced cytotoxicity. To elucidate the cytoprotective effects of curcumin and THERACURMIN, we measured the intracellular glutathione level in striatal cells. Curcumin and THERACURMIN significantly elevated the glutathione level, which was decreased by treatment with SNP. Moreover, curcumin showed potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging ability. Finally, a ferrozine assay showed that curcumin (10-100 µg/mL) has potent Fe(2+)-chelating ability. These results suggest that curcumin and THERACURMIN exert potent protective effects against SNP-induced cytotoxicity by free radical-scavenging and iron-chelating activities.

Curcumin, a polyphenolic compound has several pharmacological activities, such as anticancer, anti-inflammatory and antioxidant effects. However, curcumin shows poor oral bioavailability. The purpose of this study was to investigate the protective effects of highly bioavailable curcumin, Theracurmin(®), and curcumin, against sodium nitroprusside (SNP)-induced oxidative damage in mice brain. Intrastriatal microinjection of Theracurmin(®) or curcumin with SNP significantly protected against SNP-induced brain damage and motor dysfunction. Oral administration of Theracurmin(®) (1 and 3 g kg(-1), containing 100 and 300 mg kg(-1) curcumin, respectively) significantly protected against SNP-induced brain damage and motor dysfunction. However, oral administration of 300 mg kg(-1) curcumin did not protect against motor dysfunction induced by SNP. These results suggest that curcumin and Theracurmin(®) have protective effects against SNP-induced oxidative damage. Moreover, oral administration of Theracurmin(®), had more potency in protecting against brain damage, suggesting a higher bioavailability of Theracurmin(®) following oral administration.

Accumulating lines of evidence showed that luteolin, a polyphenolic compound, has potent neuroprotective effects. The purpose of this study was to examine whether luteolin can protect against sodium nitroprusside (SNP)-induced oxidative damage in mouse brain. Intrastriatal co-injection of luteolin (3 – 30 nmol) with SNP (10 nmol) dose-dependently protected against brain damage and motor dysfunction. Oral administrations of luteolin (600 – 1200 mg/kg) dose-dependently protected against brain damage and motor dysfunction induced by striatal injection of SNP. Furthermore, luteolin (30 – 100 μM) concentration dependently protected against Fe2+-induced lipid peroxidation in mouse brain homogenate. Luteolin (1 – 100 μg/ml) showed potent DPPH radical scavenging ability, when compared with ascorbic acid and glutathione. Finally, a ferrozine assay showed that luteolin (30 – 100 μg/ml) has Fe2+-chelating ability, but this was weaker than that of ethylenediaminetetraacetic acid. These results suggest that intrastriatal or oral administration of luteolin protected mice brain from SNP-induced oxidative damage by scavenging and chelating effects. Keywords:: sodium nitroprusside, brain damage, motor dysfunction, oxidative stress, scavenging

Sodium nitroprusside (SNP) is widely used as a potent vasodilator and a nitric oxide (NO) donor, whereas the cytotoxicity of SNP has been well documented. SNP releases several potentially toxic products such as cyanide anion, NO, and iron. We investigated the mechanisms of cell death and motor dysfunction induced by microinjection of SNP in mice to establish a brain oxidative stress model and then examined the anti-oxidant activity of glutathione. Intrastriatal microinjection of SNP (1 – 10 nmol) induced brain damage and motor dysfunction in a dose-dependent manner when the effects were evaluated with behavioral tests and TTC staining. NOC-18 (10 nmol), another NO donor, and KCN (10 nmol) did not cause motor dysfunction. However, FeCl2 (10 nmol) caused motor dysfunction. In addition, simultaneous injection of SNP and deferoxamine (10 nmol), an iron-chelating agent, prevented SNP-induced brain damage and motor dysfunction, suggesting a role of iron-related radicals in SNP-toxicity. Moreover, reduced glutathione (1 – 10 nmol), a natural anti-oxidant substance, dose-dependently prevented motor dysfunction induced by SNP-toxicity. Finally, deferoxamine and glutathione (10 nmol) significantly protected against brain damage and motor dysfunction induced by FeCl2 toxicity. These results suggest that cell death induced by injection of SNP is caused by iron-related radical reactions, but not by NO and cyanide anion. Keywords:: sodium nitroprusside, brain damage, behavior change, oxidative stress, anti-oxidant

Background: Irrational medicine use is a global problem. It can lead to increased morbidity and mortality and increased costs of drug therapy, thus imposing an adverse impact on the overall quality of the pharmaceutical care system. Objective: To evaluate drug use practices based on WHO core drug use indicators at pediatric health facilities of Kabul, Afghanistan.Methods: A cross-sectional study was conducted at outpatient departments of the three pediatric health facilities at samples that were collected using a systematic random sampling method. The sample size included 600 outpatient prescriptions. Data were evaluated as per the WHO guidelines.Results: On average 2.795, 2.745, and 4.2 drugs per prescription were prescribed in 001, 002, and 003 health facilities respectively (WHO standard is 1.6-1.8). 37.03% of drugs in 001, 42.62% in 002, and 42.64% of drugs in 003 were prescribed by the generic name (WHO standard is 100%). Antibiotics were prescribed in 79% prescriptions of the 001, 88% of the 002, and 52% of the 003 health facilities (WHO standard value is 20-26.8%). Injections were prescribed in 6% of the 001, 32% of the 002, and 19.5% of the 003 prescriptions (WHO standard is 13.4-24.1%). 65.47% of drugs in 001, 67.94% of drugs in 002, and 73.1% of drugs in 003 health facilities were prescribed from the Afghanistan national essential medicines list (WHO standard is 100%).Conclusion: Most of the core drug use indicators were not met with WHO standards in these pediatric health facilities. However, in 001 and 003 health facilities the prescribing patterns may be more complex because they are tertiary health care centers.

1. Molecular characterization of S. aureus isolates from Afghanistan: Staphylococcus aureus (SA) is a major cause of infections in human and plethora of animals. One of the main objective of this thesis was to investigate the molecular features and the antibiotic (ATB) resistance profile of infection and colonization strains of SA/methicillin-resistant SA (MRSA) isolated from human and livestock in Kabul. All strains were identified by conventional phenotypic methods. MRSA Strains were then extensively characterized using DNA microarray. Among SA isolates from human infection in the two hospitals of Kabul, from January to June 2017, MRSA prevalence was high at 66.3%. The 98 isolates (65 MRSA and 33 MSSA) were grouped into 12 clonal complexes (CCs) and 27 distinct clones. The prevalence of nasal carriage of the SA and MRSA among healthy population in Kabul was 33.3% and 12.7% respectively. Four CCs and 7 clones were identified. Around 11.8% (2/17) of SA strains caused bovine mastitis were MRSA, belonged to two distinct clones. We found a very low prevalence (1.05%) of SA nasal carriage in sheep in Kabul. Molecular characterization of the isolates, indicates a large genetic diversity and the presence of multiple virulence and ATB resistance genes among SA/MRSA strains circulating in the health-care facilities, community and livestock in Kabul. 2. Conjugative transfer of linezolid resistance gene: Linezolid is one of the last resort for the treatment of MRSA infections. The objective of this study was to investigate the risk of conjugative transfer of linezolid resistance from S. epidermidis (SE) strains to major SA clones. Five SE strains harboring different cfr-carrying plasmids (pSA737, p12-02300, p-cfr-PBR-A, p-cfr-PBR-B), and 9 major clones of SA circulating in France were used as donors and recipients respectively. The plasmid transfer rates were highly variable. The ST8-MRSA-IV USA300 was able to receive the cfr-carrying plasmids from all the donors tested. The SE ST5 strains was more able to transfer the plasmid p-cfr-PBR-B to different recipients, compared to SE ST2. The plasmids pSA737, and p12-02300 transferred to the most of the recipients tested. Plasmid fitness cost were highly variable. Under selective pressure, the linezolid resistance mediated by cfr vectors, can be efficiently transferred to major clones of SA circulating in France.; 1. Caractérisation moléculaire des isolats de S. aureus en provenance d’Afghanistan : Staphylococcus aureus (SA) est une cause majeure d'infections chez l'Homme et de nombreux animaux. L'un des principaux objectifs de cette thèse était d'étudier les caractéristiques moléculaires et le profil de résistance aux antibiotiques des souches d'infection et de colonisation de SA / SA résistante à la méticilline (SARM) isolées chez l'Homme et le bétail à Kaboul. Toutes les souches ont été identifiées par des méthodes phénotypiques conventionnelles. Les souches de SARM ont ensuite été caractérisées à l'aide d'une puce à ADN. Parmi les isolats de SA provenant d'infections humaines dans deux hôpitaux de Kaboul entre Janvier et Juin 2017, la prévalence des SARM était élevée (66,3 %). Les 98 isolats de SASM et SARM appartenaient à 12 complexes clonaux (CC) et 27 clones distincts. La prévalence du portage nasal de SA et du SARM dans la communauté, plus précisément chez des étudiants (hors médecine) de l’Université de Kaboul, était respectivement de 33,3% et 12,7%. Les 19 isolats de SARM appartenaient à 4 Enfin, les études réalisées chez l’animal ont montré qu’environ 11,8% des souches SA responsables de mammite bovine à Kabul étaient des SARM (2/17) et que la prévalence du portage nasal de SA chez les moutons était très faible (1.05 %). La caractérisation moléculaire des isolats a mis en évidence une grande diversité génétique et la présence de multiples gènes de virulence et de résistance parmi les souches SA/SARM circulant dans les établissements de soins, la communauté et le bétail à Kaboul. 2. Transfert conjugatif de gène de résistance au linézolide : Le linézolide est l'un des derniers recours pour le traitement des infections à SARM. L'objectif de cette étude était d'étudier le risque de transfert conjugatif de la résistance au linézolide des souches de S. epidermidis (SE) vers des souches SA de fonds génétiques différents. Cinq souches de SE portant différents plasmides possédant le gène cfr (pSA737, p12-02300, p-cfr-PBR-A, p-cfr-PBR-B), et 9 clones majeurs de SA circulant en France ont été respectivement utilisés comme donneuses et receveuses. Le clone ST8-MRSA-IV USA300 a pu recevoir les plasmides contenant le gène cfr de toutes les donneuses testées. Les souches SE ST5 avaient une plus grande capacité à transférer le plasmide p-cfr-PBR-B à différentes receveuses, par rapport aux souches du ST2. Les plasmides pSA737 et p12-02300 ont été transférés à la plupart des receveuses testées. Les coûts de fitness des plasmides testés étaient très variables. Les résultats ont au final montré que la résistance au linézolide, médiée par les vecteurs cfr, peut être transférée efficacement par conjugaison de SE aux clones pathogènes majeurs de SA circulant en France.

The objective of this PhD thesis was to extract the Nigella Sativa L. Seeds Essential Oil and its encapsulation together with indomethacin within polymeric nanoparticles in order to reduce taken amount and to enhance indomethacin cutaneous penetration, and anti-inflammatory activity. To this direction poly-epsilon-caprolactone based nanoparticles were designed using nanoprecipitation method. A systematic study was performed to figure out the effect of process and formulation parameters on the characteristics of obtained nanoparticles. Once the effects of all parameters were studied, then indomethacin and Nigella Sativa L. Seeds Essential Oil was encapsulated separately. Consequently, both together indomethacin and Nigella Sativa L. Seeds Essential Oil was encapsulated. Then prepared nanoparticles were characterized in terms of stability, encapsulation efficiency. In addition, ex vivo skin penetration and in vivo anti-inflammatory activity of designed nanoparticles was investigated; L'objectif de cette thèse est d’encapsuler l'indométacine dans des nanoparticules polymériques en association à l’huile essentielle de Nigella Sativa L. extraite à partir de ses graines afin d’optimiser son utilisation par voie cutanée et potentialiser son activité anti-inflammatoire.Pour ce faire, des nanoparticules à base de poly-epsilon-caprolactone ont été préparées par nanoprécipitation. Une étude systématique a été menée pour comprendre l'effet de la variation des paramètres de préparation sur les propriétés colloïdales des nanoparticules obtenues. Une fois les différents paramètres optimisés, l'indométacine et l'huile essentielle de Nigella Sativa L. ont été encapsulées séparément dans les nanoparticules polymériques. Puis, l’ensemble, indométacine et huile essentielle de Nigella Sativa L. a été encapsulé. Les nanoparticules préparées ont à chaque fois été caractérisées notamment en termes de stabilité et de performance d’encapsulation. Ensuite, nous avons mené une étude ex vivo et in vivo des nanoparticules obtenues afin d’évaluer le potentiel de pénétration cutanée d’une part, et le potentiel clinique dans la prise en charge de l’inflammation