Hanan Hassan Fouad

Chronic Inflammatory bowel diseases are usually accompanied by opportunistic colonic fungal infections. Itraconazole (ITZ), is a highly lipophilic broad-spectrum antifungal drug that is superiorly effective against several fungal species. Box-Behnken design was adopted to design ITZ-nanomixed micelles (ITZ-NMMs), aiming to enhance ITZ solubility, using various concentrations of Pluronic® L121, Cremophor EL, and with either sodium-deoxycholate or Pluronic F68 through thin film hydration technique. Optimized formula composed of 90 % Pl-L121, 9.1% Cremophor EL, 3.127 % ITZ concentration and SDC as the hydrophilic surfactant and its particle size, Polydispersity index, zeta potential, entrapment efficiency, and release extent after 3 h were found to be 17.82 ± 0.189 nm, 0.26 ± 0.014, -6.72 ± 0.725 mV, 66 ± 7.4%, and 96.3 ± 7.22%, respectively. ITZ release study implied the ability of optimal ITZ-NMMs to enhance ITZ solubility in comparison to ITZ suspension. Also, augmented anti-fungal and anti-cancer activities were proven as ITZ-NMMs IC was 16.5 times that of pure ITZ. Afterwards, lyophilized optimal ITZ-NMMs formula was loaded into Eudragit S100-coated capsules where release and X-ray imaging ensured protection of ITZ release in either the stomach or intestine and targeting it to the colon. Such results suggested promising ITZ-NMMs system, capable of enhancing ITZ solubility in the intended target site, therefore, can be used not only in the treatment of colon fungal infections but also augments colon cancer therapy.

This study aimed to design potent carbonic anhydrase inhibitors (CAIs) based on pyrazole benzenesulfonamide core. Nine series of substituted pyrazole benzenesulfonamide compounds were synthesized with variable groups like sulphamoyl group as in compounds 4a-e, its bioisosteric carboxylic acid as in compounds 5a-e and 8e, ethyl carboxylate ester as in compounds 6a-e and 9a-e, which were designed as potential prodrugs, isothiazole ring as in compound 7, hydrazide derivative 10e, hydroxamic acid derivatives 11a-e and semicarbazide derivatives 12a-c,e. All the synthesized compounds were investigated for their carbonic anhydrase (CA) inhibitory activity against two human CA isoforms hCA IX and hCA XII and compared to acetazolamide (AAZ). Also, the compounds were assessed for their anticancer activity against 60 cancer cell lines according to the US NCI protocol. Compounds 4b, 5b, 5d, 5e, 6b, 9b, 9e and 11b revealed significant inhibitory activity against both isoforms hCA IX and hCA XII, while 6e, 9d, 11d and 11e showed significant inhibitory activity against hCA XII only compared to acetazolamide as a reference. This would highlight these compounds as promising anticancer drugs. Moreover, compound 6e revealed a remarkable cytostatic activity against CNS cancer cell line (SF-539; TGI = 5.58 μM), renal cancer cell line (786-0; TGI = 4.32 μM) and breast cancer cell line (HS 578 T; TGI = 5.43 μM). Accordingly, compound 6e was subjected to cell cycle analysis and apoptotic assay on the abovementioned cell lines at the specified GI (0.45, 0.89 and 1.18 μM, respectively). Also, it revealed the increment of total apoptotic cells percentage in 786-0 (53.19%), SF-539 (46.11%) and HS 578 T (43.55%) relative to the control cells (2.07, 2.64 and 2.52%, respectively). In silico prediction of BBB permeability showed that most of the calculations for compound 6e resulted as BBB (+), which is required for a compound targeting CNS. Further, the interaction of the most active compounds with the key amino acids in the active sites of hCA IX and hCA XII was highlighted by molecular docking analysis.

Antimicrobial resistance has become a concern as a worldwide threat. A novel scaffold of phenylthiazoles was recently evaluated against multidrug-resistant to control the emergence and spread of antimicrobial resistance, showing good results. Several structural modifications are needed based on the structure-activity relationships (SARs) of this new antibiotic class. Previous studies revealed the existence of two key structural features essential for the antibacterial activity, the guanidine head and lipophilic tail. In this study, a new series of twenty-three phenylthiazole derivatives were synthesized utilizing the Suzuki coupling reaction to explore the lipophilic part. The antibacterial activity was evaluated against a range of clinical isolates. The three most promising compounds, 7d, 15d and 17d, with potent MIC values against MRSA USA300 were selected for further antimicrobial evaluation. The tested compounds exhibited potent results against the tested MSSA, MRSA, and VRSA strains (concentration: 0.5 to 4 μg mL). Compound 15d inhibited MRSA USA400 at a concentration of 0.5 μg mL (one-fold more potent than vancomycin) and showed low MIC values against ten clinical isolates, including linezolid-resistant strain MRSA NRS119 and three vancomycin-resistant isolates VRSA 9/10/12. Moreover, compound 15d retained its potent antibacterial activity using the model by the burden reduction of MRSA USA300 in skin-infected mice. The tested compounds also showed good toxicity profiles and were found to be highly tolerable to Caco-2 cells at concentrations of up to 16 μg mL, with 100% of the cells remaining viable.

AIM: To investigate the effects of a 12-week split-belt treadmill walking (Sb-TW) practice using an error augmentation strategy on temporospatial gait asymmetries, dynamic balance, and locomotor capacity in adolescents with unilateral cerebral palsy (ULCP).

METHODS: Fifty-two adolescents with ULCP (age: 10-16 years) were randomized into either the Sb-TW group ( = 26; underwent repeated Sb-TW practice, with exaggeration of the initial step-length asymmetry, three times/week, for 12 sequential weeks) or control group ( = 26; received equivalent dosages of traditional single-belt treadmill training). Step-length and swing-time asymmetries, directional (LoS) and overall (LoS) limits of stability, and locomotor capacity [6-minute walk test (6-MWT), Timed Up and Down Stair test (TUDS), and 10-m Shuttle Run Test (10mSRT)] were assessed pre- and post-intervention.

RESULTS: The Sb-TW group demonstrated more favorable changes in step-length asymmetry ( < .001,  = 0.27), LoS [affected side direction ( = .033,  = 0.09), forward direction ( = .004,  = 0.16), and backward direction ( = .01,  = 0.12)], and LoS ( < .001,  = 0.31) than the control group. Also, the Sb-TW group showed significantly higher locomotor capacity [6-MWT ( < .001,  = 0.38), TUDS ( = .032,  = 0.09), 10mSRT ( = .021,  = 0.10)] as compared to the control group.

CONCLUSION: The Sb-TW-induced adaptations can be capitalized on for remediating spatial gait asymmetry, dynamic balance deficits, and impaired locomotor performance in adolescents with ULCP.