Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators.

The synthesis and biological evaluation on AMPA and kainate receptors of new examples of 3,4-dihydro-2H-1,2,4-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxides is described. The introduction of a cyclopropyl chain instead of an ethyl chain at the 4-position of the thiadiazine ring was found to dramatically improve the potentiator activity on AMPA receptors, with compound 32 (BPAM395) expressing in vitro activity on AMPARs (EC2x = 0.24 µM) close to that of the reference 4-cyclopropyl-substituted benzothiadiazine dioxide 10 (BPAM344). Interestingly, the 4-allyl-substituted thienothiadiazine dioxide 27 (BPAM307) emerged as the most promising compound on kainate receptors being a more effective potentiator than the 4-cyclopropyl-substituted thienothiadiazine dioxide 32 and supporting the view that the 4-allyl substitution of the thiadiazine ring could be more favorable than the 4-cyclopropyl substitution to induce marked activity on kainate receptors versus AMPA receptors. The thieno-analogue 36 (BPAM279) of the clinically tested S18986 (11) was selected for in vivo evaluation in mice as a cognitive enhancer due to a safer profile than 32 after massive per os drug administration. Compound 36 was found to increase the cognition performance in mice at low doses (1 mg/kg) per os suggesting that the compound was well absorbed after oral administration and able to reach the central nervous system. Finally, compound 32 was selected for co-crystallization with the GluA2-LBD (L504Y,N775S) and glutamate to examine the binding mode of thienothiadiazine dioxides within the allosteric binding site of the AMPA receptor. At the allosteric site, this compound established similar interactions as the previously reported BTD-type AMPA receptor modulators.

Clinical validation of an elastin-derived trifunctional peptide for skin regeneration.

Aging is associated with progressive skin fragility, characterized in part by extracellular matrix (ECM) fragmentation. This degradation produces matrikines which have an impact on ECM rremodeling. Our group previously designed and characterized a trifunctional peptide (TFP), constituted of i) an elastokine motif (VGVAPG)3, able to increase the expression of matrix constituent through the stimulation of the elastin-binding protein receptor, ii) a tripeptide inhibiting matrix metalloproteinase-1 activity (GIL), and iii) a linker domain acting as a competitive substrate for urokinase (RVRL). TFP was shown to activate the production of matrix constituents while inhibiting Matrix MetalloProtease MMP-1 in vitro on fibroblasts and ex vivo on skin explants. OBJECTIVE: In the present study, TFP properties were evaluated in a clinical assay. METHODS: Twenty-two volunteers applied a TFP-based cream on one hemi-face and a placebo-based cream on the other hemi-face, twice a day during 28 days, before undergoing a surgical lifting. Cutometry and skin relief measurements were performed at days 0 and 28, and skin explants from lifting surgery were used for histological analyses. RESULTS: Cutometry and skin relief measurements reveal TFP firming properties and wrinkle depth decrease in 28 days on TFP- as compared to placebo-treated hemi-faces. These results are confirmed by histological analyses showing an increase of the ratio between basal lamina and stratum corneum. Furthermore, immunostaining of collagen reveals a modification of the ratio between type I and III collagens. CONCLUSION: The combined analysis of phenotypic and histologic parameters demonstrates a reorganization of the ECM towards a regenerative profile upon TFP treatment.

Targeting Myeloperoxidase Activity and Neutrophil ROS Production to Modulate Redox Process: Effect of Ellagic Acid and Analogues.

Malaria is an infectious disease caused by a Plasmodium genus parasite that remains the most widespread parasitosis. The spread of Plasmodium clones that are increasingly resistant to antimalarial molecules is a serious public health problem for underdeveloped countries. Therefore, the search for new therapeutic approaches is necessary. For example, one strategy could consist of studying the redox process involved in the development of the parasite. Regarding potential drug candidates, ellagic acid is widely studied due to its antioxidant and parasite-inhibiting properties. However, its low oral bioavailability remains a concern and has led to pharmacomodulation and the synthesis of new polyphenolic compounds to improve antimalarial activity. This work aimed at investigating the modulatory effect of ellagic acid and its analogues on the redox activity of neutrophils and myeloperoxidase involved in malaria. Overall, the compounds show an inhibitory effect on free radicals as well as on the enzyme horseradish peroxidase- and myeloperoxidase (HRP/MPO)-catalyzed oxidation of substrates (L-012 and Amplex Red). Similar results are obtained with reactive oxygen species (ROS) produced by phorbol 12-mystate acetate (PMA)-activated neutrophils. The efficiency of ellagic acid analogues will be discussed in terms of structure-activity relationships.

Development of Thiochroman Dioxide Analogues of Benzothiadiazine Dioxides as New Positive Allosteric Modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors.

On the basis of the activity of 1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors, thiochroman 1,1-dioxides were designed applying the isosteric replacement concept. The new compounds expressed strong modulatory activity on AMPA receptors in vitro, although lower than their corresponding benzothiadiazine analogues. The pharmacokinetic profile of three thiochroman 1,1-dioxides (12a, 12b, 12e) was examined in vivo after oral administration, showing that these compounds freely cross the blood-brain barrier. Structural analysis was achieved using X-ray crystallography after cocrystallization of the racemic compound 12b in complex with the ligand-binding domain of GluA2 (L504Y/N775S). Interestingly, both enantiomers of 12b were found to interact with the GluA2 dimer interface, almost identically to its benzothiadiazine analogue, BPAM344 (4). The interactions of the two enantiomers in the cocrystal were further analyzed (mapping Hirshfeld surfaces and 2D fingerprint) and compared to those of 4. Taken together, these data explain the lower affinity on AMPA receptors of thiochroman 1,1-dioxides compared to their corresponding 1,2,4-benzothiadiazine 1,1-dioxides.

Total Upper and Lower Eyelid Reconstruction: A Rare Procedure--A Report of Two Cases.

UNLABELLED: Reconstruction after total amputation of the upper and lower eyelids with preserved globe is rare. The primary goal is immediate corneal protection. The second goal is to restore mobility, occlusion, and facial symmetry. Two women had full-thickness excision of both upper and lower eyelids to treat a melanoma. The reconstruction method required four steps over a period of 5 months. A buccal mucosal graft was used to recreate the conjunctival lining, and an oblique forehead flap was used to recreate the skin. Resection of the flap and replacement by a full-thickness skin graft made it possible to recreate a thin and mobile upper eyelid. Visual acuity remained unchanged, and the eyelids remained functional despite a degree of ptosis and lower eyelid retraction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Satisfaction and complications after lower body lift with autologous gluteal augmentation by island fat flap: 55 case series over 3 years.

BACKGROUND: Major weight loss causes body deformities. Lower circumferential dermolipectomy with autologous gluteal augmentation by a fat island flap can restore a part of the body contour, but this procedure is associated with a high incidence of complications. The aim of this study was to analyse the benefit/risk ratio and the patients' satisfaction. METHODS: All patients who underwent this procedure at the Nancy University Hospital over a 3-year period (between January 2010 and 2013) were reviewed; the complications were analysed and the patients' satisfaction rated. RESULTS: A total of 55 patients were included with a mean age of 41.0 years. The average body mass index of the patients was 28.2 kg/m² with a mean weight of 76.8 kg at the time of the procedure and a mean weight reduction of 49.6 kg. The mean operative time was 4.85 h. The average hospital stay was 6.1 days. The average haemoglobin loss was 3.0 g/dl, and 12 (21.8%) patients required a blood transfusion. Of the total number of patients, 22 (40%) developed at least one complication, including six (10.9%) major complications. Fifty-two patients answered the questionnaire; 49 (94.2%) patients would go through this procedure again. The overall satisfaction was rated as excellent by 29 (55.8%) patients and as pleasing by 22 (42.3%). The outcome was judged as excellent or pleasing for the abdomen by 29 (55.8%) and 20 (38.35%) patients, respectively, and for the buttocks by 17 (32.7%) and 29 (55.8%) patients, respectively. The quality of life was rated better after than before the intervention by 49 (94.2%) patients. CONCLUSION: Despite a high complication rate, the majority of patients confirmed that they would opt for this procedure again, showing an improvement in their quality of life with an aesthetic and functional benefit. LEVEL OF EVIDENCE: III.

Liposuction-assisted medial brachioplasty after massive weight loss: an efficient procedure with a high functional benefit.

BACKGROUND: Brachioplasty frequently offers functional benefits but results in poor aesthetic scars and a relatively high complication rate. The authors describe the complications and risk factors inherent in liposuction-assisted medial brachioplasty and assess patient satisfaction with the functional and aesthetic benefits. METHODS: A 5-year retrospective study was performed that included all patients who underwent liposuction-assisted medial brachioplasty. Complications were reviewed and analyzed by aesthetic and nonaesthetic categories, and patient satisfaction was rated. RESULTS: Sixty-six patients were included (mean age, 44.4 years). The average body mass index was 30.2 kg/m; mean weight reduction was 50.72 kg. Thirty-seven patients (56.1 percent) developed at least one complication, including six (9.1 percent) with a nonaesthetic complication versus 31 (47.0 percent) with an aesthetic complication. Complications were significantly associated with a longer operative time (p = 0.015), 233 minutes in the complication group versus 164 minutes in the no-complication group. Fifty-three patients answered the questionnaire. Forty-six (86.8 percent) stated that they would undergo this intervention again. Overall satisfaction was reported as excellent for 12 patients (22.6 percent) and pleasing for 24 (45.3 percent). All patients rated the functional outcome superior or equal to the aesthetic outcome. Quality of life was estimated to be better after than before the intervention for 41 patients (77.4 percent). CONCLUSIONS: Liposuction-assisted medial brachioplasty is a safe and efficient technique. It offers a functional benefit with a low nonaesthetic complication rate. Despite the inherent scars, the majority of patients would undergo this intervention again because of an important satisfaction rate and improvement in quality of life. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.