Phenoxypropanolamine derivatives as selective inhibitors of the 20S proteasome ß1 and ß5 subunits.

New series of thiophene-containing phenoxypropanolamines were synthesized and evaluated for their potency to inhibit the three proteolytic activities of the mammalian 20S proteasome. Noticeable inhibition of both ChT-L and PA activities was obtained with three compounds: one with unsubstituted phenoxypropanolamine group (7) and the two others with a p-Cl-substituted group (4 and 9). For three other compounds (3, 8 and 10), ChT-L activity alone was significantly inhibited. In silico docking performed on the ß5 and ß1 subunits bearing the respective ChT-L and PA catalytic sites showed features common to poses associated with active compounds. These features may constitute a selectivity criterion for structure-guided inhibitor design.

HypnosIS to faciLitate trans-Esophageal echocardiograPhy Tolerance: The I-SLEPT study.

BACKGROUND: Trans-oesophageal echocardiography (TOE) is one of the major diagnostic tests in cardiovascular medicine, but the procedure is associated with some discomfort for the patient. AIM: To determine the additive value of hypnosis as a means of improving patient comfort during TOE. METHODS: We randomly assigned 98 patients with non-emergency indications for TOE to a 30-minute hypnosis session combined with topical oropharyngeal anaesthesia (HYP group) or topical oropharyngeal anaesthesia only (CTRL group) before the procedure. The primary efficacy endpoint was the level of patient discomfort assessed using a visual analogue scale (VAS). RESULTS: The VAS score was significantly reduced in the HYP group compared with the CTRL group (6 [5; 8] vs. 7 [5; 9]; P=0.046). No statistically significant differences were observed in terms of procedure failure (HYP group 2.2% vs. CTRL group 3.9%; P=1.00) and procedure length (HYP group 7 [5; 11] minutes vs. CTRL group 8 [7; 11] minutes; P=0.29). However, the patients' subjective estimations of the length of the procedure were significantly shorter in the HYP group than in the CTRL group (8 [5; 10] vs. 10 [10; 20] minutes; P<0.0001). There were no major adverse events in either group. The reported minor events rate was lower in the HYP group (36% vs. 57%; P=0.04). CONCLUSION: Hypnosis is an efficient alternative or complementary method for improving patient comfort during TOE.

Bisbenzimidazole derivatives as potent inhibitors of the trypsin-like sites of the immunoproteasome core particle.

In this study, a monomeric (MB) and a dimeric (DB) bisbenzimidazoles were identified as novel proteasome inhibitors of the trypsin-like activity located on ß2c sites of the constitutive 20S proteasome (IC50 values at 2-4 µM range). Remarkably, they were further shown to be 100- and 200-fold more potent inhibitors of the immunoproteasome trypsin-like activity (ß2i sites, IC50=24 nM) than of the homologous constitutive activity. Molecular models of inhibitor/enzyme complexes in the two types of trypsin-like sites and corresponding computed binding energy values corroborated kinetic data. Different binding modes were suggested for MB and DB to the ß2c and ß2i trypsic sites. Each pointed to better contacts of the ligand inside the ß2i active site than for ß2c site. MB and DB represent the first selective inhibitors of the immunoproteasome trypsin-like activity described to date and can be considered as prototypes for inhibiting this activity.

Zinc oxide as a new antimicrobial preservative of topical products: interactions with common formulation ingredients.

Zinc oxide (ZnO) appears as a promising preservative for pharmaceutical or cosmetic formulations. The other ingredients of the formulations may have specific interactions with ZnO that alter its antimicrobial properties. The influence of common formulation excipients on the antimicrobial efficacy of ZnO has been investigated in simple model systems and in typical topical products containing a complex formulation. A wide variety of formulation excipients have been investigated for their interactions with ZnO: antioxidants, chelating agents, electrolytes, titanium dioxide pigment. The antimicrobial activity of ZnO against Escherichia coli was partially inhibited by NaCl and MgSO4 salts. A synergistic influence of uncoated titanium dioxide has been observed. The interference effects of antioxidants and chelating agents were quite specific. The interactions of these substances with ZnO particles and with the soluble species released by ZnO were discussed so as to reach scientific guidelines for the choice of the ingredients. The preservative efficacy of ZnO was assessed by challenge testing in three different formulations: an oil-in-water emulsion; a water-in-oil emulsion and a dry powder. The addition of ZnO in complex formulations significantly improved the microbiological quality of the products, in spite of the presence of other ingredients that modulate the antimicrobial activity.

New C(4)- and C(1)-derivatives of furo[3,4-c]pyridine-3-ones and related compounds: evidence for site-specific inhibition of the constitutive proteasome and its immunoisoform.

A set of 18 new C(4) and C(1) derivatives of nor-cerpegin (1,1-dimethyl furo[3,4-c]pyridine-3-one), 6 model compounds (γ- and δ-lactones) and 20 furo- or thieno[2,3-d]-pyrimidine-4-one related compounds were designed and synthesized. Each compound was assayed for inhibition of CT-L, T-L and PA proteolytic activities of 20S constitutive proteasome (c20S). Most performant compounds were also assayed on 20S immunoproteasome (i20S). Compound 10 with a benzylamino group at C(4) and dimethylated at C(1) of the furopyridine ring was the most efficient PA site-specific inhibitor of the c20S (IC50(cPA) of 600nM) without noticeable inhibition of the i20S PA site (iPA). In silico docking assays for 10 at the iPA catalytic site revealed the absence of poses normally observed for this compound and related ones at the constitutive PA site (cPA). The thieno[2,3-d]pyrimidine-4-one 40 was T-L site-specific with a mild inhibition of both c20S and i20S in vitro (IC50(cT-L) of 9.9µM and IC50(iT-L) of 6.7µM). In silico docking assays of 40 at T-L sites of c20S and i20S revealed almost identical first rank poses in the two types of sites with no possibility left for nucleophilic attack by Thr1 as observed for the fused furopyridine-3-one 10.

Antimicrobial activity of zinc oxide particles on five micro-organisms of the Challenge Tests related to their physicochemical properties.

Zinc oxide is commonly used in pharmaceutical products to prevent or treat topical or systemic diseases owing to its antimicrobial properties, but it is scarcely used as preservative in topical formulations. The aim of this work was to investigate the antimicrobial activity of zinc oxide (ZnO) powders on the five microbial strains used for Challenge Tests in order to evaluate this inorganic compound as a preservative in topical formulation and assess relationships between the structural parameters of ZnO particles and their antimicrobial activity. For this purpose, the physicochemical characteristics of three ZnO grades were measured and their antimicrobial efficacy against the following micro-organisms - Escherichia coli; Staphylococcus aureus; Pseudomonas aeruginosa; Candida albicans; Aspergillus brasiliensis - was assessed using disc diffusion susceptibility tests and a broth dilution method. The comprehensive dataset of physicochemical characteristics and antimicrobial activities (MIC and MBC) is discussed regarding methodological issues related to the particulate nature of ZnO and structure-activity relationships. Every ZnO grade showed bactericidal and antifungal activity against the five tested micro-organisms in a concentration dependent manner. ZnO particles with smaller size, larger specific area and higher porosity exhibit higher antimicrobial activity. Such trends are related to their mechanisms of antimicrobial activity.

C1 and N5 derivatives of cerpegin: synthesis of a new series based on structure-activity relationships to optimize their inhibitory effect on 20S proteasome.

Thirty-two new derivatives of cerpegin (1,1,5-trimethylfuro[3,4-c]pyridine-3,4-dione) were designed and synthesized in high yield by a new method, combining several C(1) and N(5) substituents. All compounds were tested for their inhibitory effect on the CT-L, T-L and PA proteolytic activities of a purified mammalian 20S proteasome. Only one molecule inhibited both CT-L and PA activities. Sixteen molecules specifically inhibited PA at the micromolar range, out of which fourteen had IC50 values around 5 µM and two had IC50 values closer to 2 µM. Except in one case, neither calpain I nor cathepsin B was inhibited. In silico docking suggests a unique mode of binding of the most efficient compounds to the ß1 catalytic site (PA activity) in relation to the chemical nature of C(1) substituents.

A new series of N5 derivatives of the 1,1,5-trimethyl furo[3,4-c]pyridine-3,4-dione (cerpegin) selectively inhibits the post-acid activity of mammalian 20S proteasomes.

A large set of N(5)-derivatives of cerpegin (1,1,5-trimethyl furo[3,4-c]pyridine-3,4-dione) was designed and synthesized in high yields by a simple and handy method using various primary amines for a pyridine cycle synthesis. The effects of 29 derivatives on the three types of catalytic sites of purified mammalian 20S proteasomes (CT-L, T-L and PA) were measured. Most of the new compounds specifically inhibited the PA activity, in the micromolar range. Docking experiments support these results. Moreover, neither calpain I nor cathepsin B were inhibited.

Dentinogenesis imperfecta: long-term rehabilitation in a child.

The treatment of dentinogenesis imperfecta represents a challenge for the dental practitioner. The aim of this case report was to describe the chronology and problems encountered in the long-term rehabilitation of a young girl suffering from dentinogenesis imperfecta with severe attrition. A 2-stage treatment over a period of 9 years is described and discussed. This treatment comprised an initial treatment to restore esthetic appearance and function during primary and mixed dentitions and a complete prosthetic rehabilitation in a second stage to protect permanent teeth with low-fusion ceramicmetal individual crowns. Discovery of a follicular cyst is also reported and its treatment is described.

Infected immature teeth treated with surgical endodontic treatment and root-reinforcing technique with glass ionomer cement.

The authors propose surgical endodontic treatment of immature teeth characterized by necrosis and infection, especially after failure of apexification or in the presence of older, fibrous, and extensive lesion. A glass ionomer cement, autopolymerizable and condensable, is used as retro-filling material and as a reinforcement material for the canal walls. The variety of different cases presented here show that this rapid technique is reliable and reproducible.