Topical administration of dapsone can be an alternative route for treatment of leprosy and can also provide new therapeutic applications for an established drug. However, the physicochemical ...properties of dapsone make it difficult to incorporate into conventional formulations. The current study was directed toward developing a stable nanoemulsion that contains dapsone which can be adapted for topical use.
Nanoemulsions were prepared using isopropyl myristate or n-methyl-pyrrolidone as the oil phase, and characterized according to their mean droplet size, conductivity, refractive index, pH, drug content, and stability. The in vitro release of dapsone and its ability to permeate the epidermis were also evaluated.
Physicochemical characterization demonstrated that nanosystems were formed, which had a uniform droplet distribution and a pH compatible with the skin surface. Use of n-methyl-pyrrolidone provided a greater nanoemulsion region and higher solubilization of dapsone, and increased the in vitro release rate when compared with a nanoemulsion prepared using isopropyl myristate. However, use of isopropyl myristate promoted an increase in in vitro epidermal permeation that followed the Higuchi model. This demonstrates the ability of a nanosystem to influence permeation of dapsone through the skin barrier. Furthermore, the nanoemulsions developed and evaluated here had ideal physicochemical stability over a 3-month period.
Incorporation of dapsone into a nanoemulsion may be a promising system for enabling topical delivery of dapsone, while minimizing skin permeation, for the treatment of acne. The method developed here used isopropyl myristate as the oil phase, and promoted permeation of dapsone through the skin barrier for the treatment of leprosy upon use of n-methyl-pyrrolidone as the oil phase.
Titanium tetrafluoride (TiF
) is a topical agent used in the control of dental caries; however, it is highly acidic. To minimize this effect, cyclodextrins (CDs) are used. This study evaluated the
...potential of TiF
and β-CD on remineralization.
Forty bovine enamel blocks were selected by microhardness and randomly assigned to four groups (
= 10 per group): control (distilled and deionized water), 1% β-CD solution, 1% TiF
solution, and TiF
: β-CD solution. The blocks were subjected to a pH cycling regimen for 8 days. After that, samples were evaluated by cross-sectional microhardness (CSMH), scanning electron microscopy (SEM), and energy dispersive spectrometry (EDS). Data were assessed for normality and analyzed using ANOVA and Tukey's tests (α = 0.05).
Regarding CSMH, TiF
: β-CD was statistically superior to the control (
= 0.033), β-CD (
= 0.022), and TiF
(
= 0.006). SEM photomicrography revealed the titanium dioxide coating on slabs treated with TiF
and TiF
: β-CD. EDS assessment demonstrated the presence of titanium on the surface of slabs treated with TiF
and TiF
: β-CD.
The solution containing the inclusion nanocomplex formed of TiF
and β-CD was able to reharden the enamel subsurface.
Metformin is a euglycemic drug for the treatment of type 2 diabetes mellitus. To date, there are 13 dissolution methodologies described in the U.S. Pharmacopoeia (USP) to evaluate the release profile ...of metformin from extended-release tablets utilizing either a USP apparatus 1 (basket) or 2 (paddle). In the absence of a protocol for a USP apparatus 3 (reciprocating cylinder), the goal of this work was to develop an in vitro dissolution method for metformin extended-release tablets based on an in vivo–in vitro correlation (IVIVC). Following a systematic evaluation, a final dissolution method, M4, was defined. It applied 30 dips per minute (dpm) over a total period of 10 h into a series of solutions that included 2 h in HCl media (pH 1.2), 1 h in an acetate buffer solution (pH 4.5), 1 h in phosphate buffer solution (PBS) (pH 5.8) and 6 h in PBS (pH 6.8). This method showed a significant IVIVC with a calculated R2 > 0.98 (point-to-point correlation, Level A) and it was successfully used as a tool to assist in the development of generic extended release formulations for metformin consisting of a lipophilic matrix system.
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•Synthesis of thiourea derivatives exhibiting antimycobacterial and anti-inflammatory activities.•Five thioureas derivatives showed notable antimycobacterial activity with low ...cytotoxicity.•Fifteen are novel thioureas derivatives.•Five thioureas derivatives were further active when evaluated in infected macrophages in vitro and in hypervirulent extracellular aggregates of Mtb.•Thiourea derivatives 16, 28 and 29 are promising candidates for further in vivo studies.
Tuberculosis (TB) remains a serious public health problem and one of the main concern is the emergence of multidrug-resistant and extensively resistant TB. Hyper-reactive patients develop inflammatory necrotic lung lesions that aggravate the pathology and facilitate transmission of mycobacteria. Treatment of severe TB is a major clinical challenge that has few effective solutions and patients face a poor prognosis, years of treatment and different adverse drug reactions. In this work, fifteen novel and thirty-one unusual thiourea derivatives were synthesized and evaluated in vitro for their antimycobacterial and anti-inflammatory potential and, in silico for ADMET parameters and for structure–activity relationship (SAR). Thioureas derivatives 10, 15, 16, 28 and 29 that had shown low cytotoxicity and high activities were selected for further investigation, after SAR study. These five thioureas derivatives inhibited Mtb H37Rv growth in bacterial culture and in infected macrophages, highlighting thiourea derivative 28 (MIC50 2.0 ± 1.1 and 2.3 ± 1.1 µM, respectively). Moreover, these compounds were active against the hypervirulent clinical Mtb strain M299, in bacterial culture, especially 16, 28 and 29, and in extracellular clumps, highlighting 29, with MIC50 5.6 ± 1.2 µM. Regarding inflammation, they inhibited NO through the suppression of iNOS expression, and also inhibited the production of TNF-α and IL-1β. In silico studies were carried out suggesting that these five compounds could be administered by oral route and have low toxicological effects when compared to rifampicin. In conclusion, our data show that, at least, thiourea derivatives 16, 28 and 29 are promising antimycobacterial and anti-inflammatory agents, and candidates for further prospective studies aiming new anti-TB drugs, that can be used on a dual approach for the treatment of severe TB cases associated with exacerbated inflammation.
To evaluate the addition of dimethylaminohexadecyl methacrylate (DMAHDM) and chlorhexidine diacetate on cytotoxicity, antimicrobial activity, physical, and mechanical properties of a self-cured ...resin.
132 disk-shaped and 48 rectangular specimens were divided into four experimental groups as described: Control Group (CG – no addition), dCHX (1%), DMAHDM (5%), and DMAHDM+dCHX (5%+1%). The biofilm viability, flexural strength (FS - ISO 20795-1:2013), surface roughness (SR), and color stability (ΔE) were analyzed after being stored for 4 weeks in distilled water and immersed for 72h in coffee. Cytotoxicity was measured after 24h, 3, and 7 days of elution using an MTT test on L929 cells (ISO 10993-5:2009). SR and ΔE were measured by a contact profilometer and a spectrophotometer using the CIELab parameter. Data were submitted to ANOVA and Bonferroni’s/Tukey’s tests (p≤0.05).
Significant antimicrobial activity against Streptococcus mutans and Candida albicans was detected in all groups when compared to the CG (p<0.05). Only the dCHX group, in 24h of elution, demonstrated no cytotoxicity effects. There was a statistical difference for FS on the tested groups (p<0.05). No differences were detected in the initial roughness’ measurements among the groups (p>0.05). However, after storage and immersion in coffee, the groups containing DMAHDM presented with rougher surfaces and significantly lower color stability compared to the control (p<0.05).
The addition of dCHX and DMAHDM in self-cured resin presented antimicrobial properties; however, cytotoxicity, physical, and mechanical properties were compromised.
In this paper, we describe the antinociceptive activity, molecular modeling and
in silico
ADMET screening of a series of sulphonyl-hydrazone and sulphonamide imidobenzene derivatives. Among these ...compounds, the sulphonyl-hydrazones
9
and
11
showed the most potent analgesic activity (ID
50
= 5.1 and 6.8 μmol/kg, respectively). Interestingly, all derivatives evaluated in this study have a better analgesic profile than the control drugs, acetyl salicylic acid and acetaminophen. Derivative
9
was the most promising compound; with a level of activity that was 24 times higher than the control drugs. Our SAR study showed a relationship among the distribution of the frontier orbital HOMO coefficients, HOMO-LUMO energy gap of these molecules and their reactivity. The best analgesic compounds (including
6, 9, 10, 11
and
12
) fulfilled the Lipinski “rule-of-five”, which is theoretically important for good drug absorption and permeation.
This study evaluated the influence of experimental composites containing quaternary ammonium monomers (QAM) at different concentrations and alkyl chains on demineralization at enamel-composite ...margins after cariogenic challenge.
Standardized 4×4mm cavities were cut into 35 bovine enamel blocks, which were randomly divided into seven groups (n=5) and restored with the following experimental composites and commercial materials: (G12.5) – 5% dimethylaminododecyl methacrylate (DMADDM) with a 12-carbon alkyl chain (G12.10) – 10% DMADDM, (G16.5) – 5% dimethylaminohexadecyl methacrylate (DMAHDM) with a 16-carbon alkyl chain (G16.10) – 10% DMAHDM, (CG) – control group (without QAM), (GZ250) – commercial composite (Filtek Z250®), and (GIC) – glass ionomer cement (Maxxion R®). After restorative procedures, initial microhardness was measured and experimental composites were subjected to Streptococcus mutans biofilm formation for 48h. After cariogenic challenge, the samples were washed and microhardness was reassessed. A 3D non-contact profilometer was used to determine surface roughness and enamel demineralization was assessed by micro-CT. Microhardness results were analyzed by the Kruskal–Wallis and Mann-Whitney tests and micro-CT results were analyzed by Tukey’s HSD test (95% confidence interval).
None of the materials could prevent mineral loss at the enamel-restoration margins. The addition of 10% DMAHDM yielded the lowest, albeit statistically significant, mineral loss (p<0.05). 3D non-contact profilometry showed enamel surface roughness modification after biofilm exposure. The CG had the highest roughness values. Micro-CT analysis revealed mineral loss, except for GIC.
The addition of 10% QAM with a 16-carbon chain in experimental composites reduced mineral loss at the enamel-restoration margins after cariogenic challenge.
Four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis was applied on a series of 54 2-arylbenzothiophene derivatives, synthesized by Grese and coworkers, based on ...raloxifene (an estrogen receptor-alpha antagonist), and evaluated as ERa ligands and as inhibitors of estrogen-stimulated proliferation of MCF-7 breast cancer cells. The conformations of each analogue, sampled from a molecular dynamics simulation, were placed in a grid cell lattice according to three trial alignments, considering two grid cell sizes (1.0 and 2.0 Å). The QSAR equations, generated by a combined scheme of genetic algorithms (GA) and partial least squares (PLS) regression, were evaluated by "leave-one-out" cross-validation, using a training set of 41 compounds. External validation was performed using a test set of 13 compounds. The obtained 4D-QSAR models are in agreement with the proposed mechanism of action for raloxifene. This study allowed a quantitative prediction of compounds' potency and supported the design of new raloxifene analogs.
Friedreich’s Ataxia (FRDA) stands out as the most prevalent form of hereditary ataxias, marked by progressive movement ataxia, loss of vibratory sensitivity, and skeletal deformities, severely ...affecting daily functioning. To date, the only medication available for treating FRDA is Omaveloxolone (Skyclarys®), recently approved by the FDA. Missense mutations within the human frataxin (FXN) gene, responsible for intracellular iron homeostasis regulation, are linked to FRDA development. These mutations induce FXN dysfunction, fostering mitochondrial iron accumulation and heightened oxidative stress, ultimately triggering neuronal cell death pathways. This study amalgamated 226 FXN genetic variants from the literature and database searches, with only 18 previously characterized. Predictive analyses revealed a notable prevalence of detrimental and destabilizing predictions for FXN mutations, predominantly impacting conserved residues crucial for protein function. Additionally, an accurate, comprehensive three-dimensional model of human FXN was constructed, serving as the basis for generating genetic variants I154F and W155R. These variants, selected for their severe clinical implications, underwent molecular dynamics (MD) simulations, unveiling flexibility and essential dynamic alterations in their N-terminal segments, encompassing FXN42, FXN56, and FXN78 domains pivotal for protein maturation. Thus, our findings indicate potential interaction profile disturbances in the FXN42, FXN56, and FXN78 domains induced by I154F and W155R mutations, aligning with the existing literature.
The development of nanosystems in the pharmaceutical field has been growing in recent years. Polymers in particular are attractive since they can enable controlled release. Furthermore, surface ...modification is essential to increase nanosystem stability and prolong the blood circulation time. In this context, the present study obtained polycaprolactone (PCL) nanoparticles coated with poly(ethylene oxide)–poly(propylene oxide) triblock copolymer using the nanoprecipitation method, aiming to evaluate the effect of PCL concentration in this type of pharmaceutical formulation on prolongation of drug release. Nanosuspensions were evaluated by the following techniques: FT-IR, DLS, FESEM, TEM, ZP, TGA, DSC, XRD and TD-NMR. With higher PCL concentration, the particle size also increased and negative surface charge was observed. The nanoparticles' spherical shape was confirmed by FESEM and TEM while XRD and TD-NMR revealed changes in Pluronic chains' organization around the PCL matrix. Although this kind of polymer combination is already known in the pharmaceutical field, structural and molecular mobility evaluation with new perspectives were performed, mainly by XRD and TD-NMR.
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