Assessment of color changes and adverse effects of over-the-counter bleaching protocols: a systematic review and network meta-analysis.

OBJECTIVES: To assess color change efficacy and the adverse effects of varied over-the-counter (OTC) bleaching protocols. METHODOLOGY: The study included randomized clinical trials evaluating color changes from OTC bleaching agents. Nine databases were searched, including the partial capture of the grey literature. The RoB2 tool analyzed the individual risk of bias in the studies. Frequentist network meta-analyses compared treatments through common comparators (∆Eab* and ∆SGU color changes, and tooth sensitivity), integrating direct and indirect estimates and using the mean and risk differences as effect measures with respective 95% confidence intervals. The GRADE approach assessed the certainty of the evidence. RESULTS: Overall, 37 remaining studies constituted the qualitative analysis, and ten composed the meta-analyses. The total sample included 1,932 individuals. ∆Eab* was significantly higher in groups 6% hydrogen peroxide (HP) strips (≥ 14 h). ∆SGU was significantly higher in groups at-home 10% carbamide peroxide (CP) (≥ 14 h), followed by 6% HP strips (≥ 14 h) and 3% HP strips (≥ 14 h). At-home 10% CP (7-13 h) and placebo showed lower risks of tooth sensitivity without significant differences between these treatments. CONCLUSION: Considering the low level of evidence, OTC products presented satisfactory short-term effects on tooth bleaching compared to the placebo, with little to no impact on dentin hypersensitivity and gingival irritation. CLINICAL RELEVANCE: OTC products are proving to be practical alternatives for tooth whitening. However, patients should be advised about the possible risks of carrying out such procedures without professional supervision.

Sodium butyrate-loaded nanoparticles coated with chitosan for the treatment of neovascularization in age-related macular degeneration: Ocular biocompatibility and antiangiogenic activity.

Sodium butyrate-loaded nanoparticles coated chitosan (NaBu-loaded nanoparticles/CS) were developed to treat the choroidal neovascularization in wet age-related macular degeneration (AMD). The nanoparticles were produced by double emulsification and solvent evaporation technique, optimized by experimental statistical design, characterized by analytical methods, investigated in terms of in vitro and in vivo ocular biocompatibility, and evaluated as an antiangiogenic system in vivo. The NaBu-loaded nanoparticles/CS were 311.1 ± 3.1 nm in diameter with a 0.208 ± 0.007 polydispersity index; had a +56.3 ± 2.6 mV zeta potential; showed a 92.3 % NaBu encapsulation efficiency; and sustained the drug release over 35 days. The NaBu-loaded nanoparticles/CS showed no toxicity to human retinal pigment epithelium cells (ARPE-19 cells); was not irritant to the chorioallantoic membrane (CAM); did not interfere in the integrity of the retinal layers of rat's eyes, as detected by the Optical Coherence Tomography and histopathology; and inhibited the angiogenesis in CAM assay. The NaBu-loaded nanoparticles/CS could be a therapeutic alternative to limit the neovascularization in AMD.

Postoperative Pain Following Root Canal Instrumentation Using ProTaper Next or Reciproc in Asymptomatic Molars: A Randomized Controlled Single-Blind Clinical Trial.

Aim: The development of postoperative pain following root canal instrumentation may impair patient's comfort and undermine their trust in the dentist. This study assessed the effect of root canal instrumentation techniques (rotary (PTN; ProTaper Next®) and reciprocating (R; Reciproc®)) on the postoperative pain intensity (primary outcome) and tenderness on biting (secondary outcome) of patients' asymptomatic molars. Methodology: This study protocol was registered with ReBec-WHO (U1111-1182-2800). From a pool of 112 patients evaluated for eligibility (healthy adults (≤18 years old)), with a single asymptomatic molar (maxillary or mandibular) indicated for root canal treatment, diagnosed with asymptomatic irreversible pulpitis (including chronic hyperplastic pulpitis), 75 were randomly allocated in similar proportions to receive the intervention (two-appointment root canal therapy) in either the PTN or R group. The allocated procedures were performed using standardized protocols. Participants (blinded to the instrumentation technique) rated their pain intensity at 6, 12 and 24 h and from day 2 to day 7 following the root canal instrumentation appointment using a VAS and an NRS; the ibuprofen tablets taken and the presence of tenderness on biting were recorded. The instrumentation time was registered. Univariate and multivariate statistics measured the effect of independent variables on the outcomes. Results: From the 75 patients allocated, 8 patients (4 from each group) were lost; in total, 33 patients were analyzed in the PTN group and 34 in the R group. The frequencies of postoperative pain (p > 0.05) and tenderness on biting (p > 0.05) were similar between groups. The medication intake (mean of 1.31 tablets) and the time of instrumentation (approximately 11 min) were similar between groups. Conclusion: ProTaper Next and Reciproc® caused a slight risk of tenderness on biting and contributed to similar self-reported postoperative pain (low intensity) up to 7 days following root canal shaping.

Effect of an enamel matrix derivative (Emdogain) on the microhardness and chemical composition of human root dentin: an in vitro study.

The advantage of using an Enamel matrix derivative EMD Emdogain as an intracanal medication could be a manner to strength the tooth structure, improving the physical and chemical properties of dentin. We tested, in vitro, the effect of Emdogain on the surface microhardness and chemical composition of root dentin. Ten human teeth were used to produce dentin specimens originated from the canal walls (n = 30) that remained in contact to Emdogain gel for 90 days. Baseline and 90-days after Emdogain treatment measurements were performed using Fourier Transform Infrared Spectroscopy (ATR/FTIR), Scanning Electron Microscopy/Energy Dispersive Spectroscopy (SEM/EDS) and Knoop indenters. The use of EMD (Emdogain) for 90 days in contact with human root canal dentin specimens did not alter the microhardness and morphology of dentin. The elemental structure of dentin was altered because there was a reduction in carbonate content.

Does polishing of bleached enamel affect roughness and tooth color stability after exposure to coffee?

OBJECTIVE: This laboratory randomized study was designed to evaluate the effect of polishing on roughness and color stability of bleached teeth after coffee immersion. MATERIALS AND METHODS: Ninety bovine crowns were randomly allocated to six groups (n = 15), according to bleaching protocols: At-home: standard protocol using 10% hydrogen peroxide (HP) or In-office: standard protocol using 35% HP; and with polishing protocols: (1) no polishing, (2) bleached enamel polished with #0.5 µm or (3) #2-4 µm diamond particles grit pastes. Samples were daily immersed into coffee solution for 45 min followed by mechanical brushing simulation (30 s) for 30 days. The surface roughness (Ra) and color alteration, expressed by ΔEab , ΔE00 , and whitening index (WI) were analyzed at baseline, after bleaching/polishing protocols and after coffee solution staining. The surface from each group was examined using a scanning electron microscope. Data were analyzed by two-way repeated measure analysis of variance followed by the Tukey test (α = 0.05). RESULTS: Staining increases Ra, ΔEab , ΔE00 , and decreases WI values. Polishing after bleaching did not prevent staining, however, tooth polished with #0.5 µ-grit polishing paste showed better performance than #2-4 µ-grit (ΔEab : p = 0.001/ΔE00 : p = 0.003). Scanning electron microscope revealed a more irregular surface after coffee staining for all groups regardless bleaching/polishing protocols. CONCLUSIONS: Using #0.5 µ-grit diamond paste to polish 35%HP in-office bleached enamel reduces the roughness and tooth staining. However, polishing after 10%HP at-home bleached enamel neither affects roughness nor improves tooth color stability after exposure to coffee. CLINICAL SIGNIFICANCE: Polishing after at-home bleaching does not have benefits but after 35% hydrogen peroxide in-office bleaching, the polishing with #0.5 µ-grit polishing paste is indicated to reduce roughness and the tooth staining over time.

Biological parameters, discolouration and radiopacity of calcium silicate-based materials in a simulated model of partial pulpotomy.

AIM: To analyse the discolouration, radiopacity, pH and calcium ion release of Biodentine (BD), Bio-C repair (BCR) and Bio-C temp (BCT), as well as their biological effects on human dental pulp cells (hDPCs). METHODOLOGY: Sixty-four extracted bovine incisors were prepared to simulate crown fractures with pulp exposure and open root apex. The roots were filled using a mixture of agar and blood (control), and BD, BCR or BCT were placed over this mixture. Colour assessment analyses of the samples were performed before and immediately after material insertion and repeated at 30 and 90 days, using a spectrophotometer. The colour change of each specimen was evaluated at the crown and calculated based on the CIELab colour space. Digital radiographs were acquired for radiopacity analysis. hDPCs were placed in contact with different dilutions of culture media previously exposed to such materials and tested for cell viability using the MTT assay. The pH and calcium ion release of all materials were measured after 24 h; the data were assessed using one-way analysis of variance (ANOVA). Cell viability was analysed by two-way ANOVA. Differences in colour parameters and wound-healing data were assessed by two-way repeated measures ANOVA (α = 0.05). Tukey's and Dunnett's tests were used to compare the experimental groups with the control group. RESULTS: BCR had grater radiopacity and smaller colour alteration (ΔEab/ΔE00) than the other materials tested (p < .005; p < .001). No significant differences in pH were found amongst the tested materials (p > .05). BCT was associated with the largest release of calcium ions (p < .0001). BD had cell viability similar to that of the control at the lowest dilutions, and BCR was similar to that of the control, regardless of the dilution tested (p > .05). BCT had a lower percentage of viability than that of the control at all tested dilutions (p < .0001). Cell migration rates in BD and BCR were similar to those in the control group after 24 h and 48 h (p > .05), whilst BCT had larger voids than the control in both periods (p < .0001). CONCLUSIONS: BCR, BCT and BD were associated with tooth discolouration. BCR had the lowest staining values, the highest radiopacity and viability greater than 80% hDPCs.

A meta-analysis of ozone effect on tooth bleaching.

This systematic review assessed the effectiveness of ozone (O3) in the color change of in-office tooth bleaching in vital teeth (TB) and the sensitivity control. Only randomized controlled clinical trials were included. Seven databases were used as primary search sources, and three additional sources were searched to capture the "grey literature" partially. The JBI tool was used to assess the risk of bias. TB was assessed using the ΔELab color change metric comparing tooth color pre- and post-bleaching. We meta-analyzed the ΔELab estimates per method and calculated the absolute standardized mean difference using random-effect models. The GRADE approach assessed the certainty of the evidence. The ΔELab estimates ranged from 1.28 when the O3 was used alone to 6.93 when combined with hydrogen peroxide (HP). Two studies compared O3 and HP alone, but their TB was similar (SMD = - 0.02; 95%CI: - 0.54; 0.49). The bleaching effectiveness for the combination of O3 + HP compared to HP was similar (SMD = 0.38; 95%CI: - 0.04; 0.81). Thus, based on the available literature, our findings suggest that O3 is not superior to the conventional technique using HP on the change of tooth color. The O3 did not present sensitivity when used alone. When O3 was used in combination with HP, patients reported hypersensitivity only when O3 was applied before HP, i.e., no sensitivity was perceived when O3 was applied after HP.

Vancomycin-loaded N,N-dodecyl,methyl-polyethylenimine nanoparticles coated with hyaluronic acid to treat bacterial endophthalmitis: Development, characterization, and ocular biocompatibility.

Vancomycin-loaded N,N-dodecyl,methyl-polyethylenimine nanoparticles coated with hyaluronic acid (VCM-DMPEI nanoparticles/HA) were synthesized as an adjuvant for the treatment of bacterial endophthalmitis. The nanoparticles were formulated by experimental statistical design, thoroughly characterized, and evaluated in terms of bactericidal activity and both in vitro and in vivo ocular biocompatibility. The VCM-DMPEI nanoparticles/HA were 154 ± 3 nm in diameter with a 0.197 ± 0.020 polydispersity index; had a + 26.4 ± 3.3 mV zeta potential; exhibited a 93% VCM encapsulation efficiency; and released 58% of the encapsulated VCM over 96 h. VCM and DMPEI exhibited a synergistic bactericidal effect. The VCM-DMPEI nanoparticles/HA were neither toxic to ARPE-19 cells nor irritating to the chorioallantoic membrane. Moreover, the VCM-DMPEI nanoparticles/HA did not induce modifications in retinal functions, as determined by electroretinography, and in the morphology of the ocular tissues. In conclusion, the VCM-DMPEI nanoparticles/HA may be a useful therapeutic adjuvant to treat bacterial endophthalmitis.

Practice-based analysis of direct posterior dental restorations performed in a public health service: Retrospective long-term survival in Brazil.

The aim of this retrospective study was to evaluate the survival and associated factors for the longevity of direct posterior restorations and to verify whether the geographic location of public health units could influence the long-term survival of such restorations. Data were extracted from electronic patient files of the Brazilian public oral health services. The sample comprised 2,405 class I and II restorations performed 4 to 24 years ago (mean, 8.9 years) in 351 patients (6.8 teeth/patient) across 12 public health units located in different city regions (42 professionals-55 restorations). The restoration was considered successful if it had not been repaired or replaced at the time of evaluation; failure was defined as replacement of the restoration, the need for endodontic treatment, tooth/restoration fracture or tooth extraction. Data were analyzed using the Kaplan-Meier test for restoration survival and Cox regression to evaluate the factors associated with failure. The majority of the restorations involved the use of amalgam (85%), involved a single face (70%), and were without pulp/dentin capping (85%). The overall survival rate was 95%, and the mean observation time was 8.9 years. The restoration survival was 79% (95% CI: 60.6-89.5) over 24 years, and the mean survival time was 22.2 years (95% CI: 21.9-22.6 years). The annual failure rate up to 24 years was 0.9%. After the adjustment, only the number of restored faces and the geographic location where the restoration was performed remained associated with failure of the restoration. The direct posterior restorations performed at the evaluated public health service units presented high survival rates. The restorations of people with lower access to POHS had lower survival rates. Class I restorations presented higher survival rates than class II restorations with two or more faces, regardless of the restorative material used.

Amphotericin B-loaded Eudragit RL100 nanoparticles coated with hyaluronic acid for the treatment of vulvovaginal candidiasis.

The treatment of vulvovaginal candidiasis (VVC) is based on oral and vaginal formulations which show limited effectiveness. In this study, amphotericin B-loaded Eudragit RL100 nanoparticles coated with hyaluronic acid (AMP EUD nanoparticles/HA) were developed to overcome the drawbacks of the conventional formulations. AMP EUD nanoparticles/HA were synthesized by nanoprecipitation, formulated by statistical experimental design, and characterized. AMP release from EUD nanoparticles/HA and its antifungal activity in a murine model of VVC were evaluated. Nanoparticles showed 147.6 ±â€¯16.7 nm of diameter, 0.301 ±â€¯0.09 of polydispersity index, - 29.9 ±â€¯3.76 mV of zeta potential, and 87.27 % of encapsulation efficiency. They released about 81 % of AMP in 96 h; and provided the elimination of 100 % of the vaginal fungal burden in 24 h. It was suggested that the AMP EUD nanoparticles/HA penetrated into the vaginal epithelium via CD44 receptors. These AMP EUD nanoparticles/HA represent a non-conventional vaginal formulation to improve the treatment of VVC.

A long-term evaluation of experimental potassium oxalate concentrations on dentin hypersensitivity reduction: A triple-blind randomized clinical trial.

OBJECTIVE: The aim of this split-mouth, triple-blind, randomized clinical trial was to evaluate the long-term clinical efficacy of experimental potassium oxalate concentration (10%) in relieving dentin hypersensitivity (DH), after a four-session application protocol. METHODS: Potassium oxalate gels with different concentrations (5 and 10%) were randomly assigned to half of the 31 patients from the sample in a split-mouth design. The desensitizers were applied following a four-session protocol, one session every 48 h. The primary outcome was the assessment of pain level with the visual analog scale (VAS, 0-10), at baseline, immediately after each desensitizing session, and also after the seventh day and along 1-,3-, 6-, 9- and 12-months follow-ups. Statistical analyses were performed using Friedman repeated measures and Wilcoxon signed rank tests (α = 0.05). RESULTS: For both groups, the minimum of three sessions were required for the achievement of lower DH levels. Regardless of the concentration, the desensitizing effect was maintained all the way to the end of the 6-month follow-up. The 10%-potassium oxalate group was more effective for both 9 and 12-months follow-up periods (p < 0.001). No complications and adverse effects were observed. CONCLUSIONS: When a four-session protocol is applied, both concentrations of potassium oxalate (5 and 10%) proved to be effective on DH reduction for up to six months. However, the higher concentration promoted better long-term results. CLINICAL SIGNIFICANCE: The DH is an increasing condition in clinical practice, which affects the patient's life quality. This study provides primary clinical evidence, suggesting that multiple application sessions and higher concentrations of potassium oxalate may result in maintenance of the desensitizing effect for more extended periods. Trial registered under number: ClinicalTrials.gov NCT03083496.

Improvement of antimalarial activity of a 3-alkylpiridine alkaloid analog by replacing the pyridine ring to a thiazole-containing heterocycle: Mode of action, mutagenicity profile, and Caco-2 cell-based permeability.

The development of new antimalarial drugs is urgent to overcome the spread of resistance to the current treatment. Herein we synthesized the compound 3, a hit-to­lead optimization of a thiazole based on the most promising 3-alkylpyridine marine alkaloid analog. Compound 3 was tested against Plasmodium falciparum and has shown to be more potent than its precursor (IC50 values of 1.55 and 14.7 µM, respectively), with higher selectivity index (74.7) for noncancerous human cell line. This compound was not mutagenic and showed genotoxicity only at concentrations four-fold higher than its IC50. Compound 3 was tested in vivo against Plasmodium berghei NK65 strain and inhibited the development of parasite at 50 mg/kg. In silico and UV-vis approaches determined that compound 3 acts impairing hemozoin crystallization and confocal microscopy experiments corroborate these findings as the compound was capable of diminishing food vacuole acidity. The assay of uptake using human intestinal Caco-2 cell line showed that compound 3 is absorbed similarly to chloroquine, a standard antimalarial agent. Therefore, we present here compound 3 as a potent new lead antimalarial compound.

Ocular biocompatibility of dexamethasone acetate loaded poly(ɛ-caprolactone) nanofibers.

Electrospinning technique has been explored to produce nanofibers incorporated with drugs as alternative drug delivery systems for therapeutic purposes in various organs and tissues. Before such systems could potentially be used, their biocompatibility must be evaluated. In this study, dexamethasone acetate-loaded poly(ɛ-caprolactone) nanofibers (DX PCL nanofibers) were developed for targeted delivery in the vitreous cavity in the treatment of retinal diseases. Ocular biocompatibility was tested in vitro and in vivo. DX PCL nanofibers were characterized by scanning electron microscopy (SEM) and Fourier Transform InfraRed spectroscopy (FTIR) and the in vitro drug release from nanofibers was evaluated. The in vitro biocompatibility of DX PCL nanofibers was tested on both ARPE-19 and MIO-M1 cells using the cytotoxicity (MTT) test by morphological studies based on staining of the actin fibers in ARPE-19 cells and GFAP in MIO-M1 cells. The in vivo biocompatibility of DX PCL nanofibers was investigated after intravitreous injection in the rat eye, using spectral domain Optical Coherence Tomography (OCT) imaging of the retina. SEM results indicated that nanometric fibers were interconnected in a complex network, and that they were composed of polymer. FTIR showed that polymer and drug did not chemically interact after the application of the electrospinning technique. PCL nanofibers provided controlled DX release for 10 days. DX PCL nanofibers were not cytotoxic to the ocular cells, allowing for the preservation of actin fibers and GFAP in the cytoplasm of ARPE-19 and MIO-M1 cells, respectively, which are biomarkers of these ocular cell populations. DX PCL nanofibers did not affect the retinal and choroidal structures, and they did not induce abnormalities, hemorrhages, or retinal detachment, suggesting that the nanofibers were well tolerated. In eyes receiving DX PCL nanofibers, SD-OCT images were corroborated with histological analysis of neuroretina and choroid, which are ocular tissues that are extremely sensitive to toxic agents. Finally, the preservation of cone and rod photoreceptors indicated the light sensitivity of the animals. In conclusion, DX PCL nanofibers exhibited ocular biocompatibility and safety in the rodent eye and allow the release of dexamethasone. Further studies are required to appreciate the potential of these new drug delivery systems for the treatment of retinal diseases.

Amphotericin B-Loaded Poly(lactic-co-glycolic acid) Nanofibers: An Alternative Therapy Scheme for Local Treatment of Vulvovaginal Candidiasis.

Vulvovaginal candidiasis is an inflammation localized in the vulvovaginal area. It is mostly caused by Candida albicans. Its treatment is based on the systemic and local administration of antifungal drugs. However, this conventional therapy can fail owing to the resistance of the Candida species and noncompliance of patients. Amphotericin B-loaded poly(lactic-co-glycolic acid) nanofibers are single-use, antifungal, controlled drug delivery systems, and represent an alternative therapeutic scheme for the local treatment of vulvovaginal candidiasis. Nanofibers were characterized by analytical techniques and with an in vitro drug delivery study. In vitro and in vivo fungicidal activity of amphotericin B released from nanofibers was evaluated using the agar diffusion method and an experimental murine model of vulvovaginal candidiasis, respectively. Analytical techniques showed that amphotericin B was physically mixed in the polymeric nanofibers. Nanofibers controlled the delivery of therapeutic doses of amphotericin B for 8 consecutive days, providing effective in vitro antifungal activity and eliminated the in vivo vaginal fungal burden after 3 days of treatment and with only one local application. Amphotericin B-loaded poly(lactic-co-glycolic acid) nanofibers could be potentially applied as an alternative strategy for the local treatment of vulvovaginal candidiasis without inducing fungal resistance, yet ensuring patient compliance.

Etoposide-Loaded Poly(Lactic-co-Glycolic Acid) Intravitreal Implants: In Vitro and In Vivo Evaluation.

Etoposide-loaded poly(lactic-co-glycolic acid) implants were developed for intravitreal application. Implants were prepared by a solvent-casting method and characterized in terms of content uniformity, morphology, drug-polymer interaction, stability, and sterility. In vitro drug release was investigated and the implant degradation was monitored by the percent of mass loss. Implants were inserted into the vitreous cavity of rabbits' eye and the in vivo etoposide release profile was determined. Clinical examination and the Hen Egg Test-Chorioallantoic Membrane (HET-CAM) method were performed to evaluate the implant tolerance. The original chemical structure of the etoposide was preserved after incorporation in the polymeric matrix, which the drug was dispersed uniformly. In vitro, implants promoted sustained release of the drug and approximately 57% of the etoposide was released in 50 days. In vivo, devices released approximately 63% of the loaded drug in 42 days. Ophthalmic examination and HET-CAM assay revealed no evidence of toxic effects of implants. These results tend to show that etoposide-loaded implants could be potentially useful as an intraocular etoposide delivery system in the future.

Ocular safety of Intravitreal Clindamycin Hydrochloride Released by PLGA Implants.

BACKGROUND: Drug ocular toxicity is a field that requires attention. Clindamycin has been injected intravitreally to treat ocular toxoplasmosis, the most common cause of eye posterior segment infection worldwide. However, little is known about the toxicity of clindamycin to ocular tissues. We have previously showed non intraocular toxicity in rabbit eyes of poly(lactic-co-glycolic acid) (PLGA) implants containing clindamycin hydrochloride (CLH) using only clinical macroscotopic observation. In this study, we investigated the in vivo biocompatibility of CLH-PLGA implants at microscotopic, cellular and molecular levels. METHODS: Morphology of ARPE-19 and MIO-M1 human retinal cell lines was examined after 72 h exposure to CLH-PLGA implant. Drug delivery system was also implanted in the vitreous of rat eyes, retinal morphology was evaluated in vivo and ex vivo. Morphology of photoreceptors and inflammation was assessed using immunofluorescence and real-time PCR. RESULTS: After 72 h incubation with CLH-PLGA implant, ARPE-19 and MIO-M1 cells preserved the actin filament network and cell morphology. Rat retinas displayed normal lamination structure at 30 days after CLH-PLGA implantation. There was no apoptotic cell and no loss in neuron cells. Cones and rods maintained their normal structure. Microglia/macrophages remained inactive. CLH-PLGA implantation did not induce gene expression of cytokines (IL-1ß, TNF-α, IL-6), VEGF, and iNOS at day 30. CONCLUSION: These results demonstrated the safety of the implant and highlight this device as a therapeutic alternative for the treatment of ocular toxoplasmosis.

Methotrexate Locally Released from Poly(ε-Caprolactone) Implants: Inhibition of the Inflammatory Angiogenesis Response in a Murine Sponge Model and the Absence of Systemic Toxicity.

In this study, the methotrexate (MTX) was incorporated into the poly(ε-caprolactone) (PCL) to design implants (MTX PCL implants) aiming the local treatment of inflammatory angiogenesis diseases without causing systemic side effects. Sponges were inserted into the subcutaneous tissue of mice as a framework for fibrovascular tissue growth. After 4 days, MTX PCL implants were also introduced, and anti-inflammatory, antiangiogenic, and antifibrogenic activities of the MTX were determined. MTX reduced the vascularization (hemoglobin content), the neutrophil, and monocyte/macrophage infiltration (MPO and NAG activities, respectively), and the collagen deposition in sponges. MTX reduced tumor necrosis factor-α and IL-6 levels, demonstrating its local antiangiogenic and anti-inflammatory effects. Furthermore, hepatotoxicity, nephrotoxicity, and myelotoxicity, which could be induced by the drug, were evaluated. However, MTX did not promote toxicity to these organs, as the levels of AST and ALT (hepatic markers) and creatinine and urea (renal markers) were not increased, and the complete blood count was not decreased. In conclusion, MTX PCL implants demonstrated to be effective in regulating the components of the inflammatory angiogenesis locally established, and presented an acceptable safety profile.

Development of thalidomide-loaded biodegradable devices and evaluation of the effect on inhibition of inflammation and angiogenesis after subcutaneous application.

PURPOSE: To develop thalidomide-loaded poly-lactide-co-glycolide implants and evaluate its in vivo release and biological activity against inflammation and angiogenesis after subcutaneous administration. METHODS: Implants were prepared by the hot molding technique and characterized using stereomicroscopy, thermal analysis and X-ray diffraction. Swiss mice, divided in groups 1-3, received a subcutaneous implant containing 25% (w/w), 50% (w/w) or 75% (w/w) of thalidomide, respectively (n=6). The drug levels were determined during a 28-day study period. The toxicity associated with the implants was evaluated by light microscopy. The potential of the developed implant in the inhibition of inflammation and angiogenesis was evaluated in vivo using the sponge model. RESULTS: Thalidomide implant was developed and its characterization proved the stability of the drug and the polymer during preparation. Release profiles in vivo demonstrated an extended release of thalidomide from the implants during the 28 days. Histological evaluation did not show any sign of intense local inflammatory response to the presence of the implants in the subcutaneous pouch. The thalidomide implant reduced the number of vessels and N-acetyl-b-glucosaminidase (NAG) in vivo. CONCLUSION: The biodegradable implants delivered safe doses of thalidomide that were also effective to induce angiogenesis and inflammation regression.

In vitro and in vivo ocular biocompatibility of electrospun poly(ɛ-caprolactone) nanofibers.

Biocompatibility is a requirement for the development of nanofibers for ophthalmic applications. In this study, nanofibers were elaborated using poly(ε-caprolactone) via electrospinning. The ocular biocompatibility of this material was investigated. MIO-M1 and ARPE-19 cell cultures were incubated with nanofibers and cellular responses were monitored by viability and morphology. The in vitro biocompatibility revealed that the nanofibers were not cytotoxic to the ocular cells. These cells exposed to the nanofibers proliferated and formed an organized monolayer. ARPE-19 and MIO-M1 cells were capable of expressing GFAP, respectively, demonstrating their functionality. Nanofibers were inserted into the vitreous cavity of the rat's eye for 10days and the in vivo biocompatibility was investigated using Optical Coherence Tomography (OCT), histology and measuring the expression of pro-inflammatory genes (IL-1ß, TNF-α, VEGF and iNOS) (real-time PCR). The OCT and the histological analyzes exhibited the preserved architecture of the tissues of the eye. The biomaterial did not elicit an inflammatory reaction and pro-inflammatory cytokines were not expressed by the retinal cells, and the other posterior tissues of the eye. Results from the biocompatibility studies indicated that the nanofibers exhibited a high degree of cellular biocompatibility and short-term intraocular tolerance, indicating that they might be applied as drug carrier for ophthalmic use.

Development of a method to quantify clindamycin in vitreous humor of rabbits' eyes by UPLC-MS/MS: application to a comparative pharmacokinetic study and in vivo ocular biocompatibility evaluation.

Ocular toxoplasmosis may result in uveitis in the posterior segment of the eye, leading to severe visual complications. Clindamycin-loaded poly(lactide-co-glycolide) (PLGA) implants could be applied to treat the ocular toxoplasmosis. In this study, the pharmacokinetic profiles of the drug administrated by PLGA implants and by intravitreal injections in rabbits' eyes were evaluated. The implant released the drug for 6 weeks while the drug administrated by intravitreal injections remained in the vitreous cavity for 2 weeks. Compared to the injected drug, the implants containing clindamycin had higher values of area under the curve (AUC) (39.2 vs 716.7 ng week mL(-1)) and maximum vitreous concentration (Cmax) (8.7 vs 13.83 ng mL(-1)). The implants prolonged the delivery of clindamycin and increased the contact of the drug with the eyes' tissues. Moreover, the in vivo ocular biocompatibility of the clindamycin-loaded PLGA implants was evaluated regarding to the clinical examination of the eyes and the measurement of the intraocular pressure (IOP) during 6 weeks. The implantable devices caused no ocular inflammatory process and induced the increase of the IOP in the fourth week of the study. The IOP augmentation could be related to the maximum concentration of clindamycin released from the implants. In conclusion, the PLGA implants based on clindamycin may be a therapeutic alternative to treat ocular toxoplasmosis.