Prevalence of errors causing events allegedly attributable to vaccination/immunization: systematic review and meta-analysis.

OBJECTIVE: To identify the prevalence of errors that caused events supposedly attributable to vaccination or immunization. METHOD: Systematic literature review with meta-analysis carried out on the Medline, Cochrane Library, Cinahl, Web of Science, Lilacs, Scopus; Embase; Open Grey; Google Scholar; and Grey Lit databases; with studies that presented the prevalence of immunization errors that caused events or that provided data that allowed this indicator to be calculated. RESULTS: We evaluated 11 articles published between 2010 and 2021, indicating a prevalence of 0.044 errors per 10,000 doses administered (n=762; CI95%: 0.026 - 0.075; I2 = 99%, p < 0.01). The prevalence was higher in children under 5 (0.334 / 10,000 doses; n=14). The predominant events were fever, local pain, edema and redness. CONCLUSION: A low prevalence of errors causing events was identified. However, events supposedly attributable to vaccination or immunization can contribute to vaccine hesitancy and, consequently, have an impact on vaccination coverage.

Prevalence of errors causing events allegedly attributable to vaccination/immunization: systematic review and meta-analysis / Prevalencia de errores causantes de acontecimientos supuestamente atribuibles a la vacunación/inmunización: revisión sistemática y metanálisis / Prevalência de erros que causaram eventos supostamente atribuíveis à vacinação/imunização: revisão sistemática e metanálise

ABSTRACT Objective: To identify the prevalence of errors that caused events supposedly attributable to vaccination or immunization. Method: Systematic literature review with meta-analysis carried out on the Medline, Cochrane Library, Cinahl, Web of Science, Lilacs, Scopus; Embase; Open Grey; Google Scholar; and Grey Lit databases; with studies that presented the prevalence of immunization errors that caused events or that provided data that allowed this indicator to be calculated. Results: We evaluated 11 articles published between 2010 and 2021, indicating a prevalence of 0.044 errors per 10,000 doses administered (n=762; CI95%: 0.026 - 0.075; I2 = 99%, p < 0.01). The prevalence was higher in children under 5 (0.334 / 10,000 doses; n=14). The predominant events were fever, local pain, edema and redness. Conclusion: A low prevalence of errors causing events was identified. However, events supposedly attributable to vaccination or immunization can contribute to vaccine hesitancy and, consequently, have an impact on vaccination coverage.

RESUMEN Objetivo: Identificar la prevalencia de errores que causaron eventos supuestamente atribuibles a la vacunación o inmunización. Método: Revisión sistemática de la literatura con metaanálisis realizada en las bases de datos Medline, Cochrane Library, Cinahl, Web of Science, Lilacs, Scopus; Embase; Open Grey; Google Scholar; y Grey Lit; con estudios que presentaran la prevalencia de errores de inmunización que causaron eventos o que aportaran datos que permitieran calcular este indicador. Resultados: Se evaluaron 11 artículos publicados entre 2010 y 2021, indicando una prevalencia de 0,044 errores por cada 10.000 dosis administradas (n=762; IC95%: 0,026 - 0,075; I2 = 99%, p < 0,01). La prevalencia fue mayor en niños menores de 5 años (0,334 / 10.000 dosis; n=14). Los eventos predominantes fueron fiebre, dolor local, edema y enrojecimiento. Conclusión: Se identificó una baja prevalencia de eventos causantes de errores. Sin embargo, los eventos supuestamente atribuibles a la vacunación o inmunización pueden contribuir a la indecisión sobre la vacunación y, en consecuencia, repercutir en la cobertura vacunal.

RESUMO Objetivo: Identificar a prevalência de erros que causaram eventos supostamente atribuíveis à vacinação ou imunização. Método: Revisão sistemática da literatura com metanálise realizada nas bases Medline, Cochrane Library, Cinahl, Web of Science, Lilacs, Scopus; Embase; Open Grey; Google Scholar; e Grey Lit; com estudos que apresentassem prevalência de erros de imunização que causaram eventos ou que disponibilizassem dados que permitissem o cálculo deste indicador. Resultados: Avaliou-se 11 artigos publicados entre 2010 e 2021, apontando prevalência de 0,044 erros por 10.000 doses administradas (n=762; IC95%: 0,026 - 0,075; I2= 99%, p < 0,01). A prevalência foi maior em crianças menores de 5 anos (0,334 / 10.000 doses; n=14). Quanto aos eventos, predominou-se: febre, dor local, edema, rubor. Conclusão: Identificou-se uma prevalência baixa de erros que causaram eventos. Entretanto, os eventos supostamente atribuíveis à vacinação ou imunização podem contribuir para a hesitação vacinal e, consequentemente, impactar nas coberturas vacinais.

The Potential of Films as Transmucosal Drug Delivery Systems.

Pharmaceutical films are polymeric formulations used as a delivery platform for administration of small and macromolecular drugs for local or systemic action. They can be produced by using synthetic, semi-synthetic, or natural polymers through solvent casting, electrospinning, hot-melt extrusion, and 3D printing methods, and depending on the components and the manufacturing methods used, the films allow the modulation of drug release. Moreover, they have advantages that have drawn interest in the development and evaluation of film application on the buccal, nasal, vaginal, and ocular mucosa. This review aims to provide an overview of and critically discuss the use of films as transmucosal drug delivery systems. For this, aspects such as the composition of these formulations, the theories of mucoadhesion, and the methods of production were deeply considered, and an analysis of the main transmucosal pathways for which there are examples of developed films was conducted. All of this allowed us to point out the most relevant characteristics and opportunities that deserve to be taken into account in the use of films as transmucosal drug delivery systems.

Redox Profiling of Selected Apulian Red Wines in a Single Minute.

Wine is a complex bioproduct whose chemical composition is highly variable across production regions. In order to shed light on affordable ways to promote the characterization of wines and explore the physicochemical basis of their antioxidant capacity, this work reported on the quick and easy redox profiling of selected red wines from Apulia, Italy. Therefore, an affordable and quickly performed semiempirical quantum chemistry approach, i.e., the extended Hückel method, was used to compute the bandgaps of the main phytochemical markers attributed to red wines. The findings of these calculations were then compared to an electroanalytical investigation in the form of cyclic and square-wave voltammetry, and the electric current of the redox profiles was used as the input dataset for principal component analysis. Results showcased that the semiempirical quantum chemistry calculations allowed the correlation of the bandgaps to the observed faradaic signals upon voltammetry; thereby, also providing insights on their antioxidant appeal by highlighting the feasibility of charge-transfer processes at low electric potentials. Furthermore, the principal component analysis showed that the electric current dataset gathered in a time span of 55 s allowed the appropriate separation of the samples, which hints at the possible use of quick voltammetric assays as fingerprinting tools.

Spray-drying of casein/pectin bioconjugate microcapsules containing grape (Vitis labrusca) by-product extract.

Novel microcapsules containing grape peel by-product extract were obtained. In this pursuit, complex coacervation of casein/pectin bioconjugate and spray-drying were combined. We have investigated the role of the dispersion feed rate (FR), drying air inlet temperature (IT) and drying air flow rate (AR) in the drying yield, microencapsulation efficiency, total polyphenols and anthocyanins contents, antioxidant activity, and morphology of the products. Also, the first-order degradation kinetics of the phytochemicals for both the extract and dried microcapsules was assessed and compared. The loss on the phytochemicals during spray-drying was attenuated in up to 88%, and the IT was the main factor affecting the particle properties. The polyphenols on the extract interacted with the polymers, influencing the assemble of the bioconjugate and the particle's features. Such microencapsulation strategy enhanced the thermal stability of the phytochemicals and rendered biocompatible and biodegradable products of which the nutraceutical and cosmeceutical application may have potential.

Needle-free anesthesia: clinical efficacy of a mucoadhesive patch for atraumatic anesthesia in dental procedures.

This study showcases the clinical efficacy of mucoadhesive patches designed for the buccal delivery of lidocaine and prilocaine hydrochlorides (1:1, 30 mg/patch). Such patches were developed for needle-free pre-operative local anesthesia in dentistry, aiming at mitigating the use of infiltrative anesthesia for medium-complexity clinical procedures. The patches were manufactured encompassing drug-release, mucoadhesive and backing layers, all prepared through film casting using biocompatible materials. Fifty-eight (n = 58) adult patients (65% women and 35% men) were randomly selected and included in a one-arm open clinical prospective cohort study. The average age of the subjects was of 50 years. The majority (59%) of the subjects, mostly women (82%), reported needle-phobia or anxiety due to dental procedures, which was assessed through a questionnaire approved by the ethical council for human use in research. The patches were positioned in the gingival region of the teeth involved in the procedure (86% on the maxillary and 14% on the mandibular bone). Two anesthetic patches were applied on each patient: one in the vestibular region and another in the palate/lingual portion, and these patches remained attached to the placement sites throughout the procedures. Concerning the dental procedures performed, 40% were cavity preparations and dental restorations of medium cavities; 29% staple facilities; 10% gingival retractions; 9% subgingival scrapings; 3% gingivalplasties; 3% supragingival preparations; 3% occlusal adjustments; and 2% subgingival preparations. In 90% of the cases, it was not necessary to complement with conventional infiltrative local anesthesia during the procedures. Patients did not report any discomfort or side effect during or after the administration of the patches. Among the cases in which there was the need for complementation, 50% were cavity preparations and dental restorations; 33% supragingival preparations; and 17% gingivoplasties. The complementary anesthesia volume was of 0.63 ± 0.23 mL and women corresponded to 83% of the participants who needed such intervention. Furthermore, in most cases, the patch was capable of initiating the anesthesia within a short time frame (5 minutes) and reaching the maximum anesthetic effect within 15 and 25 min, lasting at least 50 min. Undesirable side effects were not reported either 2 h after the administration or within the 6-month follow-up. Therefore, the anesthetic patches developed provide needle-free, painless, safe, and patient/dentist-friendly advances in performing routine medium-complexity dental procedures.

Towards the advance of a novel iontophoretic patch for needle-free buccal anesthesia.

The aim of this work was to develop a mucoadhesive iontophoretic patch for anesthetic delivery in the buccal epithelium. The patch was comprised of three different layers, namely i) drug release (0.64 cm2); ii) mucoadhesive (1.13 cm2); and iii) backing (1.13 cm2). Prilocaine and lidocaine hydrochlorides were used as model drugs (1:1 ratio, 12.5 mg per unit). An anode electrode (0.5 cm2 spiral silver wire) was placed in between the drug release and mucoadhesive/backing layers to enable iontophoresis. Surface microscopy; mechanical and in vitro mucoadhesive properties; drug release kinetics and mechanism; and drug permeation through the porcine esophageal epithelium were assessed. Topographic analysis evidenced differences in the physical structures for the several layers. All layers presented suitable handling properties i.e., flexibility, elasticity and resistance. Both the release and mucoadhesive layers presented features of a soft and tough material, while the backing layer matched the characteristics of a hard and brittle material. A synergy between the drug release and mucoadhesive layers on the mucoadhesive force and work of adhesion of the tri-layered patch was observed. Passive drug release of both drugs fitted to First-order, Hixson-Crowell and Weibull kinetic models; and the release mechanism was attributed to anomalous transport. Iontophoresis remarkably enhanced the permeation of both drugs, but mainly prilocaine through the mucosa as evidenced by the permeability coefficient parameter (3.0-fold). The amount of these amino amide salts retained in the mucosa were also equally enhanced (4.7-fold), while the application of a tiny constant electric current (1 mA·cm-2·h-1) significantly decreased the lag time for lidocaine permeation by about 45%. In view of possible in vitro / in vivo correlations, the buccal iontophoretic patch displays a promising strategy for needle-free and patient-friendly local anesthesia in dentistry.

Can parabens be added to cosmetics without posing a risk to human health? A systematic review of its toxic effects Pode adicionar parabenos a cosméticos sem risco para a saúde humana? Uma revisão sistemática de seus efeitos tóxicos

Objective: To summarize evidence regarding the toxic potential of administering parabenscontaining cosmetics in humans. Methods: The systematic review followed the methodology proposed in Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA). Electronic searches of the PubMed, Virtual Health Library (BVS), and Science Direct databases were performed between October 1st and 31st, 2018. No language restriction was determined. Original articles reporting observational, in vitro and in silico studies of toxicity caused by parabens in human or human cells were considered for eligibility. Two independent reviewers performed data extraction and assessed the methodological quality and risk of bias of articles by using the Downs & Black Scale. Score levels greater than 70% were assumed to reflect good methodological quality. The Kappa coefficient was calculated. Results: A total of 254 studies were found. Following the eligibility evaluation, 22 studies were included for the qualitative synthesis. The concordance between the reviewers was substantial (Kappa coefficient = 0.650). The meaningful reported outcomes were: high concentrations of parabens in the body; apoptosis damage to sperm DNA; oxidative stress; DNA damage; irritative potential; interference in the control of adipogenesis; estrogenic activity; genotoxicity; necrosis; role in carcinogenesis of breast cancer; harmful effects on human skin when exposed to the sun; stimulation of oncogenes expression; and interference with DNA transcription. Despite most included articles presenting appreciable methodological quality, remarkable limitations were observed and the mechanisms by which parabens exert toxicity on humans remained unclear. Conclusions: The accumulation of parabens in the human organism following repeated cosmetics administration on the skin is noteworthy. However overall, the evidence so far does not make it possible to determine whether, and in what extent, the use of paraben-containing cosmetics can disturb human health. Further investigations are still required for clarifying these issues.

Antifungal efficacy of atorvastatin-containing emulgel in the treatment of oral and vulvovaginal candidiasis.

Drug repositioning has been an important ally in the search for new antifungal drugs. Statins are drugs that act to prevent sterol synthesis in both humans and fungi and for this reason they are promissory candidates to be repositioned to treat mycoses. In this study we evaluated the antifungal activity of atorvastatin by in vitro tests to determine the minimum inhibitory concentration against azole resistant Candida albicans and its mechanisms of action. Moreover, the efficacy of both atorvastatin-loaded oral and vaginal emulgels (0.75%, 1.5% and 3% w/w) was evaluated by means of in vivo experimental models of oral and vulvovaginal candidiasis, respectively. The results showed that atorvastatin minimal inhibitory concentration against C. albicans was 31.25 µg/ml. In oral candidiasis experiments, the group treated with oral emulgel containing 3.0% atorvastatin showcased total reduction in fungal load after nine days of treatment. Intravaginal delivery atorvastatin emulgel showed considerable effectiveness at the concentration of 3% (65% of fungal burden reduction) after nine days of treatment. From these findings, it is possible to assert that atorvastatin may be promising for drug repositioning towards the treatment of these opportunistic mycoses.

Atorvastatin is a statin drug that presents antifungal activity. This study showed that atorvastatin-containing oral and vaginal emulgels were able to treat vulvovaginal and oral candidiasis of infected animal model. Therefore, we showcased that atorvastatin may be a possible therapeutic agent in order to be a used to control opportunistic mucosal fungal infections caused by Candida albicans.

Electroanalysis Applied to Compatibility and Stability Assays of Drugs: Carvedilol Study Case.

Carvedilol (CRV) is a non-selective blocker of α and ß adrenergic receptors, which has been extensively used for the treatment of hypertension and congestive heart failure. Owing to its poor biopharmaceutical properties, CRV has been incorporated into different types of drug delivery systems and this necessitates the importance of investigating their compatibility and stability. In this sense, we have investigated the applicability of several electroanalytical tools to assess CRV compatibility with lipid excipients. Voltammetric and electrochemical impedance spectroscopy techniques were used to evaluate the redox behavior of CRV and lipid excipients. Results showed that Plurol® isostearic, liquid excipient, and stearic acid presented the greatest anode peak potential variation, and these were considered suitable excipients for CRV formulation. CRV showed the highest stability at room temperature and at 50 °C when mixed with stearic acid (7% w/w). The results also provided evidence that electrochemical methods might be feasible to complement standard stability/compatibility studies related to redox reactions.

Novel Eudragit® -based polymeric nanoparticles for sustained release of simvastatin

This paper reports on the development of nanoparticles aiming at the in vitro controlled release of simvastatin (SVT). The nanoparticles were prepared by the nanoprecipitation method with polymers Eudragit® FS30D (EDGFS) or Eudragit® NE30D (EDGNE). EDGFS+SVT nanoparticles showed mean size of 148.8 nm and entrapment efficiency of 76.4%, whereas EDGNE+SVT nanoparticles showed mean size of 105.0 nm and entrapment efficiency of 103.2%. Infrared absorption spectra demonstrated that SVT incorporated into the polymer matrix, especially EDGNE. Similarly, the differential scanning calorimeter (DSC) curve presented no endothermic peak of fusion, indicating that the system is amorphous and the drug is not in the crystalline state. The maintenance of SVT in the amorphous state may favors its solubilization in the target release sites. In the in vitro dissolution assay, the SVT incorporated into the EDGFS+SVT nanoparticles showed a rapid initial release, which may be related to the pH of the dissolution medium used. Regarding the EDGNE+SVT nanoparticles, the in vitro release occurred in a bimodal behavior, i.e., an initial "burst" followed by a sustained delivery, with the kinetics of drug release following Baker-Lonsdale's mathematical model. All these features suggest the nanoparticulate system's potential to modulate SVT delivery and enhance its bioavailability.

Combining amino amide salts in mucoadhesive films enhances needle-free buccal anesthesia in adults.

Needle-phobia is usually a great concern in dentistry, and the replacement of painful injections by patient-friendly needle-free topical formulations would bring several advantages in dental practice worldwide. In this pursuit, the effects of combining prilocaine hydrochloride (PCL) and lidocaine hydrochloride (LCL) in different proportions in mucoadhesive films on their in vitro permeation and retention through porcine esophageal mucosa was studied. Complementarily, the permeation and retention of isolated LCL was investigated. The in vitro model used for evaluating buccal anesthetic penetration and retention in buccal epithelium was validated. In addition, the feasibility of a novel in vivo model to evaluate the painful sensation due to puncture "needle-shaped" gum jaw of adults at shallow and deep levels was demonstrated. The in vivo clinical survey revealed the efficiency of the films, which had onset of anesthesia at 5min, peak of anesthetic effect within 15 and 25min and anesthesia duration of 50min after being placed in maxillary sites. The in vitro drug flux, permeability coefficient and retention in the epithelium significantly correlated with in vivo onset, peak and extent of shallow and deep anesthetic effect. At shallow level, the permeation of LCL has shown to be closely related to the onset of anesthesia, while the penetration of PCL has a significant impact in the peak of anesthetic effect. Concerning the deep level, the penetration of PCL is required to attain the onset of anesthetic effect. The total amount of drug retained in the epithelium showed to modulate the extent of both shallow and deep anesthesia. Thus, the combination of LCL and PCL in mucoadhesive films may offer dentists and their patients a safe improvement for pain management during dental procedures.

In vitro safety and efficacy evaluations of a complex botanical mixture of Eugenia dysenterica DC. (Myrtaceae): Prospects for developing a new dermocosmetic product.

In the context of developing a new natural product-based cosmetic, the in vitro efficacy and safety evaluations of a complex botanical mixture based on Eugenia dysenterica leaf hydroalcoholic extract (EDE) (2.5-1000µg/mL) were carried out. Chromatographic analysis demonstrated the presence of the tannin (ellagic acid) and flavonoids (quercetin and gallic acid) which characterize the EDE as a polyphenol-rich mixture. Using HFF-1 fibroblasts, it was shown that EDE promoted cell regeneration after UVA exposure. It also led to the inhibition of the collagenase, elastase and tyrosinase enzymes, which are involved in skin-related disorders. In terms of toxicological evaluation, the EDE was classified as non-phototoxic through the 3T3 Neutral Red Uptake Phototoxicity Test (OECD N° 432, 2004) and non-eye irritant by Bovine Corneal Opacity and Permeability (OECD N° 437, 2013) assay, in conjunction with corneal histomorphometric analysis. Furthermore, the EDE has no skin sensitization potential as demonstrated by a two-out-of-three prediction model [protein-binding/haptenization (OECD N° 442C, 2015), keratinocyte and dendritic cell activations]. In addition, it was shown that the EDE seems to be non-genotoxic through the cytokinesis-block micronucleus assay (OECD N° 487, 2014) using HepG2 cells. When considered together, these findings support the use of EDE botanical mixture in cosmetic/pharmaceutical products.

Needle-free buccal anesthesia using iontophoresis and amino amide salts combined in a mucoadhesive formulation.

Iontophoresis is a strategy to increase the penetration of drugs through biological membranes; however, its use has been underexplored in mucosa. The aim of this work was to investigate the influence of iontophoresis in the mucosal penetration of prilocaine hydrochloride (PCL) and lidocaine hydrochloride (LCL), which are largely used in dentistry as local anesthetics, when combined in the same formulation. Semisolid hydrogels containing these drugs either alone or in combination were developed at two different pHs (7.0 and 5.8) and presented adequate mechanical and mucoadhesive properties for buccal administration. The distribution coefficients between the mucosa and the formulations (Dm/f) and the in vitro mucosa permeation and retention rates were evaluated for both PCL and LCL. At pH 7.0, the combination of the drugs decreased the Dm/f of PCL by approximately 3-fold but did not change the Dm/f of LCL; iontophoresis increased the permeation rate of PCL by 12-fold and did not significantly change LCL flux compared with the passive permeation rate of the combined drugs. Combining the drugs also resulted in an increase in both PCL (86-fold) and LCL (12-fold) accumulation in the mucosa after iontophoresis at pH 7.0 compared with iontophoresis of the isolated drugs. Therefore, applying iontophoresis to a semisolid formulation of this drug combination at pH 7.0 can serve as a needle-free strategy to speed the onset and prolong the duration of buccal anesthesia.

Chemical variability of the essential oils from fruits of Pterodon emarginatus in the Brazilian Cerrado

Pterodon emarginatus Vogel, Fabaceae, is a tree species commonly known as "sucupira-branca". It is a popular medicinal plant in the Brazilian cerrado (Savanna). This study investigates the chemical variability of the essential oils from fruits of P. emarginatus. The fruits were collected from five sites in the Brazilian Cerrado and their essential oils were analyzed by GC/MS. The results obtained by Principal Component and Cluster Analysis identified two groups: cluster I containing β-caryophyllene and δ-elemene and cluster II containing α-copaene, β-cubebene, allo-aromadendrene, α-cubebene and γ-muurulene. The Canonical Discriminant Analysis was used to differentiate between clusters on the basis of essential oil composition. The results showed high variability in the composition of the essential oils from fruits of P. emarginatus, contributing to studies of domestication of this species.

Preliminary studies of gastroprotective effect of Celtis iguanaea (Jacq.) Sargent leaves (Ulmaceae).

Antiulcerogenic activity of crude ethanolic extract of Celtis iguanaea leaves (CEE) was observed with experimental models such as ethanol, indomethacin, stress and pyloric ligation-induced gastric ulcers. Results obtained from indomethacin-induced ulcer showed the hexane fraction (HF) as the active fraction of CEE. This fraction inhibits the gastric acid secretion, increasing the gastric pH, decreasing the gastric acidity and total gastric contents. Neither the CEE nor the HF alters intestinal motility, thereby excluding a cholinergic antagonist mechanism. Further studies need to be conducted with HF in order to elucidate the active principle and the pharmacological mechanism involved.