Protein-based microneedles for biomedical applications: A systematic review.

Microneedles are minimally-invasive devices with the unique capability of bypassing physiological barriers. Hence, they are widely used for different applications from drug/vaccine delivery to diagnosis and cosmetic fields. Recently, natural biopolymers (particularly carbohydrates and proteins) have garnered attention as safe and biocompatible materials with tailorable features for microneedle construction. Several review articles have dealt with carbohydrate-based microneedles. This review aims to highlight the less-noticed role of proteins through a systematic search strategy based on the PRISMA guideline from international databases of PubMed, Science Direct, Scopus, and Google Scholar. Original English articles with the keyword "microneedle(s)" in their titles along with at least one of the keywords "biopolymers, silk, gelatin, collagen, zein, keratin, fish-scale, mussel, and suckerin" were collected and those in which the proteins undertook a structural role were screened. Then, we focused on the structures and applications of protein-based microneedles. Also, the unique features of some protein biopolymers that make them ideal for microneedle construction (e.g., excellent mechanical strength, self-adhesion, and self-assembly), as well as the challenges associated with them were reviewed. Altogether, the proteins identified so far seem not only promising for the fabrication of "better" microneedles in the future but also inspiring for designing biomimetic structural biopolymers with ideal characteristics.

Development and evaluation of a novel methotrexate-loaded electrospun patch to alleviate psoriasis plaques.

OBJECTIVE: To achieve an effective topical formulation of Methotrexate (MTX) as a first-line treatment of psoriasis, we formulated three MTX-loaded electrospun nanofibrous patches composed of polycaprolactone (PCL), Eudragit L100, and a mixture of them. SIGNIFICANCE: Topical delivery of MTX provides an appropriate therapeutic performance while circumventing the life-threatening side effects of systemic administration. METHODS: Three MTX-loaded electrospun nanofibrous patches were prepared and characterized in terms of size and morphology (using SEM), thermal behavior (by TGA and DSC), and crystalline structure (using XRD). Furthermore, the wettability and mechanical strength of samples were investigated through water contact angle and tensile strength tests. Also, the encapsulation efficiency of MTX was calculated. Subsequently, in vitro drug release profile of each formulation was obtained and different kinetic models were fitted to achieve the best-matched model. Accordingly, the ex vivo skin permeation of MTX was studied for the optimum formulation. RESULTS: All samples showed appropriate morphology, thermal behavior, and encapsulation efficiency. Also, XRD results showed that MTX is dispersed within the polymeric matrices in the amorphous state (with no crystalline region). Release studies demonstrated that MTX-loaded Eudragit L100-PCL formulation outperformed in terms of mechanical behavior and in vitro drug release. This formulation also exhibited better skin permeation. CONCLUSION: The obtained controlled-release MTX-loaded electrospun patches seem promising to provide a long-acting topical treatment of psoriatic plaques with minimized systemic side effects.

Skin permeability, a dismissed necessity for anti-wrinkle peptide performance.

BACKGROUND: The skin offers various benefits and potential for peptide delivery if its barrier performance can be reduced temporarily and reversibly. As peptides possess high molecular weight, hydrophilic nature (in most cases), and ionizable groups in the structure, their skin delivery is highly challenging. Apart from this, they are susceptible to the proteolytic enzymes in the skin. Anti-wrinkle peptides, like other peptides, suffer from insufficient skin permeability, while most of them must penetrate deep in the skin to present their efficacy. Although the cellular studies indicate the effectiveness of such peptides, without the ability to permeate the skin sufficiently, this efficacy is useless. Poor skin permeability of anti-wrinkle peptides has led to ongoing research for finding feasible and noninvasive enhancement methods that would be desirable for consumers of cosmetic products. METHOD: In this paper, the possibility of skin permeation of anti-wrinkle peptides as well as the chemical, physical, and encapsulation approaches that have been employed to date to increase permeability of these difficult molecules are thoroughly reviewed. RESULTS: Most anti-wrinkle peptides are not appropriate candidates for skin permeation and the use of enhancement methods is essential to increase their permeability. To do so, only some permeability enhancement approaches have been applied so far, including chemical modification with hydrophobic moieties or cell penetrating peptides, metal complexation, chemical permeation enhancers, iontophoresis, microneedles, and encapsulation in nanocarriers. The results of studies published on the skin permeability of anti-wrinkle peptides carnosine, GHK, PKEK, GEKG, GQPR, and KTTKS indicate that the skin permeability of these peptides can be successfully increased. CONCLUSION: Although the skin permeability of most anti-wrinkle peptides is not high enough and most anti-wrinkle peptides might not reach their targets in the skin at right concentrations, their permeability can be increased to therapeutic concentrations using various enhancement approaches.

CONTEXTE: La peau offre divers avantages et a la faculté de recevoir des peptides si l'on parvient à réduire temporairement et de manière réversible sa capacité à fonctionner comme une barrière. Comme les peptides ont un poids moléculaire élevé, une nature hydrophile (dans la plupart des cas) et possèdent des groupes ionisables dans leur structure, il est très difficile d'en faire bénéficier la peau. En outre, ils sont sensibles aux enzymes protéolytiques de la peau. Les peptides antirides, comme d'autres peptides, souffrent d'une capacité insuffisante de perméation de la peau ; or, la plupart d'entre eux doivent y pénétrer profondément pour avoir une efficacité. Bien que les études cellulaires indiquent l'efficacité de ces peptides, s'ils sont incapables de pénétrer suffisamment la peau, cette efficacité est inopérante. Face à cette perméabilité médiocre de la peau aux peptides antirides, des recherches sont menées actuellement pour trouver des méthodes d'amélioration à la fois réalisables et non invasives, qui soient attractives pour les consommateurs de produits cosmétiques. MÉTHODE: Dans cet article, nous étudions de manière approfondie la possibilité de perméation des peptides antirides à travers l'épiderme, ainsi que les approches chimiques, physiques et d'encapsulation utilisées à ce jour pour augmenter l'aptitude à la perméation de ces molécules difficiles. RÉSULTATS: La plupart des peptides antirides ne sont pas de bons candidats à la perméation de l'épiderme, et il est essentiel d'avoir recours à des méthodes de renforcement pour augmenter leur capacité de pénétration. Pour ce faire, seules certaines approches de renforcement de la perméation ont été appliquées jusqu'à présent : une modification chimique avec des fractions hydrophobes ou des peptides pénétrants la cellule ; la complexation métallique ; les amplificateurs de perméation chimique ; l'iontophorèse ; les micro-aiguilles et l'encapsulation dans les nano supports. Les résultats des études publiées sur la perméabilité de l'épiderme aux peptides antirides que sont la carnosine, le GHK, le PKEK, le GEKG, le GQPR et le KTTKS indiquent que l'augmentation de la capacité de perméation de l'épiderme de ces peptides est possible et donne de bons résultats. CONCLUSION: Bien que la capacité de perméation de la plupart des peptides antirides ne soit pas suffisamment élevée et qu'ils n'atteignent pas leurs cibles dans la peau aux bonnes concentrations, cette capacité peut être augmentée jusqu'à des concentrations thérapeutiques en recourant à diverses approches de renforcement.

RAB5A is associated with genes involved in exosome secretion: Integration of bioinformatics analysis and experimental validation.

Exosomes, as cell-cell communicators with an endosomal origin, are involved in the progression of various diseases. RAB5A, a member of the small Rab GTPases family, which is well known as a key regulator of cellular endocytosis, is expected to be involved in exosome secretion. Here, we found the impact of RAB5A on exosome secretion from human hepatocellular carcinoma cell line using a rapid yet reliable bioinformatics approach followed by experimental analysis. Initially, RAB5A and exosome secretion-related genes were gathered from bioinformatics tools, namely, CTD, COREMINE, and GeneMANIA; and published papers. Protein-protein interaction (PPI) was then constructed by the Search Tool for Retrieval of Interacting Genes (STRING) database. Among them, several genes with different combined scores were validated by the real-time quantitative polymerase chain reaction (RT-qPCR) in stable RAB5A knockdown cells. Thereafter, to validate the bioinformatics results functionally, the impact of RAB5A knockdown on exosome secretion was evaluated. Bioinformatics analysis showed that RAB5A interacts with 37 genes involved in exosome secretion regulatory pathways. Validation by RT-qPCR confirmed the association of RAB5A with candidate interacted genes and interestingly showed that even medium to low combined scores of the STRING database could be experimentally valid. Moreover, the functional analysis demonstrated that the stable silencing of RAB5A could experimentally decrease exosome secretion. In conclusion, we suggest RAB5A as a regulator of exosome secretion based on our bioinformatics approach and experimental analysis. Also, we propose the usage of PPI-derived from the STRING database regardless of their combined scores in advanced bioinformatics analysis.

RAB5A effect on metastasis of hepatocellular carcinoma cell line via altering the pro-invasive content of exosomes.

Tumor microenvironment exerts a critical role in cancer progression and metastasis. Exosomes, cell-cell communicators and major players of the tumor microenvironment are considered as a serious mediator of cancer metastasis. Here, we determined the effect of RAB5A gene on the hepatocellular carcinoma (HCC) cells particularly whether RAB5A could affect HCC metastasis via regulating the pro-invasive content of exosomes. In response to RAB5A knockdown, we analyzed the proliferation rate and migration capability of HCC cells. Then, we estimated changes in the total protein composition of exosomes via analyzing the expression of exosomal markers, CD63 and Alix. Thereafter, alterations of the pro-invasive content of exosomes were functionally evaluated using matrigel invasion assay. Our results revealed that knockdown of RAB5A could decrease HCC cell proliferation rate and migration capability significantly. Moreover, no significant changes in the expression of exosomal CD63 and Alix reflected that no differences might be occurred in protein composition of RAB5A knockdown cell-derived exosomes. Matrigel invasion assay functionally showed that exosomes-derived from RAB5A knockdown cells still had pro-invasive properties and their pro-invasive content was not affected in response to RAB5A knockdown. In conclusion, we believe that our results propose a new explanation about RAB5A and metastatic potentials of exosomes-derived from HCC cells.

Release behavior, mechanical properties, and antibacterial activity of ciprofloxacin-loaded acrylic bone cement: a mechanistic study.

OBJECTIVE: To evaluate the effect of ciprofloxacin concentration and cement geometry on release, mechanical, and antibacterial properties of PMMA bone cement. Significance: Cements are used in different geometries and drug concentrations. These can affect cement strength, drug release behavior, and its antibacterial activity. METHODS: Antibiotic-loaded bone cement (ALBC) containing 2.5, 5.0, and 10.0 wt% ciprofloxacin were prepared as slab, rectangular prism and short cylinder. Drug release and compression strength of the cements were investigated for 28 days at 37 °C. The ALBC efficacies against prevalent bone infection bacteria, S. aureus, E. coli, and P. aeruginosa, were investigated. Drug determination was by HPLC. RESULTS: A two-stage behavior of fast release through dissolution/diffusion (stage A; <96 h) and 2-5 times slower Fickian diffusion (stage B; 96-672 h) was observed. Significant differences for release rate were observed among different geometries in the order of cylinder > prism > slab, in correlation with systems' thickness, indicating lower drug depletion in thicker systems. Release rates were proportional to concentration for 2.5 and 5% systems. At 10.0% loading, however, apparently interconnected channels and higher porosity reduced the diffusional resistance and provided higher release rates than what expected from concentration increment. Growth of Gram-negative bacteria and S. aureus was inhibited at the lowest dose of drug over 1 and 48 h, respectively. ALBCs with 5.0 and 10.0% ciprofloxacin showed decrease of compression strength to below ISO standard. CONCLUSIONS: Different properties of acrylic cements are affected by geometry and drug concentration and should be considered for optimized drug therapy.

Effect of Palmitic Acid Conjugation on Physicochemical Properties of Peptide KTTKS: A Preformulation Study.

Lys-Thr-Thr-Lys-Ser (KTTKS) minimally crosses the skin because of hydrophilicity; therefore, its palmitoyl derivative, palmitoyl-KTTKS (Pal-KTTKS), is used in cosmetic products. In spite of this, there is insuffi cient information on its physicochemical properties and the effects of palmitoylation on such properties. The aim of this study was to investigate these properties. Such information would help appropriate formulation development. KTTKS and Pal-KTTKS were synthesized and characterized for ultra violet (UV) absorption, structure [X-ray diffraction (XRD)], morphology (electron microscopy), birefringence (polarized light microscopy), partitioning,solubility, thermal behavior (melting, thermogravimetric analysis, and differential scanning calorimetry), surface activity, critical micelle concentration (CMC, by tensiometry), and stability. KTTKS and Pal-KTTKS decomposed at about 154 and 150°C, respectively, and did not show a melting point before decomposition. The maximum UV absorbance of peptides was less than 200 nm. Both peptides showed birefringence, irregular flake morphologies, and hygroscopicity. KTTKS was freely soluble in water at room temperature (logP = -1.6 ± 0.15), indicating its hydrophilic nature. logP of Pal-KTTKS was calculated to be about 3.7, indicating a lipophilic compound. Pal-KTTKS showed surface activity with a CMC value of 0.024 ± 0.004 mM (19.25 ± 2.9 mg/L),whereas KTTKS did not show such surface activity. Palmitoylation demonstrated sharp peaks in the XRD pattern of KTTKS. KTTKS and Pal-KTTKS differ mainly in terms of chemical properties and show some similarity in physical properties. These results can be used for formulation developments.

PAMAM-dendrimer Enhanced Antibacterial Effect of Vancomycin Hydrochloride Against Gram-Negative Bacteria.

PURPOSE: The antibacterial activity of some antibiotics is specific to either Gram-positive or Gram-negative bacteria.  There are different mechanisms behind such insensitivities like inability of antibiotics to permeate through some bacterial membranes, as is the case for vancomycin in Gram-negative bacteria. The present investigation tries to overcome this problem by dendrimers, in order to make Gram-negative bacteria responsive to vancomycin. METHODS: The effects of generations 3 (G3) and 5 (G5) polyamidoamine amine-terminated dendrimers (NH2-PAMAM), on the antibacterial activity of vancomycin, were evaluated. Vancomycin-PAMAM dendrimers complexes were prepared and their antibacterial activities were evaluated by determination of their "minimum inhibitory concentration (MIC)", "minimum bactericidal concentration" and "fractional inhibitory concentration index" values against two Gram-positive and four Gram-negative bacteria, using broth micro-dilution method. The complexation of vancomycin and dendrimers was also assessed by in vitro release studies across dialysis tubing using a developed HPLC method. RESULTS: Results showed that vancomycin solution was effective against Gram-positive bacteria, but, was not effective in Gram-negative ones. Vancomycin-PAMAM dendrimers exhibited significant antibacterial efficacy against Gram-negative bacteria resulting in a decline of vancomycin MIC values by about 2, 2, 4 and 64 times in E. coli, K. pneumonia, S. typhimurium and P. aeruginosa, respectively. Results also showed that enhanced effect by G5 is more than G3. Dendrimers did not affect antibacterial activity of vancomycin in Gram-positive bacteria, as no permeation problem exists here. CONCLUSIONS: The present study revealed that both G3 and G5 cationic PAMAM dendrimers are able to make Gram-negative bacteria sensitive to vancomycin, resulting in decline of MIC values up to 64 times, possibly by increasing its permeation through bacterial membrane. These results look promising for broadening the antibacterial spectrum of vancomycin and such a strategy might be used for increasing the overall life of antibiotics.

Efficacy of fractional CO2 laser in treatment of atrophic scar of cutaneous leishmaniasis.

Cutaneous leishmaniasis is an endemic disease in Iran. Unfortunately, it can lead to unsightly atrophic scars with limited treatment options. Fractional CO2 laser is accepted for treatment of atrophic acne scars and recently has been used to treat cutaneous leishmaniasis, so we planned to use fractional CO2 laser on leishmaniasis scar. We conducted this study on 60 leishmaniasis scars on the face of 40 patients. The lesions were treated by a fractional CO2 laser with beam size of 120 µm, with energy of 50-90 mJ, and 50-100 spots/cm(2) density with two passes in three monthly sessions. Evaluation was done in the first and second months after the first treatment and 3 and 6 months after the last treatment. Digital photography was performed at each visit. Assessment of improvement rate by patient and physician was rated separately as follows: no improvement (0%), mild (<25%), moderate (25-50%), good (51-75%), and excellent (76-100%). Based on patients' opinion, in the first and second follow-up, 48.3 and 90% of them reported moderate to excellent healing, respectively (p < 0.001). In 3 and 6 months follow-up after the end of the experiment, most of the patients (88.3 and 95%, respectively) reported moderate to excellent healing of scars. Based on two observers' opinion, healing in the first follow-up in most of the patients (65%) was mild to moderate and 33% were reported as having no healing. In the second follow-up, only 5% of the patients were reported with no healing and 60% were reported as having moderate healing (p < 0.001). In 3 and 6 months follow-up, most of the patients (95 and 96.6%) were reported as having moderate to excellent healing (p = <0.001). Our results underlined the high efficacy of fractional CO2 laser for leishmaniasis scar. No significant adverse effects were noted.

Fabrication of controlled-release silver nanoparticle polylactic acid microneedles with long-lasting antibacterial activity using a micro-molding solvent-casting technique.

Most topical drug delivery techniques do not provide therapeutic concentrations for treatment of surgical site and other local infections and, therefore, require some kind of enhancement, such as physical methods like microneedles, the subject of the present investigation. Here, controlled-release long-lasting antibacterial polylactic acid (PLA) microneedles containing 1, 3, and 5% silver nanoparticles (AgNP) were prepared using micro-molding solvent-casting technique. Microneedles were characterized using optical microscopy, SEM, FTIR, XRD, and DSC. Also, mechanical strength, barrier disruption ability, insertion depth, in-vitro release kinetics, antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa, and silver permeation through rat skin were studied. Microneedles showed good mechanical strength with no signs of failure at an optimum PLA concentration of 25% (w/v). FTIR revealed no chemical interaction between ingredients, and XRD confirmed presence of AgNP in microneedles. Microneedles penetrated the skin model at depth of up to 1143 µm resulting 5-7 times increase in transepidermal water loss (TEWL). Release studies showed 2.2, 6.8, and 8.1 µg silver release from the whole body (obeying Higuchi's release model) and 0.33, 0.45, and 0.78 µg from the needles alone (obeying Fickian-cylindrical type release) for 1, 3, and 5% AgNP microneedles, respectively. Also, prolonged antibacterial activity (for 34 days) was observed. Skin studies over 72 h indicated that besides needles, silver is also released from the baseplate which had a marginal share in total silver permeation through the skin. In conclusion, a straightforward solvent-casting technique can be used to successfully prepare strong AgNP-containing PLA microneedles capable of long-lasting antibacterial activity.

COVID-19 vaccines breakthrough infection and adverse reactions in medical students: a nationwide survey in Iran.

Introduction: There are different types of COVID-19 vaccines approved worldwide. Since no national studies focus on vaccine-related adverse reactions and breakthrough cases, this study aimed to investigate the rate of adverse events and COVID-19 infection in medical students in Iran. Methods: This retrospective cohort study included Iranian medical students who received two doses of COVID-19 vaccines. The medical team gathered the demographic characteristics, comorbidities, type of vaccine, adverse events following vaccination, and history of COVID-19 infection data through a phone interview. The frequency of adverse events and breakthrough infection was stratified by vaccine type (ChAdOx1-S, Gam-COVID-Vac, and BIBP-CorV). Results: A total of 3,591 medical students enrolled in this study, of which 57.02% were females, with a mean age of 23.31 + 4.87. A PCR-confirmed and suspicious-for-COVID-19 breakthrough infection rate of 4.51 and 7.02% was detected, respectively. There was no significant relation between breakthrough infection and gender, BMI, blood groups, and comorbidities. However, there was a significant difference in breakthrough infection rate among different types of vaccines (p = 0.001) and history of COVID-19 infection (p = 0.001). A total of 16 participants were hospitalized due to COVID-19 infection after vaccination for reasons such as dyspnea, abnormal imaging, or decreased oxygen saturation. No severe infection or death was observed in the studied population. Conclusion: Vaccination prevented severe COVID-19 infection, although a high breakthrough infection rate was evident among Iranian medical students during the Delta variant's peak. Vaccine effectiveness may be fragile during emerging new variants and in high-exposure settings. Moreover, adverse events are rare, and the benefits of vaccination outweigh the side effects. However, many limitations challenged this study, and the results should be cautious.

Improving cellular uptake and in vivo tumor suppression efficacy of liposomal oligonucleotides by urea as a chemical penetration enhancer.

BACKGROUND: Liposomes are among the most widely used carriers for the delivery of antisense oligonucleotides (AsODNs) to intracellular targets. Although different strategies have been employed, the question of how to improve liposomal uptake and enhance the release of AsODN into cytoplasm still remains to be answered with respect to the use of a safe, easy and economic method. In the present study, the possibility of enhancing such processes at cellular and animal levels using urea as a penetration enhancer was investigated. METHODS: To perform this investigation, a cationic liposome containing an AsODN against protein kinase (PKC)-α was prepared, and the effect of urea on its cellular internalization and the related sequence-specific inhibition of gene expression in human lung adenocarcinoma A549 cells were investigated by flow cytometry and the reverse transcriptase-polymerase chain reaction, respectively. In in vivo studies, a xenograft lung tumor was established in nude mice by A549 cells and the enhancement effect of urea toward the effects of liposomal AsODN on tumor growth was investigated. RESULTS: Cellular studies revealed that urea treatment increases liposomal uptake and the release of AsODN into the cytoplasm by approximately 40%. Sequence-specific inhibition of target gene PKC-α expression was also increased by approximately two-fold by urea at 200-300 nM AsODN. In animal studies, urea significantly decreased the tumor volume (approximately 40%) and increased its doubling time from approximately 13 days to 17 days. CONCLUSIONS: Urea, and possibly other membrane fluidizers, could be regarded as penetration enhancers for liposomal AsODN delivery and may improve the therapeutic effect of these gene-therapy vectors at both cellular and animal levels.

A Mechanistic Study on the Fluidization and Enhancement Effects of Cineole Toward Stratum Corneum Intercellular Lamellar Lipids: A Liquid Crystalline Model Approach.

Background: The stratum corneum (SC) serves as the primary barrier for permeation in human skin. Penetration enhancers, such as 1,8-cineole, are utilized to enhance the permeation of drugs. Cineole increases the permeation of chemicals through different mechanisms. However, its mechanism, particularly at high concentrations, has not been well-studied and is the subject of the present investigation. Objectives: In continuation of our previous studies, the present investigation aims to elucidate the mechanism of action and concentration dependency of the effects of 1,8-cineole on the structure, diffusional properties, and partitioning behavior of the SC at high concentrations. This will be achieved through lamellar liquid crystalline models and ex-vivo skin studies. Methods: A lamellar liquid crystalline lipid matrix model in the presence (25 - 90%, w/w) and absence of cineole was prepared from SC lipids and characterized by X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and polarized light microscopy (PLM) studies. Release of the model lipophilic drug (diazepam) from cineole and cineole-treated matrices and the permeation of the drug from cineole and cineole-containing matrices (as a vehicle similar to the stratum corneum lipids) through excised rat skin were studied. Drug assay was performed by HPLC. Results: The PLM, DSC, and X-ray studies showed that the model matrix had a lamellar gel-liquid crystalline structure, and cineole fluidized the structure concentration-dependently and created other mesomorphic textures, such as myelinic figures. Release experiments showed that diffusion coefficients remained almost constant at high cineole concentrations of 40-90%, suggesting similar fluidization states. Skin permeation studies indicated that the diffusion coefficient (estimated from lag-time) increased concentration-dependently and played a role in permeability coefficient (Kp) increments alongside the increased partitioning of the model drug into the skin. Data suggest that high concentrations of cineole at the skin surface might not provide enough cineole in the skin for full fluidization, despite the similarity of the vehicle to SC lipids and even at high concentrations. Conclusions: The enhancement effect of cineole is concentration-dependent and might reach maximum fluidization at certain concentrations, but this maximum might not be easily achievable when cineole is used in formulations as pure or in a vehicle.

A topical gel of tea tree oil nanoemulsion containing adapalene versus adapalene marketed gel in patients with acne vulgaris: a randomized clinical trial.

Adapalene is used for treatment of acne vulgaris, a common dermatological disease. Nano-based carriers have been developed to improve solubility and bioavailability of adapalene and other acne treatment drugs. In our previous report, tea tree oil nanoemulsion containing adapalene gel (TTO NE + ADA Gel) showed appropriate physical and biological properties such as stability, viscosity, pH, size, morphology and biocompatibility in an animal model. The present study was designed to assess efficacy and safety of the TTO NE + ADA Gel in comparison with 0.1% adapalene marketed gel (ADA Marketed Gel). A total of 100 patients were randomized to receive TTO NE + ADA Gel or ADA Marketed Gel, once daily at night, for 12 weeks. Analysis for efficacy was conducted by acne lesion count (total, inflammatory and non-inflammatory) and acne severity index at weeks 4, 8 and 12 using generalized estimating equation along with the safety assessments in each measurement for assessing dryness, erythema, burning sensation and irritation. Significantly better reduction in total, inflammatory, and non-inflammatory acne lesions were reported for TTO NE + ADA Gel as compared to the ADA Marketed Gel overall and on each measurement occasion (p value < 0.001 for all). Mean acne severity index also reduced with TTO NE + ADA Gel significantly in comparison with ADA Marketed Gel (p value < 0.001). Dryness was the most common adverse effect reported in both groups and it was higher in TTO NE + ADA Gel group. In conclusion, TTO NE + ADA Gel compared to ADA Marketed Gel appears more effective in the treatment of acne vulgaris, with no important change in adverse effects.

Evaluation of the Effect of Ciprofloxacin and Vancomycin on Mechanical Properties of PMMA Cement; a Preliminary Study on Molecular Weight.

Antibiotic-loaded bone cement (ALBC) is commonly used in joint replacement therapy for prevention and treatment of bone infection and mechanical properties of the cement is still an important issue. The effects of ciprofloxacin and vancomycin was investigated on mechanical characterization of PMMA bone cement. Different properties of cement containing (0, 2.5, 5 and 10% W/W) antibiotics, including compressive and bending properties, microstructural, porosity and density were evaluated. Both antibiotics significantly reduced the density values and mechanical properties (compressive and flexural strength and modulus) in all groups in comparison to control over first two weeks (p < 0.05). This reduction was due to increased porosity upon antibiotic addition (3.05 and 3.67% for ciprofloxacin and vancomycin, respectively) in comparison to control (2.08%) (p < 0.001) and exposure to aqueous medium. Vancomycin as antibiotic with higher molecular weight (MW = 1485) had significant effect on compressive strength reduction of the cement at high amount compared to ciprofloxacin (MW = 367) (P < 0.01), there was no difference between two antibiotics at lower concentrations (P > 0.05). The effect of antibiotic loading is both molecular weight and drug content dependent. The time is also an important parameter and the second week is the probably optimum time to study mechanical behavior of ALBC.

Measurement of Hansen Solubility Parameters of Human Stratum Corneum.

Hansen Solubility Parameters (HSP) of human stratum corneum (SC) represent its polarity and are very important for design and optimization of dermatological formulations. However, there is no directly measured data available in the literature for such a crucial property, which is the subject of the present investigation. HSP of the SC was measured by solvent uptake here. 18 solvents/mixtures with different HSP values were selected and their uptake by the SC was measured at 32 °C. The solvents were then divided into good and bad solvents according to their uptake into the SC. The HSP discrete parts of "atomic dispersion forces (δD)", "dipolar intermolecular forces (δP)", and "hydrogen bonding (δH)" were then calculated using uptake data and HSPiP software. Results showed that δD, δP, and δH values of the SC at 32 °C are 16.5, 12, 7.7 respectively. The obtained HSP values, which were measured for the first time here, were then used to interpret enhancement effects of permeation enhancers and the uptake of vehicles by the SC using Relative Energy Difference (RED), with good correlations. SC HSP values can be further used in transdermal drug delivery, cosmetic formulations, safety issues, etc.

The efficacy and safety of topical 5% methimazole vs 4% hydroquinone in the treatment of melasma: A randomized controlled trial.

BACKGROUND: The management of melasma is still challenging, and new treatment modalities with favorable side effect profile are required. Methimazole, a peroxidase inhibitor, seems to have a beneficial effect in the management of melasma but there is a paucity of studies for evaluation of its efficacy. This double-blinded trial was aimed to evaluate the efficacy and safety of methimazole vs hydroquinone 4% which is the gold standard treatment in the management of melasma. METHODS: Fifty patients with melasma were enrolled and randomly divided into two groups to receive 4% hydroquinone or 5% methimazole once daily for 8 weeks. Forty patients completed the study. The clinical response was assessed at 4th, 8th, and 12th weeks after treatment by MASI score, patient satisfaction, and physician scores. RESULTS: Both groups showed a reduction in the MASI score at the 8th week which was more significant in hydroquinone group but higher relapse rate was also observed in this group after discontinuing the drug. The side effects were similar between groups. Also, patient and physician satisfaction scores were also more in favor of hydroquinone 4%. CONCLUSION: Methimazole could be an alternative treatment of melasma alone or in combination with other depigmenting drugs. Although not as effective as hydroquinone, the noncytotoxic and nonmutagenic aspects of methimazole may make it a promising alternative for the treatment of melasma.

Intra tester reliability of sympathetic skin responses in subjects with primary palmar hyperhidrosis.

BACKGROUND: Primary palmar hyperhidrosis (PPH) is a disorder related to sympathetic dysfunction. Iontophoresis can be used to reduce sweating rate. Sympathetic skin response (SSR) is commonly used to evaluate the sympathetic system. However, scarce evidence exists about the reliability of SSR parameters. OBJECTIVE: To assess the relative and absolute reliability of SSR before and after the application of iontophoresis with aluminum chloride hexahydrate (ACH) gel or tap water in subjects with PPH. METHODS: Twenty subjects were randomized to receive either iontophoresis with ACH gel or tap water. Three SSRs (amplitude and latency) with 5 s intervals from both hands in both groups were recorded before and after the application of iontophoresis for 30 min. Reliability of amplitude and latency of the SSR was assessed using intraclass correlation coefficient (ICC) with 95% confidence intervals, standard error of measurement (SEM), and minimal detectable change (MDC). RESULTS: Amplitudes and latencies of SSR showed good to excellent test-retest reliability for ICC in both groups before iontophoresis. Except for right hand latency which was moderate (0.5-0.75). After iontophoresis, the ACH gel group still showed good to excellent agreement for SSR parameters, while the reliability of SSR parameters in the tap water group was reduced. CONCLUSION: Subjects with PPH showed high intra-rater reliability for SSR parameters which was maintained after ACH gel iontophoresis and decreased after tap water iontophoresis. It seems that media used for iontophoresis or the state of media (gel vs liquid) may affect the reliability of SSR. Further research is recommended.

Intracellular Delivery of siRNAs Targeting AKT and ERBB2 Genes Enhances Chemosensitization of Breast Cancer Cells in a Culture and Animal Model.

: Pharmacotherapy as the mainstay in the management of breast cancer suffers from various drawbacks, including non-targeted biodistribution, narrow therapeutic and safety windows, and also resistance to treatment. Thus, alleviation of the constraints from the pharmacodynamic and pharmacokinetic profile of classical anti-cancer drugs could lead to improvements in efficacy and patient survival in malignancies. Moreover, modifications in the genetic pathophysiology of cancer via administration of small nucleic acids might pave the way towards higher response rates to chemotherapeutics. Inorganic pH-dependent carbonate apatite (CA) nanoparticles were utilized in this study to efficiently deliver various classes of therapeutics into cancer cells. Co-delivery of drugs and genetic materials was successfully attained through a carbonate apatite delivery device. On 4T1 cells, siRNAs against AKT and ERBB2 plus paclitaxel or docetaxel resulted in the largest increase in anti-cancer effects compared to CA/paclitaxel or CA/docetaxel. Therefore, these ingredients were selected for further in vivo investigations. Animals receiving injections of CA/paclitaxel or CA/docetaxel loaded with siRNAs against AKT and ERBB2 possessed significantly smaller tumors compared to CA/drug-treated mice. Interestingly, synergistic interactions in target protein knock down with combinations of CA/AKT/paclitaxel, CA/ERBB2/docetaxel were documented via western blotting.