Co-Delivery of Aceclofenac and Methotrexate Nanoparticles Presents an Effective Treatment for Rheumatoid Arthritis.

Background: Rheumatoid arthritis (RA) is a common acute inflammatory autoimmune connective tissue arthropathy. The genetic studies, tissue analyses, experimental animal models, and clinical investigations have confirmed that stromal tissue damage and pathology driven by RA mounts the chronic inflammation and dysregulated immune events. Methods: We developed methotrexate (MTX)-loaded lipid-polymer hybrid nanoparticles (MTX-LPHNPs) and aceclofenac (ACE)-loaded nanostructured lipid carriers (ACE-NLCs) for the efficient co-delivery of MTX and ACE via intravenous and transdermal routes, respectively. Bio-assays were performed using ex-vivo skin permeation and transport, macrophage model of inflammation (MMI) (LPS-stimulated THP-1 macrophages), Wistar rats with experimental RA (induction of arthritis with Complete Freund's adjuvant; CFA and BCG), and programmed death of RA affected cells. In addition, gene transcription profiling and serum estimation of inflammatory, signaling, and cell death markers were performed on the blood samples collected from patients with RA. Results: Higher permeation of ACE-NLCs/CE across skin layers confirming the greater "therapeutic index" of ACE. The systemic delivery of MTX-loaded LPHNPs via the parenteral (intravenous) route is shown to modulate the RA-induced inflammation and other immune events. The regulated immunological and signaling pathway(s) influence the immunological axis to program the death of inflamed cells in the MMI and the animals with the experimental RA. Our data suggested the CD40-mediated and Akt1 controlled cell death along with the inhibited autophagy in vitro. Moreover, the ex vivo gene transcription profiling in drug-treated PBMCs and serum analysis of immune/signalling markers confirmed the therapeutic role co-delivery of drug nanoparticles to treat RA. The animals with experimental RA receiving drug treatment were shown to regain the structure of paw bones and joints similar to the control and were comparable with the market formulations. Conclusion: Our findings confirmed the use of co-delivery of drug nanoformulations as the "combination drug regimen" to treat RA.

Corrigendum: Nanostructured lipid carrier-mediated transdermal delivery of aceclofenac hydrogel present an effective therapeutic approach for inflammatory diseases.

[This corrects the article DOI: 10.3389/fphar.2021.713616.].

Nanostructured Lipid Carrier-Mediated Transdermal Delivery of Aceclofenac Hydrogel Present an Effective Therapeutic Approach for Inflammatory Diseases.

Aceclofenac (ACE), a cyclooxygenase-2 inhibitor, is the derivative of the diclofenac group that has been in use for the symptomatic treatment of systemic inflammatory autoimmune disease, rheumatoid arthritis (RA). Partial solubility, high lipophilic nature, and stability challenge its use in developing topical formulations. Hence, we developed and characterized nanostructured lipid carrier (NLC)-based ACE (ACE-NLC) hydrogel for an efficient transdermal delivery. NLC microemulsion was prepared using different lipids by various methods and was characterized with respect to particle size, zeta potential, surface morphology, and drug encapsulation efficiency. The optimized NLC formulation was incorporated into Carbopol® 940 gel, and this arrangement was characterized and compared with the existing marketed gel (Mkt-gel) formulation to assess in vitro drug release, rheology, texture profile, in vivo skin retention and permeation, and stability. Furthermore, prepared and characterized ACE-loaded NLC formulation was evaluated for skin integrity and fitted in a dermatokinetic model. The results of this study confirmed the spherical shape; smooth morphology and nanometric size attested by Zetasizer and scanning and transmission electron microcopy; and stability of the ACE-NLC formulation. The ACE-NLC-gel formulation showed good rheological and texture characteristics, and better skin distribution in the epidermis and dermis. Moreover, ACE-NLC permeated deeper in the skin layers and kept the skin integrity intact. Overall, NLC-based gel formulation of ACE might be a promising nanoscale lipid carrier for topical application when compared with the conventional Mkt-gel formulation.

Efficient in vitro and in vivo docetaxel delivery mediated by pH-sensitive LPHNPs for effective breast cancer therapy.

The present study was designed to develop pH-sensitive lipid polymer hybrid nanoparticles (pHS-LPHNPs) for specific cytosolic-delivery of docetaxel (DTX). The pHS-LPHNPs-DTX formulation was prepared by self-assembled nano-precipitation technique and characterized for zeta potential, particle size, entrapment efficiency, polydispersity index (PDI), and in vitro drug release. In vitro cytotoxicity of pHS-LPHNPs-DTX was assessed on breast cancer cells (MDA-MB-231 and MCF-7) and compared with DTX-loaded conventional LPHNPs and bare DTX. In vitro cellular uptake in MDA-MB-231 cell lines showed better uptake of pHS-LPHNPs. Further, a significant reduction in the IC50 of pHS-LPHNPs-DTX against both breast cancer cells was observed. Flow cytometry results showed greater apoptosis in case of pHS-LPHNPs-DTX treated MDA-MB-231 cells. Breast cancer was experimentally induced in BALB/c female mice, and the in vivo efficacy of the developed pHS-LPHNPs formulation was assessed with respect to the pharmacokinetics, biodistribution in the vital organs (liver, kidney, heart, lungs, and spleen), percentage tumor burden, and survival of breast cancer-bearing animals. In vivo studies showed improved pharmacokinetic and target-specificity with minimum DTX circulation in the deep-seated organs in the case of pHS-LPHNPs-DTX compared to the LPHNPs-DTX and free DTX. Mice treated with pHS-LPHNPs-DTX exhibited a significantly lesser tumor burden than other treatment groups. Also, reduced distribution of DTX in the serum was evident for pHS-LPHNPs-DTX treated mice compared to the LPHNPs-DTX and free DTX. In essence, pHS-LPHNPs mediated delivery of DTX presents a viable platform for developing therapeutic-interventions against breast-cancer.

Lipid-polymer hybrid nanocarrier-mediated cancer therapeutics: current status and future directions.

The new generation of nanoparticles (NPs) encompass attributes of lipids and polymers and are referred to as 'lipid-polymer hybrid nanoparticles' (LPHNPs). LPHNPs have helped shed light on the mechanisms involved in targeted and non-specific drug delivery. Research has also highlighted the opportunities and challenges faced by the use of nanomedicine as personalized therapies in oncology. Here, we review the development of LPHNPs as cancer therapeutics, focusing on the methods deployed for enhancing the targeting efficiency and applications of LPHNPs.

The Molecular Targets of Swertiamarin and its Derivatives Confer Anti- Diabetic and Anti-Hyperlipidemic Effects.

The herbal plant extract of Enicostemma littorale is widely used to medicate and treat type II Diabetes. This extract in medicine has shown its value in reducing blood glucose & lipid levels, and improving the kidney functioning, lipid profile, controlling blood pressure and heart rate. The well characterized chemical components such as iridoid and secoiridoid glycosides are present in aqueous and ethanolic extracts of the plant. Swertiamarin, a secoiridoid glycoside, is identified as the lead compound that confers anti-hyperglycemic & anti-hyperlipidemic effects. The swertiamarin binds with one or more molecular targets to alter their expression and/or activity. The in silico, in vivo and in vitro studies have been carried out to uncover the underlying molecular mechanism of action of swertiamarin and its derivatives for showing the better anti-diabetic & anti-hyperlipidemic activities. In brief, the present review focuses on unraveling the information about molecular targets of swertiamarin. Our review will open new avenues to develop therapeutic approaches and drugs to treat diabetes and other inflammatory diseases.

Treatment of syndrome-associated congenital talipes equinovarus using the Ponseti method: 4-12 years of follow-up.

to evaluate the effectiveness of the Ponseti method in treating syndrome-associated (nonidiopathic) congenital talipes equinovarus. This was a retrospective consecutive review over a 12-year period in a tertiary centre of all patients with syndrome-associated talipes equinovarus treated with the Ponseti method. The primary outcome measure at the final follow-up was the functional correction of the deformity. There were 16 (28 feet) children, with an average follow-up of 7 years (range: 4-12). The average age at presentation was 6.1 (range: 2-17) weeks. Deformities were severe, with an average Pirani score of 5.0 (range: 3.0-6.0). Initial correction was achieved in all children, with an average of 6 (range: 4-9) Ponseti casts and a tendo-Achilles tenotomy performed in 21/28 (75%) feet. Satisfactory outcome at the final follow-up was achieved in 23/28 (82%) feet. The Ponseti method is an effective first-line treatment for syndrome-associated talipes equinovarus to achieve functional painless feet; children will often require more casts and have a higher risk of relapse.

Methotrexate and beta-carotene loaded-lipid polymer hybrid nanoparticles: a preclinical study for breast cancer.

AIM: This work was intended to investigate the targeting potential of fructose-tethered lipid-polymeric hybrid nanoparticles (F-BC-MTX-LPHNPs) co-loaded with beta carotene (BC) and methotrexate (MTX) in breast cancer therapeutics and find out the possible protective role of BC on MTX-induced toxicity. MATERIALS & METHODS: F-BC-MTX-LPHNPs were fabricated using self-assembled nano-precipitation technique. Fructose was conjugated on the surface of the particles. The in vitro cytotoxicity, sub-cellular localization and apoptotic activity of F-BC-MTX-LPHNPs were evaluated against MCF-7 breast cancer cells. The antitumor potential of F-BC-MTX-LPHNPs was further studied. RESULTS & CONCLUSION: Outcomes suggested that F-BC-MTX-LPHNPs induced the highest apoptosis index (0.89) against MCF-7 cells. Following 30 days of treatment, the residual tumor progression was assessed to be approximately 32%, in animals treated with F-BC-MTX-LPHNPs. F-BC-MTX-LPHNPs are competent to selectively convey the chemotherapeutic agent to the breast cancers. Beta carotene ameliorated MTX-induced hepatic and renal toxicity.

Functionalized Lipid-Polymer Hybrid Nanoparticles Mediated Codelivery of Methotrexate and Aceclofenac: A Synergistic Effect in Breast Cancer with Improved Pharmacokinetics Attributes.

The present study was aimed to coencapsulate methotrexate (MTX) and aceclofenac (ACL) in fucose anchored lipid-polymer hybrid nanoparticles (Fu-LPHNPs) to achieve target specific and controlled delivery for developing therapeutic interventions against breast cancer. The effective combination therapy requires coadministration of drugs to achieve synergistic effect on tumor with minimum adverse effects. Present study investigates the potential of codelivery of MTX and ACL through LPHNPs in MCF-7 and triple negative breast cancer cells (MDA-MB-231). We obtained LPHNPs in the nanosize range (<150 nm) with better particle size distribution (<0.3). The entrapment and loading efficiency of MTX and ACL was calculated as 85-90% and 10-12%, respectively. The coumarin-6 LPHNP formulations showed rapid internalization within 2 h incubation with MCF-7 and MDA-MB-231 cells. With 8-10 times, greater bioavailability of drug-loaded LPHNPs than free MTX and ACL was obtained. Also, antitumor efficacy of MTX- and ACL-loaded LPHNPs was determined on DMBA-induced experimental breast cancer mouse model. This model showed better control over tumor growth with MTX- and ACL-loaded LPHNPs than the combination of MTX and ACL or MTX alone. ACL-loaded LPHNPs showed prophylactic and anticancer activity in DMBA-induced mouse model at higher dose (10 mg/kg). ACL-LPHNPs confer synergistic anticancer effect when administered in combination with MTX. In conclusion, ACL enhances the therapeutic and anticancer efficacy of MTX, when coencapsulated into fucose-anchored LPHNPs, as confirmed by cell viability and serum angiogenesis (IL-6, TNF-α, IL-1ß, COX2, and MMP1) at both transcript and proteome level.

Human IDO-competent, long-lived immunoregulatory dendritic cells induced by intracellular pathogen, and their fate in humanized mice.

Targeting of myeloid-dendritic cell receptor DC-SIGN by numerous chronic infectious agents, including Porphyromonas gingivalis, is shown to drive-differentiation of monocytes into dysfunctional mDCs. These mDCs exhibit alterations of their fine-tuned homeostatic function and contribute to dysregulated immune-responses. Here, we utilize P. gingivalis mutant strains to show that pathogen-differentiated mDCs from primary human-monocytes display anti-apoptotic profile, exhibited by elevated phosphorylated-Foxo1, phosphorylated-Akt1, and decreased Bim-expression. This results in an overall inhibition of DC-apoptosis. Direct stimulation of complex component CD40 on DCs leads to activation of Akt1, suggesting CD40 involvement in anti-apoptotic effects observed. Further, these DCs drove dampened CD8+ T-cell and Th1/Th17 effector-responses while inducing CD25+Foxp3+CD127- Tregs. In vitro Treg induction was mediated by DC expression of indoleamine 2,3-dioxygenase, and was confirmed in IDO-KO mouse model. Pathogen-infected &CMFDA-labeled MoDCs long-lasting survival was confirmed in a huMoDC reconstituted humanized mice. In conclusion, our data implicate PDDCs as an important target for resolution of chronic infection.

Effectiveness of the Ponseti method for treating clubfoot associated with myelomeningocele: 3-9 years follow-up.

Clubfoot in myelomeningocele patients is characterized by its stiffness, severe rigidity and has traditionally been treated with extensive soft-tissue release surgery with poor outcomes. We present our experience using the Ponseti method to treat clubfoot associated with myelomeningocele. This was a retrospective, consecutive review over a 10-year period in our tertiary centre. On initial presentation, patients were assessed using the Pirani scoring system and the standard Ponseti method was initiated. Our outcome measures were successful functional correction of deformity defined as achieving a plantigrade pain-free foot. Secondary outcome measures included relapse and the need for surgical procedures. A total of 11 children with 18 myelomeningocele-associated clubfeet were included, with an average follow-up duration of 4.5 years (range 3-9 years). The average age at presentation was 4.7 weeks, with an average Pirani score of 5.5. Initial correction was achieved in all children with an average of 7 (range 4-9) Ponseti casts and tendo-achilles tenotomy was performed in 17 of 18 feet (94.4%). Nine children with 15 of 18 (83.3%) myelomeningocele-associated clubfeet achieved a satisfactory outcome at the final follow-up, with functional, pain-free feet. Recurrence occurred in five of 15 (33.3%) feet, which was managed successfully with a second tendo-achilles tenotomy and further Ponseti casting. Two children three of 18 (16.7%) failed Ponseti treatment. Ponseti method is an effective first-line treatment for myelomeningocele-associated clubfoot to achieve functional painless feet; children will often require more casts and have a higher risk of relapse.

Treatment of complex idiopathic clubfoot using the modified Ponseti method: up to 11 years follow-up.

Complex idiopathic clubfeet are distinguished by significant shortening, rigid equinus with a deep crease above the heel, severe plantar flexion of all metatarsals, a deep plantar crease seven across the full width of the sole of the foot and high cavus with a short and hyperextended big toe. Ponseti has devised a modified technique for treating complex clubfeet. We retrospectively identified 11 children (nine males and two females) with 17 complex clubfeet who were treated with the modified Ponseti method. Demographics, severity of clubfoot, number of casts, rate of tendoachilles tenotomy, relapse rate and their management, any additional procedures and data on complications were collected. The average follow-up was 7 years (range 3-11 years) and the average Pirani score was 5.5 (range 4.5-6.0). Initial correction was achieved in all children, with an average of 7 (range 5-10) Ponseti casts. Tendoachilles tenotomy was performed in all 17 feet (100%). The overall relapse rate was 53% (nine feet). Five relapses were managed successfully with repeat casting and four feet were subjected to a second tendoachilles tenotomy. Four feet required extensive surgical releases. A satisfactory outcome was achieved at the final follow-up in 13 of 17 feet (76.5%). Two of these children (two feet) required an additional tibialis anterior transfer. In our experience, the modified Ponseti method is an effective first-line treatment for complex idiopathic clubfoot; however, such children will often require more casts than usual and have a higher rate of tendoachilles tenotomy and a higher risk of relapse requiring surgical procedures. LEVEL OF EVIDENCE: level IV.

Quality by Design (QbD)-enabled development of aceclofenac loaded-nano structured lipid carriers (NLCs): An improved dermatokinetic profile for inflammatory disorder(s).

Present study was designed to prepare and characterize aceclofenac loaded nanostructured lipid carriers (NLCs) employing Quality by Design (QbD)-oriented approach. The NLCs were evaluated for their transdermal penetration potential and stability. Aceclofenac loaded nanostructured lipid carriers (NLCs) were prepared & characterized, by employing Quality by Design (QbD)-oriented approach and further evaluated for transdermal penetration potential and stability. Different lipids and surfactants were chosen to prepare NLCs using microemulsion method as critical material attributes (CMAs). A 33 factorial design was used for optimization of NLCs, and evaluating them for different critical quality attributes (CQAs), viz. particle size, polydispersity index (PDI), zeta potential, in vitro drug release, entrapment efficiency. The effect of CMAs such as lipids, oil: lipid ratio and concentration of surfactants on CQAs viz. drug entrapment efficiency and particle size were systematically evaluated to optimize NLCs. The optimized NLCs were further incorporated into carbopol gel and characterized for texture and rheology profile followed by in vitro and in vivo evaluations. The optimized ACE-NLCs were found to be spherical, nanometric in size with higher drug loading and entrapment efficiency. Results of the in vitro drug release study showed that the developed formulation followed Korsmeyer-Peppas model showing Fickian diffusion. The release was biphasic i.e., initial burst release followed by sustained drug release upto 48h. The optimized NLCs-based gel formulation showed superior texture, rheological profile and showed better cell uptake efficiency on hyperkeratinocytic cells (HaCaT cell lines) with higher ex vivo skin permeability efficiency vis-à-vis marketed formulation. In conclusion, dermatokinetic modeling and pharmacodynamic study using carrageenan induced edema mice suggests that aceclofenac loaded NLCs hydrogel may provide a better delivery alternative to target various skin layers.

Effective transdermal delivery of methotrexate through nanostructured lipid carriers in an experimentally induced arthritis model.

Rheumatoid arthritis (RA), an autoimmune and inflammatory pathology, is resulted due to the disruption of immune-homeostasis and failure of host immune-surveillance mechanism leading to cartilage degradation and bone erosion. Orally and parenterally administered methotrexate (MTX) have had adverse systemic complications in RA therapeutics. Therefore, transdermal application of MTX is recommended for the treatment of RA [1]. Present study is designed to develop MTX loaded nanostructured lipid carriers and chemical enhancer co-incorporated hydrogel (gel-(MTX-NLCs+CE)) for an efficient transdermal delivery of MTX in a Freund's adjuvants induced experimental animal model of RA. A gel-(MTX-NLCs+CE) was formulated and evaluated for its biocompatibility in hyper keratinocytes (HaCaT) and human monocytic cells (U937). Further, systemic and local inflammation was assessed by the estimation of pro-inflammatory cytokines & joint-destructive enzymes (TNF-α, IL-6, MMP-1 & IL-1ß,; iNOS & COX-2) in the serum and synovial fluid, respectively in an experimentally induced RA animal model. Prepared formulations were also evaluated with respect to arthritis index, arthritis score and histopathology of paw and ankle bones. The biocompatibility study of formulation on U937 and HaCaT is suggestive of safe and greater therapeutic efficacy of the developed formulations. Our results show that transcutaneous ability of MTX loaded nanostructured lipid carries (NLCs) and chemical enhancer (CE) co-incorporated hydrogel significantly (p<0.001) decreases the inflammation in RA animal model. In conclusion, developed NLCs-based gel formulation loaded with MTX opens new avenues for developing novel therapeutic modality for RA patients with the acceptably minimum adverse effects.

Fucose decorated solid-lipid nanocarriers mediate efficient delivery of methotrexate in breast cancer therapeutics.

The present study is designed to engineer fucose anchored methotrexate loaded solid lipid nanoparticles (SLNs) to target breast cancer. The developed nano-carriers were characterized with respect to particle size, PDI, zeta potential, drug loading and entrapment, in-vitro release etc. The characterized formulations were used to comparatively assess cellular uptake, cell-viability, apoptosis, lysosomal membrane permeability, bioavailability, biodistribution, changes in tumor volume and animal survival. The ex-vivo results showed greater cellular uptake and better cytotoxicity at lower IC50 of methotrexate in breast cancer cells. Further, we observed increased programmed cell death (apoptosis) with altered lysosomal membrane permeability and better rate of degradation of lysosomal membrane in-vitro. On the other hand, in-vivo evaluation showed maximum bioavailability and tumor targeting efficiency with minimum secondary drug distribution in various organs with formulated and anchored nano-carrier when compared with free drug. Moreover, sizeable reduction in tumor burden was estimated with fucose decorated SLNs as compared to that seen with free MTX and SLNs-MTX. Fucose decorated SLNs showed promising results to develop therapeutic interventions for breast cancer, and paved a way to explore this promising and novel nano-carrier which enables to address breast cancer.

The ligand (s) anchored lipobrid nanoconstruct mediated delivery of methotrexate: an effective approach in breast cancer therapeutics.

The present study was designed to engineer surface-anchored and methotrexate loaded lipobrid nano-constructs for targeting breast cancer. Ligands (fucose, galactose and mannose) anchored lipobrid nano-constructs were used to compare and assess delivery efficiency in breast cancer cell lines as well as in DMBA induced breast cancer animal model. The developed and characterized formulations were used to comparatively assess cellular uptake, cell-viability, apoptosis, lysosomal membrane permeability, bioavailability, bio-distribution, changes in tumor volume and animal survival. Our results show greater cellular uptake, cytotoxicity at low IC50, apoptosis with altered lysosomal membrane permeability and greater rate of degradation of lysosomal membrane. We saw better bioavailability and tumor targeting efficiency with minimum secondary organ drug distribution. The significant reduction was seen in tumor burden with ligand anchored lipobrids in comparison to plain and MTX-lipobrid formulations. In conclusion, fucose anchored MTX-lipobrid formulation showed promising results, and warrants to explore the development of therapeutic interventions for breast cancer.

Transdermal immunization of P. falciparum surface antigen (MSP-119) via elastic liposomes confers robust immunogenicity.

As transdermal immunization results in poor immunogenicity, which is attributed to poor permeability of antigens through the skin, we believed ultradeformable lipid vesicles (elastic liposome) might address the challenges encountered during transdermal immunization. The elastic liposome, versatile carrier, proves better vehicle for transcutaneous delivery of protein, peptide and nucleic acid antigens. Our recently published article (1) is suggestive of improved immunogenicity of carboxyl-terminal 19 kDa fragment of merozoite surface protein-1 (PfMSP-119) of Plasmodium falciparum when administered subcutaneously via elastic liposomes ( Fig. 1 ).

Nanostructured lipid carrier mediates effective delivery of methotrexate to induce apoptosis of rheumatoid arthritis via NF-κB and FOXO1.

Present study was designed to develop novel nano-structured lipid carriers (NLCs) formulated by lipid mixture and chemical permeation enhancer-based hydrogel for an effective transdermal delivery of methotrexate (MTX). The prepared NLCs were optimized with different preparative variables such as particle size <200 nm, poly-dispersity index (PDI) <0.2, and entrapment efficiency ∼85%. The drug incorporated into NLCs-gel base showed excellent spread ability without any grittiness during rheological behavior and texture profile analysis. The in vitro release showed biphasic release pattern with initial fast release of drug (>50%) in 8h followed by sustained release (up to 85%) by the end of 48thh. NLCs showed greater uptake in human hyper-proliferative keratinocyte cell line (HaCaT). NLCs showed increased expression of inflammatory mediators as well asapoptosis in U937 monocytic cells. The greater expression of pro-apoptotic gene Bim regulated by NF-κB-IkB and FOXO1 is supported by fold regulations calculated for various apoptotic and pro-inflammatory biomarkers carried out by RT-PCR. The immunocytochemistry to detect IL-6 expression and immunofluorescence assay suggested that induced apoptosis occurs in experimentally induced in vitro arthritis model treated with NLCs-MTX. We saw reduced inflammation and triggered apoptosis through NF-κB & FOXO1 pathways induced by MTX loaded NLCs in rheumatoid arthritic cells. In addition, formulated NLCs exhibit better skin permeation with higher permeation flux & enhancement ratio as shown by confocal laser scanning microscopy (CLSM). Moreover, histopathological examinations of skin are suggestive of safety potential of NLCs.

A synergistic approach of adapalene-loaded nanostructured lipid carriers, and vitamin C co-administration for treating acne.

The present study documents the fabrication and characterization of a topically applicable gel loaded with nanostructured lipid carriers (NLCs) of adapalene (ADA) and vitamin C (ascorbyl-6-palmitate [AP]). The NLCs were prepared by high pressure homogenization (HPH) method followed by incorporation into AP loaded gel. The fabricated system was characterized for size, poly dispersity index, entrapment efficiency (EE) and in vitro drug release properties, and was further investigated for skin compliance, skin transport characteristics (skin permeation and bio-distribution), rheological behavior, texture profile analysis and anti-acne therapeutic potential against testosterone-induced acne in male Wistar rats. The NLC-based formulation improved targeting of the skin epidermal layer and reducing systemic penetration. The co-administration of vitamin C led to an adjunct effect in acne therapy in physiological conditions. In brief, the present results suggest the potential of NLCs as a novel carrier for the dermal delivery of ADA and also the synergistic effect of vitamin C in topical therapeutics.

Congenital talipes equinovarus associated with hereditary congenital common peroneal nerve neuropathy: a literature review.

We present a unique case of a congenital hereditary common peroneal nerve neuropathy with congenital idiopathic congenital talipes equinovarus that had been treated with the Ponseti method with satisfactory outcome at 5-year follow-up, along with a literature review.