The association of ABCB1 gene polymorphism with clinical response to carbamazepine monotherapy in patients with epilepsy.

BACKGROUND: Epilepsy is a common neurological disease but around 30% of patients fail to respond to antiepileptic drug (AED) treatment. Genetic variation of the ATP-binding cassette subfamily B, member 1 (ABCB1) gene, a drug efflux transporter may infer treatment resistance by decreasing gastrointestinal absorption and preventing AED entry into the brain. This study examined the impact of ABCB1 genetic variants on carbamazepine responsiveness. MATERIALS AND METHODS: Genomic DNA was extracted from whole blood of 104 epileptic patients. Genotyping of 3 ABCB1 variants (c.C3435T, c.G2677T/A and c.C1236T) was undertaken using validated TaqMan allelic discrimination assays. Plasma carbamazepine levels were measured at 3 and 6 months following the initial dose using high-performance liquid chromatography (HPLC) alongside clinical outcomes evaluation. RESULTS: Nonresponse to carbamazepine (CBZ) was associated significantly with the ABCB1 variants c.C3435T, c.G2677T/A, c.C1236T and TTT, TTC haplotypes (P < 0.05). There was no significant association between variants and plasma CBZ level (P > 0.05). CONCLUSIONS: Our results showed that variant alleles of the ABCB1 gene and TTT, TTC haplotypes were significantly associated with CBZ resistance without affecting the plasma level of carbamazepine. The findings of this study may help to predict patient's response to treatment ultimately it will improve the personalized and evidence based treatment choice of patients with epilepsy.

An overview of viral mutagenesis and the impact on pathogenesis of SARS-CoV-2 variants.

Viruses are submicroscopic, obligate intracellular parasites that carry either DNA or RNA as their genome, protected by a capsid. Viruses are genetic entities that propagate by using the metabolic and biosynthetic machinery of their hosts and many of them cause sickness in the host. The ability of viruses to adapt to different hosts and settings mainly relies on their ability to create de novo variety in a short interval of time. The size and chemical composition of the viral genome have been recognized as important factors affecting the rate of mutations. Coronavirus disease 2019 (Covid-19) is a novel viral disease that has quickly become one of the world's leading causes of mortality, making it one of the most serious public health problems in recent decades. The discovery of new medications to cope with Covid-19 is a difficult and time-consuming procedure, as new mutations represent a serious threat to the efficacy of recently developed vaccines. The current article discusses viral mutations and their impact on the pathogenicity of newly developed variants with a special emphasis on Covid-19. The biology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), its mutations, pathogenesis, and treatment strategies are discussed in detail along with the statistical data.

An Extensive Pharmacological Evaluation of New Anti-Cancer Triterpenoid (Nummularic Acid) from Ipomoea batatas through In Vitro, In Silico, and In Vivo Studies.

Prostate cancer (PCa) is the most common cancer in men, accounting for approximately 10% of all new cases in the United States. Plant-derived bioactive compounds, such as pentacyclic triterpenoids (PTs), have the ability to inhibit PCa cell proliferation. We isolated and characterized nummularic acid (NA), a potent PT, as a major chemical constituent of Ipomoea batatas, a medicinal food plant used in ethnomedicine for centuries. In the current study, in vitro antiproliferative potential against PCa cells (DU145 and PC3) via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay; Western blot protein expression analysis; absorption, distribution, metabolism, excretion (ADME); pharmacokinetic prediction studies; and bisphenol A (BPA)-induced prostate inhibition in Sprague Dawley rats were conducted to gauge the anti-cancer ability of NA. Significant (p < 0.05 and p < 0.01) time- and dose-dependent reductions in proliferation of PCa cells, reduced migration, invasion, and increased apoptotic cell population were recorded after NA treatment (3−50 µM). After 72 h of treatment, NA displayed significant IC50 of 21.18 ± 3.43 µM against DU145 and 24.21 ± 3.38 µM against PC3 cells in comparison to the controls cabazitaxel (9.56 ± 1.45 µM and 12.78 ± 2.67 µM) and doxorubicin (10.98 ± 2.71 µM and 15.97 ± 2.77 µM). Further deep mechanistic studies reveal that NA treatment considerably increased the cleavage of caspases and downstream PARP, upregulated BAX and P53, and downregulated BCL-2 and NF-κB, inducing apoptosis in PCa cells. Pharmacokinetic and ADME characterization indicate that NA has a favorable physicochemical nature, with high gastrointestinal absorption, low blood−brain barrier permeability, no hepatotoxicity, and cytochrome inhibition. BPA-induced perturbations of prostate glands in Sprague Dawley rats show a potential increase (0.478 ± 0.28 g) in prostate weight compared to the control (0.385 ± 0.13 g). Multi-dose treatment with NA (10 mg/kg) significantly reduced the prostate size (0.409 ± 0.21 g) in comparison to the control. NA-treated groups exhibited substantial restoration of hematological and histological parameters, reinstatement of serum hormones, and suppression of inflammatory markers. This multifaceted analysis suggests that NA, as a novel small molecule with a strong pharmacokinetic and pharmacological profile, has the potential to induce apoptosis and death in PCa cells.

Development and In Vitro/In Vivo Evaluation of pH-Sensitive Polymeric Nanoparticles Loaded Hydrogel for the Management of Psoriasis.

Methotrexate (MTX), the gold standard against psoriasis, poses severe problems when administered systemically viz increased toxicity, poor solubility and adverse reactions. Hence, a topical formulation of MTX for the management of psoriasis can be an effective approach. The present study aimed to develop an MTX based nanoparticle-loaded chitosan hydrogel for evaluating its potential efficacy in an imiquimod-induced psoriatic mice model. MTX-NPs loaded hydrogel was prepared and optimized using the o/w emulsion solvent evaporation method. Particle size, zeta potential, entrapment efficiency, in vitro drug release, ex vivo permeation, skin irritation and deposition studies were performed. Psoriatic Area and Severity Index (PASI) score/histopathological examinations were conducted to check the antipsoriatic potential of MTX-NPs loaded hydrogel using an imiquimod (IMQ)-induced psoriatic model. Optimized MTX-NPs showed a particle size of 256.4 ± 2.17 nm and encapsulation efficiency of 86 ± 0.03%. MTX-NPs loaded hydrogel displayed a 73 ± 1.21% sustained drug release in 48 h. Ex vivo permeation study showed only 19.95 ± 1.04 µg/cm2 of drug permeated though skin in 24 h, while epidermis retained 81.33% of the drug. A significant decrease in PASI score with improvement to normalcy of mice skin was observed. The developed MTX-NPs hydrogel displayed negligible signs of mild hyperkeratosis and parakeratosis, while histopathological studies showed healing signs of mice skin. So, the MTX-NPs loaded hydrogel can be a promising delivery system against psoriasis.

Development of an intelligent, stimuli-responsive transdermal system for efficient delivery of Ibuprofen against rheumatoid arthritis.

The present study aimed to fabricate and evaluate the therapeutic efficacy of pH-responsive Ibuprofen (IB) nanoparticles (NPs) loaded transdermal hydrogel against rheumatoid arthritis (RA). The IB loaded Eudragit® L 100 (EL 100) nanoparticles were formulated through a modified nanoprecipitation technique and optimized using central composite design software. The optimized NPs were loaded into Carbopol® 934-based hydrogel by solvent evaporation method and were analyzed for physicochemical characteristics. The mean particle size of the prepared NPs was 48 nm with an entrapment efficiency of 90%. The transdermal hydrogel showed a pH-responsive sustained drug release and high penetration through the skin. Moreover, the prepared nanocarrier system exhibited therapeutic efficacy at inflamed joints' sites both in acute and chronic RA mice model. The therapeutic efficacy of the prepared formulation was confirmed through the results of various behavioral, biochemical, and cytokines-based assays. Similarly, the assessment of histopathological and radiological images, as well as the skin irritation studies further strengthens the potential use of the prepared formulation through the transdermal route. The current findings suggested that IB loaded pH-responsive NPs based transdermal hydrogel can be used as an efficient agent to manage RA.

Development of novel biopolymer-based nanoparticles loaded cream for potential treatment of topical fungal infections.

OBJECTIVE: Biodegradable polymers are extensively used due to their efficient safety profiles. The aim of the current study was to fabricate, evaluate, and characterize biodegradable, biocompatible fluconazole (FLZ) loaded chitosan (CHS) chondroitin sulfate (CS) nanoparticles (NPs) for topical delivery. Polymers utilized in the formulation not only served as a carrier system but also aided in fighting with complex etiology of the disease due to their innate antifungal activities. METHODS: NPs were prepared by the complex coacervation method, then were optimized for various parameters and subsequently loaded into a cream. RESULTS: Scanning electron microscopic (SEM) analysis showed spherical morphology of the NPs. Prepared NPs showed an average particle size in the range of 350-450 nm and an encapsulation efficiency (EE) of 86%. The polydispersity index (PDI) was found to be 0.148 that showed a uniform distribution of NPs. Fourier transform infrared (FTIR) spectroscopy confirmed the absence of any electrostatic interaction between ingredients. In vitro drug release analyses exhibited a sustained release of the drug and higher antifungal activity than free FLZ. Ex vivo permeability and drug distribution in different skin layers ensured a site-specific delivery of the FLZ-NPs. As compared with free FLZ and other control groups, the prepared NPs also exhibited significantly higher antifungal activity against Candida albicans (p < .01). CONCLUSION: It was concluded from the results that the FLZ-NPs laden cream could be a potential candidate for topical and site-specific delivery of the drug cargo for the potential treatment of fungal infections.