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Ketoconazole (KETO) is the drug of choice to control local, systemic, and resistant types of fungal infections. Subcutaneous (sub-Q) delivery offers several benefits. The present study investigated the sub-Q delivery of KETO using HSPiP software based on optimized concentrations of dimethylacetamide (DMA) in binary solvents (DMA + water)

Pyrazolines are a significant class of heterocyclic compounds with essential biological activities. They are quite stable, which has inspired medicinal chemists to experiment with the ring's structure in many different ways to create a variety of pharmacological activities. The structures of numerous commercially available therapeutic agents contain a pyrazoline ring. Pyrazolines are well-known for their ability to treat neurodegenerative diseases. The neurodegenerative diseases that affect huge populations globally include Alzheimer's disease (AD), Parkinson's disease (PD), and psychiatric disorders. The neuroprotective properties of pyrazolines published since 2003 are covered in the current review. Structure-activity relationships (SARs), molecular docking simulation, anticholinesterase (anti-AChE), and monoamine oxidase (MAO A/B) inhibitory actions are all covered in this article. Pyrazolines were discovered to have beneficial effects in the management of AD and were revealed to be inhibitors of acetylcholine esterase (AChE) and beta-amyloid (A

Abstract: Nanocapsules are polymeric nanoparticles encased in a polymeric coating composed of a predominantly non-ionic surfactant, macromolecules, phospholipids, and an oil core. Lipophilic drugs have been entrapped using various nanocarriers, including lipid cores, likely lipid nanocapsules, solid lipid nanoparticles, and others. A phase inversion temperature approach is used to create lipid nanocapsules. The PEG (polyethyleneglycol) is primarily utilised to produce nanocapsules and is a critical parameter influencing capsule residence time. With their broad drug-loading features, lipid nanocapsules have a distinct advantage in drug delivery systems, such as the capacity to encapsulate hydrophilic or lipophilic pharmaceuticals. Lipid nanocapsules, as detailed in this review, are surface modified, contain target-specific patterns, and have stable physical and chemical properties. Furthermore, lipid nanocapsules have target-specific delivery and are commonly employed as a marker in the diagnosis of numerous illnesses. This review focuses on nanocapsule synthesis, characterisation, and application, which will help understand the unique features of nanocapsules and their application in drug delivery systems.

Abstract: General anaesthetics (GA) have been in continuous clinical use for more than 170 years, with millions of young and elderly populations exposed to GA to relieve perioperative discomfort and carry out invasive examinations. Preclinical studies have shown that neonatal rodents with acute and chronic exposure to GA suffer from memory and learning deficits, likely due to an imbalance between excitatory and inhibitory neurotransmitters, which has been linked to neurodevelopmental disorders. However, the mechanisms behind anaesthesia-induced alterations in late postnatal mice have yet to be established. In this narrative review, we present the current state of knowledge on early life anaesthesia exposure-mediated alterations of genetic expression, focusing on insights gathered on propofol, ketamine, and isoflurane, as well as the relationship between network effects and subsequent biochemical changes that lead to long-term neurocognitive abnormalities. Our review provides strong evidence and a clear picture of anaesthetic agents' pathological events and associated transcriptional changes, which will provide new insights for researchers to elucidate the core ideas and gain an in-depth understanding of molecular and genetic mechanisms. These findings are also helpful in generating more evidence for understanding the exacerbated neuropathology, impaired cognition, and LTP due to acute and chronic exposure to anaesthetics, which will be beneficial for the prevention and treatment of many diseases, such as Alzheimer's disease. Given the many procedures in medical practice that require continuous or multiple exposures to anaesthetics, our review will provide great insight into the possible adverse impact of these substances on the human brain and cognition.

Aging is a significant risk factor for the majority of prevalent human illnesses. The chance of having severe chronic conditions grows dramatically with advancing age. Indeed, more than 90% of people over 65 get at least one chronic disease, including diabetes, heart disease, malignancy, memory loss, and kidney disease, whereas more than 70% have two or more of these ailments. Mouse and human aging lead to increased senescent cells and decreased klotho concentrations. Mice lacking the protein α-klotho show faster aging, similar to human aging. α-Klotho upregulation extends life and slows or suppresses the onset of many age-related illnesses and kidney diseases. Like the consequences of α-klotho deficiency, senescent cell accumulation is linked to tissue dysfunction in various organs and multiple age-related kidney diseases. In addition, α-klotho and cell senescence are negatively and presumably mechanistically linked. Earlier research has demonstrated that klotho exerts its protective effects in age-related and kidney disease by interacting with Wnt ligands, serving as an endogenous antagonist of Wnt/β-catenin signaling. In addition, decreasing senescent cell burden with senolytics, a class of drugs that remove senescent cells selectively and extend the life span of mice. In this work, we are studying the molecular mechanism of the combination of quercetin and dasatinib as senolytic in easing age-related chronic renal illness by altering the level of klotho/Wnt/β-catenin. PRACTICAL APPLICATIONS: There is an inverse relationship between the onset and the development of age-related disorders and cellular senescence and Klotho. Earlier attempts to suppress transforming growth factor-beta 1 (TGF-β1) in kidney disease with anti-TGF-β1 antibodies were ineffective, and this should be kept in mind. Senolytic medications may benefit from targeting senescent cells, which enhances the protective factor α-klotho. In addition, our study provides a unique, translationally feasible route for creating orally active small compounds to enhance α-klotho, which may also be a valuable biomarker for age-related kidney disease. Additionally, other aspects of aging can be affected by senolytics, such as limiting age-related mitochondrial dysfunction, lowering inflammation and fibrosis, blunting reactive oxygen species (ROS) generation, decreasing deoxyribonucleic acid (DNA) damage, and reinforcing insulin sensitivity. Senolytic agents have been shown to increase adipose progenitor and cardiac progenitor cell activity in aging animals and animals with cellular senescence-related diseases, such as heart, brain, and kidney disease.

As the second-oldest atypical antipsychotic, risperidone has a long history of off-label usage for treating behavioural and psychological signs and symptoms of dementia (BPSD), such as agitation, aggressiveness, and psychosis. Risperidone has been shown in several trials to have a statistically significant benefit when used in a therapeutic context. Several lines of evidence suggest a possible role of risperidone via the antagonistic effect of Dopamine D2 and 5HT-receptor in different neurological diseases like cognitive dysfunction of schizophrenia, neuroinflammation, Huntington's disease, and sleep cycle management. Therefore, the pharmacological interactions of risperidone in all these diseases were investigated. Some reports on the use of risperidone in the treatment of dopaminergic psychosis have been slightly conflicting. However, more research is needed to evaluate the role of risperidone in the treatment of these neurological diseases.

Osteoarthritis (OA) is a disease due to the aging of the articular cartilage, a post-mitotic tissue that stays functioning until primary homeostatic processes fail. Because of pain and disability, OA significantly influences national healthcare expenses and patient quality of life. It is a whole-joint illness characterized by inflammatory and oxidative signaling pathways and significant epigenetic alterations that cause cartilage extracellular matrix degradation. The canonical Wnt pathway (Wnt/β-catenin pathway) and nuclear factor kappa B (NF-κB) signaling pathways may function in joint tissues by modulating the activity of synovial cells, osteoblasts, and chondrocytes. However, finding innovative ways to treat osteoarthritis and get the joint back to average balance is still a struggle. Nutraceuticals are dietary supplements that promote joint health by balancing anabolic and catabolic signals. New therapeutic methods for OA treatment have been developed based on many research findings that show nutraceuticals have strong anti-inflammation, antioxidant, anti-bone resorption, and anabolic properties. For the treatment of osteoarthritis, we explore the possible involvement of nutraceuticals that target the Wnt/β-catenin and NF-κB pathways. PRACTICAL APPLICATIONS: In keeping with the aging population, osteoarthritis is becoming more widespread. In this extensive research, we studied the role of the Wnt/β-catenin and NF-κB pathway in OA formation and progression. Nutraceuticals that target these OA-related signaling pathways are a viable therapy option. Wnt/β-catenin and NF-κB signaling pathway are inhibited by polyphenols, flavonoids, alkaloids, and vitamins from the nutraceutical category, making them possible therapeutic drugs for OA therapy.

The present work aimed to remove azithromycin (AZM) from the contaminated aqueous system using a water/ethanol/transcutol/Capryol-90 green nanoemulsion. The drug is identified as a potential pharmaceutical contaminant detrimental for flora and fauna of aquatic lives as well as human health. Green nanoemulsions were tailored and characterized for thermodynamic stability, size, polydispersity index (PDI), zeta potential, viscosity, refractive index (RI), and morphological assessment using a transmission electron microscopy (TEM). Moreover, nanoemulsions were investigated for percent removal efficiency (%RE) and factors affecting percent removal efficiency (%RE). The results suggested that the developed green nanoemulsions (ANE1-ANE5) were transparent (˂ 200 nm) and stable. ANE5 exhibited the lowest value of globular size (49 nm), PDI (0.17), viscosity (~ 93 cP), and optimum zeta potential (-27.8 mV). The value of %RE depended upon the content of water and Capryol-90 of the nanoemulsion. Furthermore, the value of %RE was found to be increased with increased content of water, whereas this was decreased on increasing the Capryol-90 content in the nanoemulsions. Similarly, on decreasing the values of size and viscosity, the %RE values were observed to be increased. There was insignificant impact of the duration of exposure time on %RE. Thus, the maximum %RE value (96.8%) was obtained by ANE5 from the aqueous solution after 20 min of contact time with ANE5. Thus, this method could be a promising approach to remove AZM from the contaminated water and serve as an alternative to conventional methods.

This study describes the development and characterization of curcumin with graphene oxide complex (CUR + GO) loaded into liposomes for treating skin disease. The developed complex was characterized by X-ray diffraction and showed a broad halo pattern, confirming the amorphous nature of the resulting complex. Furthermore, scanning electron microscopy revealed the irregular porous morphology of the complex-highlighting loss of the crystallinity and the emergence of the amorphous phase. Additionally, the liposomes showed long-term stability at 2-8 °C and 25 ± 2 °C/60 ± 5%RH with nonsignificant variations in the particle size, polydispersity index, and zeta potential. Overall, optical and high-resolution transmission electron microscopy images of liposomes showed a consistent shape, and no aggregation with uniform particle size distribution was observed. Furthermore, the cumulative drug release in the first 6 h was 71.24 and 64.24% for CUR-loaded liposomes and CUR-GO-loaded liposomes, respectively. The lower value of drug release might be attributed to the complex development. The drug release model found the first order with non-Fickian diffusion process, which is often observed at higher

The present study described the development of a reversed-phase liquid chromatographic method for the estimation of abiraterone acetate by Quality by Design (QbD) approach. Using an isocratic solvent system for the mobile phase, the chromatographic estimation of analyte was performed on a Hypersil BDS C18 column using mobile phase mixture containing acetonitrile and water with pH adjusted with 0.1% v/v orthophosphoric acid (15:85%v/v ratio), flow rate 1.0 mL.min−1 and detection at 250 nm using photodiode array detector. Systematic development of the chromatographic method was carried out by factor screening using a half-factorial design which suggested organic modifier (%), flow rate (mL.min−1) and autosampler temperature (°C) as influential variables. Further, the method was optimized by Box–Behnken design and trials performed were evaluated for the area under peak, retention time, theoretical plate count and tailing factor as the responses. Validation of the developed method showed good linearity, accuracy, precision and sensitivity. Evaluation of the stability-indicating profile of the method using forced degradation studies revealed the formation of a possible degradation product under acidic and alkaline conditions, while no such degradation product peaks were observed under the oxidative environment. Overall, the study construed the successful development of HPLC assay method for pharmaceutical applications.

Ionic liquids (ILs) are widely used as solvents, co-solvents and permeation enhancers in the biomedical and pharmaceutical fields. There are many advantages to using active pharmaceutical ingredients (APIs) in the production of ILs for drug delivery, including the ability to tailor solubility, improve thermal stability, increase dissolution, regulate drug release, improve API permeability, and modulate cytotoxicity on tumor cells. Such an approach has shown significant potential as a tool for drug delivery. As a result, APIs converted into ILs are used as active components in solutions, emulsions, and even nanoparticles (NPs). In this review, we explore the use and physiochemical characteristics of APIs via ILs, including improvements of their physicochemical properties in preformulation and formulation development.

Among women, breast cancer (B·C.) is a common form of cancer that can strike either developed or developing countries. In addition to pregnancy-related variables, hormone therapy lifestyle factors (e.g., physical inactivity, smoking, and alcohol use) may all influence the progression of B·C. The creation of anti-B·C. medication carriers with better stability, controlled and targeted administration, and the goal of minimizing unwanted effects has taken a lot of time and effort. Naturally generated biopolymers-based pharmaceutical delivery techniques have attracted attention for their potential use in treating B·C. It's been shown that natural polymers can deliver high medication concentrations to the desired place and provide prolonged release of pharmaceuticals useful in treating B.C. Alginate is one of the most commonly used drug carriers for delayed and targeted release. In present review will discuss the utilization of sodium alginate as an carrier of anticancer drug, such as paclitaxel, doxorubicin, tamoxifen, curcumin, and others.

Ketoconazole (KTZ) is a potential oral antifungal agent to control systemic and local infections. This study addresses the impact of composition (tween 80 and compritol as CATO) and morphology on permeation (stomach, jejunum, and ileum) profiles of KTZ-loaded solid lipid nanoparticles (SLNs) in rats followed by

Acute kidney injury (AKI) has a poor clinical prognosis and increases the risk of chronic kidney failure (CKD). It is a common complication of organ failure in hospitalised patients (10-15% of all hospitalizations) and in intensive care unit (ICU) patients, with an incidence of up to 50%. Concerning ICU, AKI has a mortality rate ranging from 27% to 35%, rising to 60%-65% when dialysis is needed, with roughly 5%-20% of survivors requiring dialysis on discharge. AKI is believed to cause over 7 million deaths per year worldwide. Currently, there is no treatment for AKI or its progression to CKD. When activated by AKI, numerous pathways have been suggested as possible contributors to CKD progression. Wnt/β-catenin is a crucial regulator of kidney development that increases following the injury. Despite the overwhelming evidence that Wnt/β-catenin promotes AKI, tubulointerstitial fibrosis, a hallmark of CKD progression, is also promoted by this pathway. The therapeutic potential of Wnt/β-catenin in the treatment of AKI and the progression from AKI to CKD is being studied. This hypothesis aims to determine whether the Wnt/β-catenin inhibitor pyrvinium has a beneficial effect on the renal dysfunction and damage caused by Gentamicin.

Coronavirus disease (COVID-19), a coronavirus-induced illness attributed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, is thought to have first emerged on November 17, 2019. According to World Health Organization (WHO). COVID-19 has been linked to 379,223,560 documented occurrences and 5,693,245 fatalities globally as of 1st Feb 2022. Influenza A virus that has also been discovered diarrhea and gastrointestinal discomfort was found in the infected person, highlighting the need of monitoring them for gastro intestinal tract (GIT) symptoms regardless of whether the sickness is respiration related. The majority of the microbiome in the intestines is Firmicutes and Bacteroidetes, while Bacteroidetes, Proteobacteria, and Firmicutes are found in the lungs. Although most people overcome SARS-CoV-2 infections, many people continue to have symptoms months after the original sickness, called Long-COVID or Post COVID. The term "post-COVID-19 symptoms" refers to those that occur with or after COVID-19 and last for more than 12 weeks (long-COVID-19). The possible understanding of biological components such as inflammatory, immunological, metabolic activity biomarkers in peripheral blood is needed to evaluate the study. Therefore, this article aims to review the informative data that supports the idea underlying the disruption mechanisms of the microbiome of the gastrointestinal tract in the acute COVID-19 or post-COVID-mediated elevation of severity biomarkers.

Visceral leishmaniasis (VL) or kala-azar is a vector-borne dreaded protozoal infection that is caused by the parasite

Dermatophyte infections are widespread worldwide and are the most prevalent cause of fungal infection of the skin, hair, and nails. Tinea corporis is most commonly caused by dermatophytes belonging to three genera: Trichophyton , Microsporum , and Epidermophyton. The disease may be acquired through person-to-person transmission, typically by direct communication with an infected individual. Since dermatophytes causing tinea corporis infection are restricted to superficial keratinized tissue, topical treatments are most effective in patients with naïve tinea corporis unless the disease is widespread. Dermatophyte adherence to a keratinized structure is an essential step in dermatophytosis pathogenesis, whereby proteolytic enzyme activity is converted into a particular keratolytic activity that encourages the dermatophyte to use keratin as the sole source of carbon. Despite increasing dermatophytosis worldwide, particularly in the tropics, this research has often been neglected, appears to predominate globally, and presents practitioners with a therapeutic challenge. However, experts supported the use of allylamines in the pleiotropic molecular exploration of azoles, including reactive oxygen species (ROS) inducer, anti-inflammatory, antibacterial, and wide-spectrum antimycotic effects. Therefore, the current review aims to update and reform this essential subject and illustrate the recent advancement of the hidden pleiotropic activity of azoles at the molecular level on dermatophytes in human tinea corporis infection.

The present research work describes development of dual drug-loaded lipid-polymer hybrid nanoparticles (LPHNPs) of anticancer therapeutics for the management of colon cancer. The epidermal growth factor (EGF)-functionalized LPHNPs coloaded with 5-fluorouracil (FU) and sulforaphane (SFN) were prepared by one-step nanoprecipitation method. Box-Behnken design was applied for optimizing the material attributes and process parameters. The optimized LPHNPs revealed particle size 198 nm, polydispersity index 0.3, zeta potential -25.3 mV, and drug loading efficiency 19-20.3% for 5-FU and SFN, respectively. EGF functionalization on LPHNPs was confirmed from positive magnitude of zeta potential to 21.3 mV as compared with the plain LPHNPs. In vitro drug release performance indicated sustained and non-Fickian mechanism release nature of the drugs from LPHNPs. Anticancer activity evaluation in HCT-15 colon cancer cells showed significant reduction (p 0.001) in the cell growth and cytotoxicity of the investigated drugs from various treatments in the order: EGF-functionalized LPHNPs plain LPHNPs free drug suspensions. Overall, the research work corroborated improved treatment efficacy of EGF-functionalized LPHNPs for delivering chemotherapeutic agents for the management of colon carcinoma.

Background: Carbamazepine (Cbz) is the first-line drug for epileptic seizures but exhibits fluctuation at the plasma level and side effects after oral administration.To overcome these problems, Cbz should be targeted directly into the brain. Therefore, the current experimental design was aimed to formulate and optimize the Cbz containing solid lipid nanoparticles (SLNs) for brain delivery via intranasal administration to get rid of oral complications associated with Cbz. Methods: A full factorial design was performed to evaluate the effect of variables (X1 lipid concentration, X2 surfactant concentration, and X3 sonication time) on the response variables (size of nanoparticles, entrapment efficiency, and drug release). A two-level, three-factor design was employed herewith, and eight formulations were developed. Further, the formation of Cbz containing SLNs was characterized by compatibility, particle size, entrapment efficiency, and drug release with the support of Fourier Transform Infra-Red (FTIR), Zeta sizer, Transmission Electron Microscopy (TEM), Ultra-violet (U.V.), and High-Performance Liquid Chromatography (HPLC). Results: All eight formulations were characterized through particle size, entrapment efficiency, and invitro drug release performance. Out of eight characterized formulations, SN1 showed the most promising results, including particle size of 210 ± 2.14 nm, entrapment efficiency of 42.1 ± 1.09%, and drug release of 61.3 ± 2.02% and considered an optimized batch. Additionally, the optimized batch SN1was further evaluated for an in-vivo study on male Wistar Rats. Conclusion: The study revealed that a high amount of drug was reached into the brain through intranasal administration compared to the intravenous route. Therefore, it can minimize the unwanted side effects of the Cbz associated with oral administration. The formulation SN1 possesses an excellent drug targeting efficiency of 3.014. Finally, the current experimental work concluded that there is a direct pathway from the intranasal route to the brain. This delivery system can be beneficial for directly delivering CNS-active drugs into the brain.

Epithelial growth factor receptor (EGFR) is a cell surface transmembrane receptor that mediates the tyrosine signaling pathway to carry the extracellular messages inside the cell and thereby alter the function of nucleus. This leads to the generation of various protein products to up or downregulate the cellular function. It is encoded by cell erythroblastosis virus oncogene B1, so called C-erb B1/ERBB2/HER-2 gene that acts as a proto-oncogene. It belongs to the HER-2 receptor-family in breast cancer and responds best with anti-Herceptin therapy (anti-tyrosine kinase monoclonal antibody). HER-2 positive breast cancer patient exhibits worse prognosis without Herceptin therapy. Similar incidence and prognosis are reported in other epithelial neoplasms like EGFR + lung non-small cell carcinoma and glioblastoma (grade IV brain glial tumor). Present study highlights the role and connectivity of EGF with various cancers via signaling pathways, cell surface receptors mechanism, macromolecules, mitochondrial genes and neoplasm. Present study describes the EGFR associated gene expression profiling (in breast cancer and NSCLC), relation between mitrochondrial genes and carcinoma, and several in vitro and in vivo models to screen the synergistic effect of various combination treatments. According to this study, although clinical studies including targeted treatments, immunotherapies, radiotherapy, TKi-EGFR combined targeted therapy have been carried out to investigate the synergism of combination therapy; however still there is a gap to apply the scenarios of experimental and clinical studies for further developments. This review will give an idea about the transition from experimental to most advanced clinical studies with different combination drug strategies to treat cancer.

Introduction: Glaucoma affects more than 70 million people worldwide. One of the major therapeutic options for its management is based on the inhibition of the metalloenzyme carbonic anhydrases (CAs, EC 4.2.1.1). CA inhibitors (CAIs) diminish ocular hypertension in glaucomatous patients by reducing the rate of bicarbonate formation and thus, the secretion of the aqueous humor. Areas covered: This review is intended to cover the major contributions in terms of patent literature reports for the treatment of ophthalmic diseases by means of CAIs in a time frame spanning from 2013 to date. Expert opinion: The patent literature is dominated by innovative pharmaceutical formulations including a CAI alone or in combination with other therapeutic agents. Very few novelties within drug discovery are currently present and they mainly account for new CAI moieties and classical CAIs merged into scaffolds bearing additional chemical functionalities beneficial for the pharmacological treatment of the disease. It is reasonable to expect that in the near future the so-called 'old drugs' will achieve pharmacological performances in the management of ocular hypertension beyond any expectations and thus open a new era of drug repurposing merely based on material science advancements.

During the past two decades, the era of digitalization in pharmaceutical device manufacturing has gained significant momentum for maintaining human health. From various available technologies, internet of things (IoT) sensors are being increasingly used as wearable devices (e.g., smart watches, wrist bands, mobile phones, tablets, implantable pumps, etc.) that enable real-time monitoring of data. Such devices are integrated with smart materials that typically monitor the real-time data (blood pressure, blood sugar, heart and pulse rate, cytokine levels, etc.) to advise patients and physicians. Hence, there has been a great demand for wearable devices as potential tools for remote clinical trial monitoring in cancers and other diseases and they are proving to be very cost-effective.

The re-emergence of Chikungunya virus (CHIKV) infection in humans with no approved antiviral therapies or vaccines is one of the major problems with global significance. In the present investigation, we screened 80 in-house quinoline derivatives for their anti-CHIKV activity by computational techniques and found 4-hydroxy-1-methyl-3-(3-morpholinopropanoyl)quinoline-2(1H)-one (QVIR) to have potential binding affinities with CHIKV nsP2 and E2 glycoproteins. QVIR was evaluated in vitro for its anti-CHIKV potential. QVIR showed strong inhibition of CHIKV infection with an EC50 (50% effective concentration) value of 2.2 ± 0.49 μM without significant cytotoxicity (CC50 > 200 μM) and was chosen for further elucidation of its antiviral mechanism. The infectious viral particle formation was abolished by approximately 72% at a QVIR concentration of 20 μM during infection in the BHK-21 cell line, and the CHIKV RNA synthesis was diminished by 84% for nsP2 as well as 74% for E2, whereas the levels of viral proteins were decreased by 69.9% for nsP2 and 53.9% for E2. Flow cytometry analysis confirmed a huge decline in the expression of viral nsP2 and E2 proteins by 71.84 and 67.7%, respectively. Time of addition experiments indicated that QVIR inhibited viral infection at early and late stages of viral replication cycle, and the optimal inhibition was observed at 16 h post infection. The present study advocates for the first time that QVIR acts as a substantial and potent inhibitor against CHIKV and might be as an auspicious novel drug candidate for the development of therapeutic agents against CHIKV infections.

A systematic methodology was used to quantify ganoderic acid-A (GA-A) loaded nano-lipid carriers (NLC) in rat plasma using UPLC-MS/MS. Separation of the analyte was achieved using ACQUITY UPLC BEH C18 column (1.7 µm) and mobile phase as water containing 0.1% Acetonitrile (40: 60% v/v) at a flow rate of 0.4 mL·min−1. The analyte was detected using MRM mode to track precursor-to-product ion transitions of 515.37 → 285.31 m/z (time scan of 2 min) for GA-A, and 175.11 → 115.08 m/z (time scan of 4 min) for ascorbic acid as an internal standard (IS), respectively. The developed method was validated for linearity, accuracy, within and between day precisions, limit of quantification and recovery of the analyte. The results indicated intra and inter-day consistency and precision values were found to be within the acceptance limit for the plasma samples. The method applicability for determination of pharmacokinetic parameters of GA-A was assessed after oral administration of free GA-A solution and GA-A-loaded NLC, which indicated significant difference (p

Chrysin is the major bioactive compound of blue passionflower, an important medicinal plant used in traditional herbal formulations since ancient times. In the present study, we report that chrysin nanoparticles (chrysin NPs) protect Wistar rats against kindling-induced epilepsy. Nanoparticles of sizes less than 150 nm with a spherical shape were prepared using poly(d,l-lactic-co-glycolic acid) and polyvinyl alcohol, respectively, as polymer and stabilizer. Rats were injected with subconvulsive doses of pentylenetetrazole (PTZ) (35 mg/kg, intraperitoneal) every second day, with 22 injections in total, and on the same days, they received protective doses of the chrysin NPs (5 and 10 µg/mL, PO), respectively, 45 min before each PTZ injection. After the last PTZ injection, an average of thirteen seizure scores was recorded. Animals were killed by decapitation 24 h after a seizure. The cortex and hippocampus were removed and stored in liquid nitrogen for determining oxidative stress terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, histopathology, and reverse transcription-polymerase chain reaction for messenger RNA expression. The result showed chrysin NPs treatment has counteracted oxidative stress, reduced neuronal apoptosis, and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase 1. In conclusion, our findings demonstrate that the neuroprotective effect of chrysin NPs against kindling-induced epilepsy might be escorted by the alleviation of oxidative stress through the Nrf2/antioxidant response element/HO-1 pathway signal pathway.

Eighteen pyrrolidin-2-one linked benzothiazole, and benzimidazole derivatives (10-27) were designed and synthesized. The structure of the compounds was confirmed by elemental and spectral (IR, 1 H-NMR and MS) data analysis. All the compounds were screened by human monoacylglycerol lipase (hMAGL) inhibition assay. Three benzimidazole compounds, 22 (4-Cl phenyl), 23 (3-Cl,4-F phenyl) and 25 (4-methoxy phenyl) were found to be the most potent, having an IC50 value of 8.6, 8.0 and 9.4 nm, respectively. Among them, the halogen-substituted phenyl derivatives, compound 22 (4-Cl phenyl) and compound 23 (3-Cl,4-F phenyl), showed micromolar potency against fatty acid amide hydrolase (FAAH), having an IC50 value of 35 and 24 µm, respectively. Benzimidazole derivative having 4-methoxyphenyl substitution (compound 25) was found to be a selective MAGL inhibitor (IC50 = 9.4 nm), with an IC50 value above 50 µm against FAAH. In the formalin-induced nociception test, compound 25 showed a dose-dependent reduction of pain response in both acute and late phases. At 30 mg/kg dose, it significantly reduced the pain response and showed greater potency than the reference drug gabapentin (GBP).

We aimed to identify a suitable solvent [dimethyl acetamide (DMA), ethyl acetate, (EA), N-methyl pyrrolidone (NMP), cremophor-EL (CEL), transcutol-HP (THP), polyethylene glycol 400 (PEG-400), limonene and ethanol] based on experimental solubility, thermodynamic/computational parameters for subcutaneous (sub-Q) delivery. The “vanʼt Hoff” model validated solubility values in several solvents at “T = 298.2 K–318.2 K” and “p = 0.1 MPa”. In silico prediction study was carried out for sub-Q delivery using GastroPlus. The selected KETO-DMA construct was evaluated for cellular interaction, cellular uptake (L929 cells), cytotoxicity (L929 and J774A.1) and antifungal activities (C. albicans, C. glabrata, C. Tropicalis, and A. niger). The maximum mole fractional solubility of KETO were found in three solvents such as DMA (4.8 × 10−2) ˃ EA (2.8 × 10−2) ˃ NMP (11.7 × 10−3) at “T = 318.2 K”. Analysis confirmed “endothermic and entropy” driven solubilization process. GastroPlus predicted pharmacokinetics parameters were influenced with nonsaturable metabolic clearance in subcutaneous tissue of human. Interaction study of KETO-DMA solution with Candida cells showed maximized cellular internalization. KETO-DMA solution exhibited poor cellular uptake by L929 cell lines (murine fibroblast cells) compared to KETO aqueous solution which was further supported with cytotoxicity study in L929 and J774A.1 cell lines. Reduced MIC values of KETO-DMA solution as compared to KETO aqueous solution against four strains corroborated improved efficacy of KETO probably due to augmented solubility in DMA and lack of surfactant. Thus, KETO-DMA solution can be a suitable construct for sub-Q delivery to control fungal infections.

The current study focuses on development of nasal mucoadhesive microspheres for nose-to-brain delivery of rivastigmine for Alzheimer treatment. A systematic development was employed for optimization of the formulation and process parameters influential on the quality attributes of the microspheres. The risk assessment study revealed major influence of the polymer concentration (ethylcellulose: chitosan), the concentration of surfactant solution (polyvinyl alcohol), and stirring speed as the critical factors for optimization of the microspheres. These factors were systematically optimized using Box-Behnken design and microspheres were evaluated for the particle size, entrapment efficiency, and in vitro drug release as the response variables. The optimized microspheres containing 4.4% wt/vol polymers, 1% wt/vol surfactant, and stirring speed at 1500 rpm showed particle size of 19.9 µm, entrapment efficiency of 77.8%, and drug release parameters as T80% of 7.3 h. The surface modification of microspheres was performed with lectin by carbodiimide activation reaction and confirmed by difference in surface charge before and after chemical functionalization by zeta potential measurement which was found to be − 25.7 mV and 20.5 mV, respectively. Ex vivo study for bioadhesion strength evaluation on goat nasal mucosa indicated a significant difference (p

Epacadostat (EPA), a new and promising anti-cancer small molecule is firmly established as selective inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). The X-Ray structure of the human CA IX mimic in complex with EPA is investigated here for the first time and compared to previously reported EPA-CA II adduct. The structural information obtained are all in agreement with the in vitro kinetic data which accounted for a selective inhibition of the CA IX over the CA II isoform.

The present study describes the systematic development of a phospholipid-based nanomixed micellar formulation of olmesartan medoxomil (OLM) surface-decorated with bile salt for improved lymphatic drug targeting ability and enhanced systemic availability. The micellar formulation was prepared from the drug and phospholipid mixture, and surface modified with sodium deoxycholate as a penetration enhancer. The formulation was systematically developed and optimized using Quality by Design (QbD) principles. Impact assessment of the formulation and process parameters was conducted by risk analysis and response surface optimization was performed using Box-Behnken experimental design. The optimized nanomixed micellar formulation exhibited a particle size of 168 nm, zeta potential of −22.4 mV and a drug loading efficiency of 70%. Drug release evaluation showed a sustained release profile with 70% release within 12 h and a nearly complete release of OLM within 24 h. A Caco-2 cell culture study on the nanomixed micelles revealed more than 90% viability and uptake of the drug within the study period of 6 h. Bidirectional permeability measurements showed over a 60% reduction in P-gp efflux of OLM from the nanomixed micelles over the pure drug studied for the period of 3 h, as calculated from the values of the efflux ratio. Pharmacokinetic evaluation in rat plasma revealed nearly 10.62 and 6.02-fold improvements in AUC0-t and Cmax of OLM from nanomixed micelles over a pure drug suspension, while lymphatic uptake evaluation in rats also revealed nearly a 3.04-fold increase in the concentration of OLM in lymph from the nanomixed micelles over the pure drug suspension within the study period of 24 h. The intestinal safety evaluation of the nanomixed micelles by histopathology analysis revealed the biocompatible nature of the formulation without any organ toxicity. Overall, the results obtained from the above in vitro and in vivo studies indicated the strong suitability of the developed nanomicellar formulation for enhancing the oral bioavailability of the drug to manage hypertension.

The present work focuses on the development and evaluation of the diosmin-loaded solid lipid nanoparticles (SLNs) with the goal of improving its therapeutic efficacy in hepatic carcinoma (HCC) treatment. HCC was induced by administration of diethyl nitrosamine (DEN) intraperitoneally at a dose of 200 mg/kg in male Wistar rats. The formulation and optimization of diosmin-loaded SLNs was performed using a five-factor and two-level full factorial design. The optimized SLNs exhibited particle size of 37.48 nm, polydispersity index of 0.29 nm, entrapment efficiency of 73.46% and drug loading capacity of 9.075%. In vitro drug release analysis of SLNs performed with dialysis bag technique revealed cumulative drug release >60% in 6 h. In vitro cytotoxicity study of diosmin-SLNs on HepG2 cells showed relatively higher cytotoxicity than diosmin solution and blank SLN. After 48 h of treatment, IC50 values for the diosmin-SLNs and diosmin solution were found to be 22.01 μg/mL and 33.11 μg/mL, respectively. In vivo animal study demonstrated that the hepatic DEN group rats shown hepatic nodules and antioxidant parameters that were altered by the diosmin in a dose-related fashion dramatically (p

A cationic nanoemulsion of tamoxifen (Tmx) containing a charge inducer was developed for improving biopharmaceutical attributes and anticancer potential of the drug. The lipidic formulation constituted of corn oil, labrasol and transcutol HP and optimized using a mixture design by selecting these excipients as the independent variables. The formulation was evaluated for globule size, polydispersity index and drug release characteristics as the dependent variables. Oleylamine was incorporated into the optimized nanoemulsion for inducing a positive charge. The optimized cationic Tmx-nanoemulsion with 34%:48%:17% of the aforementioned excipients and 0.5% v/v of the charge inducer showed particle size of 138 nm and a polydispersity index 0.31, zeta potential +35.45 mV and more than 85% Tmx release in a 1 h time period. In vitro evaluation of the cytotoxicity, qualitative and quantitative uptake studies on Caco-2 and MCF-7 cells revealed satisfactory results. In vivo pharmacokinetic study in rats under fasting condition showed a significant increase in the rate and extent of drug absorption (2 to 4-folds) from the optimized cationic Tmx-nanoemulsion vis-a-vis the pure drug (p

The current review is intended to highlight recent advances in the search of new and effective modulators of the metalloenzymes Carbonic Anhydrases (CAs, EC 4.2.1.1) expressed in humans (h). CAs reversibly catalyze the CO2 hydration reaction, which is of crucial importance in the regulation of a plethora of fundamental processes at cellular level as well as in complex organisms. The first section of this review will be dedicated to compounds acting as activators of the hCAs (CAAs) and their promising effects on central nervous system affecting pathologies mainly characterized from memory and learning impairments. The second part will focus on the emerging chemical classes acting as hCA inhibitors (CAIs) and their potential use for the treatment of diseases.