WITHDRAWN: Pharmaceutical Nanoemulsion System: A Strategy to Enhance the Bioavailability of Drugs

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Role of nitazoxanide as a repurposed drug in the treatment and management of various diseases.

Nitazoxanide (NTZ) is an orally active drug with significant postmarketing experience including more than 75 million adults and children. Presently, this drug is widely used for a number of infectious conditions and diseases. It has a wide range of applications such as antiprotozoal, anthelmintic and antiviral against various types of Gram-positive and Gram-negative bacteria, parasites and certain viruses. Chemically, NTZ nitrothiazole is a [2-[(5-nitro-1,3- thiazol-2-yl) carbamoyl]phenyl] acetate compound. A number of clinical trials have suggested that it can be used in cryptosporidiosis, hepatitis B, hepatitis C, ovarian cancer, viral infections and helicobacter infection. Recent research has proposed its beneficial effect in treating the symptoms of coronavirus infection. It is proposed that the activity of NTZ is due to interference with pyruvate-ferredoxin oxidoreductase (PFOR), which is an enzyme that catalyzes the ferredoxin-dependent electron transfer reaction completed in anaerobiotic energy metabolism. The available literature suggested the importance of NTZ and its efficiency against various bacterial infections as well as in viral infectious diseases. The aim of this review is to examine and discuss the most important aspects of NTZ in different types of microbial infections.

Envisioning the Future of Nanomedicines in Management and Treatment of Neurological Disorders.

Neurodegenerative disorders are a result of continuous deterioration of the structure and function of neurons, involving the death of neurons. Neurodegenerative disorders affect millions of people around the world. Several conventional drug delivery strategies are available to treat neurological disorders. However, they are unable to provide adequate cytoarchitecture restoration and connection patterns due to lower solubility, poor bioavailability, drug resistance and incapability to traverse the blood-brain barrier (BBB). Therefore, designing and developing new and efficient delivery systems, that can bring drugs to CNS and have good bioavailability in the brain is very important. Nano drug delivery system acts as a ray of hope in the diagnosis and treatment of neurological disorders. The use of nanomedicines encapsulating therapeutic molecules may enhance transport of drug across BBB, absorption of drug and its controlled release in the human body with minimum adverse effects. This review article includes a comprehensive overview of the BBB, recent developments and application of nanomedicines, including liposomes, nanoparticles, nanomicelles, carbon nanotubes, etc., to the management as well as clinical therapy of various neurodegenerative disorders.

Nanotechnology Driven Approaches for the Management of Parkinson's Disease: Current Status and Future Perspectives.

Parkinson's disease (PD) is believed to be one of the commonly found adult-onset movement disorder occurring due to neurodegeneration and striatal dopamine deficiency. Although clinical diagnosis depends on the occurrence of bradykinesia and other cardinal motor features, PD is linked with many non-motor symptoms that are responsible for overall disability. Among several factors, genetic and environment-related factors are thought to be the major ones accountable for PD. Comprehensive research has shown that a number of drugs are effective in providing symptomatic relief to the patients suffering from PD. But some drug molecules suffer from significant drawbacks such as poor bioavailability and instability, therefore, they sometimes fail to deliver the expected results. Hence, to resolve these issues, new promising novel drug delivery systems have been developed. Liposomes, solid lipid nanoparticles, nanoemulsion, self-emulsifying drug delivery system (SEDDS), niosomes are some of the novel drug delivery system (NDDS) carriers that have been explored for enhancing the CNS concentration of levodopa, apomorphine, resveratrol, and other numerous drugs. This paper elucidates various drugs that have been studied for their potential contribution to the treatment and management of PD and also reviews and acknowledges the efforts of several scientists who successfully established various NDDS approaches for these drugs for the management of PD.

Proteomic Analysis of Huntington's Disease.

Huntington's disease (HD) is a neurodegenerative disease that is genetically inherited through an autosomal dominant gene located on chromosome 4. HD is caused by DNA mutation (generally 37 or more repetition of CAG nucleotides) that leads to an excessive stretch of glutamine residues. However, the main pathogenesis pathway resulted by polyglutamine expansion in mutant HD is unknown. The characteristics of this disease mostly appear in adults. Patients who suffer from this disease have shown an inability to control physical movements, emotional problems, speech disturbance, dementia, loss of thinking ability and death occurs between 15-20 years from the time of symptomatic onset. This review article suggested that investigation of mutation in the HD gene can be done by proteomic analysis such as mass spectroscopy, gel electrophoresis, western blotting, chromatographic based technology, and X-ray crystallography. The primary aim of proteomics is to focus on the molecular changes occurring in HD, there by enhancing the effectiveness of treatment.

Prevalence and associations of moderately increased albuminuria in patients with type 2 diabetes in United Arab Emirates.

BACKGROUND AND AIMS: Our study sought to investigate the prevalence of moderately increased albuminuria in United Arab Emirates (UAE) nationals with type 2 diabetes, and to identify the associated factors. METHODS: This prospective cross-sectional study was conducted in two hundred and seven UAE nationals with type 2 diabetes mellitus attending the internal medicine department of a secondary care hospital. Moderately increased albuminuria was estimated in random spot urine samples and was defined as urinary albumin-to-creatinine ratio (UACR) of 3-30 mg/mmoL. Prevalence and associations of moderately increased albuminuria were evaluated. RESULTS: The study population had a mean UACR of 7.2 ± 10.2 mg/mmoL with mean eGFR of 94.5 ± 11.7 mL/min/1.73 m2. Prevalence of moderately increased albuminuria in our study population was found to be 44.0%. Multivariate logistic regression analysis showed that duration of diabetes (OR:1.72, 95% CI:1.34-2.19; p<0.001), presence of hypertension (OR:3.42, 95% CI:0.96-12.20; p=0.050) and neuropathy (OR:2.85, 95% CI:1.03-7.84; p=0.042), BMI (OR:1.08, 95% CI:1.01-1.16; p=0.019), HbA1c (OR:1.39, 95% CI:1.00-1.93; p=0.045), CRP (OR:1.10, 95% CI:1.00-1.22; p=0.035), serum creatinine (OR:1.04, 95% CI:1.02-1.06; p<0.001) and HDL-C (OR:0.10, 95% CI:0.01-0.28; p<0.001) were independently correlated with moderately increased albuminuria. Stepwise multiple linear regression analysis demonstrated that duration of diabetes, HbA1c, CRP and serum creatinine were independent predictors of UACR. CONCLUSION: We report a high prevalence of moderately increased albuminuria in UAE nationals with type 2 diabetes in a secondary care setting. Routine screening and timely management of moderately increased albuminuria in type 2 diabetes mellitus can lead to better patient outcomes.

Lipid-based nanoformulations in the treatment of neurological disorders.

The neurological disorders affect millions of people worldwide, and are bracketed as the foremost basis of disability-adjusted life years (DALYs). The treatment options are symptomatic and often the movement of drugs is restricted by a specialized network of endothelial cell layers (adjoined by tight cell-to-cell junction proteins; occludin, claudins, and junctional adhesion molecules), pericytes and astroglial foot processes. In recent years, advances in nanomedicine have led to therapies that target central nervous system (CNS) pathobiology via altering signaling mechanisms such as activation of PI3K/Akt pathway in ischemic stroke arrests apoptosis, interruption of α-synuclein aggregation prevents neuronal degeneration in Parkinson's. Often such interactions are limited by insufficient concentrations of drugs reaching neuronal tissues and/or insufficient residence time of drug/s with the receptor. Hence, lipid nanoformulations, SLNs (solid lipid nanoparticles) and NLCs (nanostructured lipid carriers) emerged to overcome these challenges by utilizing physiological transport mechanisms across blood-brain barrier, such as drug-loaded SLN/NLCs adsorb apolipoproteins from the systemic circulation and are taken up by endothelial cells via low-density lipoprotein (LDL)-receptor mediated endocytosis and subsequently unload drugs at target site (neuronal tissue), which imparts selectivity, target ability, and reduction in toxicity. This paper reviews the utilization of SLN/NLCs as carriers for targeted delivery of novel CNS drugs to improve the clinical course of neurological disorders, placing some additional discussion on the metabolism of lipid-based formulations.

Raloxifene potentiates the effect of fluoxetine against maximal electroshock induced seizures in mice.

The evidence to guide clinicians regarding rationale polytherapy with current antiepileptic drugs (AEDs) is lacking, and current practice recommendations are largely empirical.  The excessive drug loading with combinatorial therapies of existing AEDs are associated with escalated neurotoxicity, and that emergence of pharmacoresistant seizures couldn't be averted. In pursuit of judicious selection of novel AEDs in combinatorial therapies with mechanism based evidences, standardized dose of raloxifene, fluoxetine, bromocriptine and their low dose combinations, were experimentally tested for their impact on maximal electroshock (MES) induced tonic hind limb extension (THLE) in mice. Hippocampal neuropeptide Y (NPY) levels, oxidative stress and histopathological studies were undertaken. The results suggest the potentiating effect of 4 mg/kg raloxifene on 14 mg/kg fluoxetine against MES induced THLE, as otherwise monotherapy with 4 mg/kg raloxifene was unable to produce an effect. The results also depicted better efficacy than carbamazepine (20 mg/kg), standard AED. Most profoundly, MES-induced significant (P < 0.001) reduction in hippocampal NPY levels, that were escalated insignificantly with the duo-drug combination, suggesting some other mechanism in mitigation of electroshock induced seizures. These results were later corroborated with assays to assess oxidative stress and neuronal damage. In conclusion, the results demonstrated the propitious therapeutic benefit of duo-drug low dose combination of drugs; raloxifene and fluoxetine, with diverse mode of actions fetching greater effectiveness in the management of generalized tonic clonic seizures (GTCS).

Role of Rutin Nanoemulsion in Ameliorating Oxidative Stress: Pharmacokinetic and Pharmacodynamics Studies.

Parkinson's disease is caused due to free radical generation in dopamine neurons leading to oxidative stress induced damage. The aim of this work was to ameliorate the free radical induced oxidative stress in rats by using TPGS (Tocopheryl polyethylene glycol 1000 succinate) loaded rutin nanoemulsion after oral administration. For this purpose, pharmacokinetic and pharmacodynamics studies were performed in albino wistar rats. Various behavioural tests (photoactometer test, rota rod, akinesia and catalepsy) and biochemical estimations for determination of GSH, TBARS and SOD were carried out. The results showed an increase in relative bioavailability of rutin after oral administration of nanoemulsion as compared to pure drug suspension. The AUC and Cmax of rutin nanoemulsion after oral administration were 1.8-fold and 1.9-fold higher than those of drug suspension respectively. Pharmacodynamic studies have shown good results with the rutin nanoemulsion than pure drug suspension. The rats treated with the rutin nanoemulsion exhibited significantly greater locomotor activity, better muscle coordination and improvement in cataleptic behaviour than the normal and haloperidol-induced rats (p < 0.001).Treatment with rutin suspension and rutin nanoemulsion helped in improving the stressed condition by increasing the levels of GSH, SOD and decrease in MDA levels in the brain. Anticancer activity was observed in a dose-dependent manner from 1 to 100 µg/ml. IC50 values for rutin suspension and rutin NE were found to be 36.7 and 25.4 µg/ml respectively. The rutin nanoemulsion has proven to be beneficial in ameliorating oxidative stress.

Screening of the whole human cytochrome P450 complement (CYPome) with enzyme bag cocktails / 药物分析学报

We have previously introduced the use of permeabilized fission yeast cells (enzyme bags) that recom-binantly express full-length CYPs for drug metabolism studies. Such enzyme bags are cells with pores that function as enzymes in situ. They can easily be prepared without a need for ultracentrifugation and may be used in similar protocols as microsomes. In this study we report the preparation of enzyme bag cocktails that permit the testing of multiple CYPs in a single enzyme bag reaction. Moreover, we established a convenient testing scheme that permits a rapid screen of all human CYPs for activity to-wards any given candidate substrate. An important aspect of this approach is the reduction of individual CYP test assays. If a cocktail containing many CYPs tests negative, it follows that all CYPs included in that cocktail need not be tested individually, thus saving time and resources. The new protocol was validated using two probe substrates.

Bioresponse Inspired Nanomaterials for Targeted Drug and Gene Delivery.

The traditional drug delivery techniques are unresponsive to the altering metabolic states of the body and fail to achieve target specific drug delivery, which results in toxic plasma concentrations. In order to harmonize the drug release profiles, diverse biological and pathological pathways and factors involved have been studied and consequently, nanomaterials and nanostructures are engineered in a manner so that they respond and interact with the target cells and tissues in a controlled manner to induce promising pharmacological responses with least undesirable effects. The bioinspired nanoparticles such as carbon nanotubes, metallic nanoparticles, and quantum dots sense the localized host environment for diagnosis and treatment of pathological states. These biocompatible polymeric- based nanostructures bind drugs to the specific receptors, which renders them as ideal vehicles for the delivery of drugs and gene. The ultimate goal of bioinspired nanocomposites is to achieve personalized diagnostic and therapeutic outcomes. This review briefly discussed current trends; role, recent advancements as well as different approaches, which are being used for designing and fabrication of some bioinspired nanocarriers.

Bioinspired Nanocomposites: Applications in Disease Diagnosis and Treatment.

Recent advancement in the field of synthesis and application of nanomaterials provided holistic approach for both diagnosis as well as treatment of diseases. Briefly, three-dimensional scaffold and geometry of bioinspired nanocarriers modulate bulk properties of loaded drug at molecular/ atomic structures in a way to conjointly modulate pathological as well as altered metabolic states of diseases, in very predictable and desired manners at a specific site of the target. While, from the pharmacotechnical point of views, the bioinspired nanotechnology processes carriers either favor to enhance the solubility of poorly aqueous soluble drugs or enable well-controlled sustained release profiles, to reduce the frequency of drug regimen. Consequently, from biopharmaceutical point of view, these composite materials, not only minimize first pass metabolism but also significantly enhance in-vivo biodistribution, permeability, bio-adhesion and diffusivity. In lieu of the above arguments, the nano-processed materials exhibit an important role for diagnosis and treatments. In the diagnostic center, recent emergences and advancement in the tools and techniques to diagnose the unrevealed diseases with the help of instruments such as, computed tomography, magnetic resonance imaging etc; heavily depend upon nanotechnology-based materials. In this paper, a brief introduction and recent application of different types of nanomaterials in the field of tissue engineering, cancer treatment, ocular therapy, orthopedics, and wound healing as well as drug delivery system are thoroughly discussed.

Synergistic antioxidant action of vitamin E and rutin SNEDDS in ameliorating oxidative stress in a Parkinson's disease model.

PURPOSE: Oxidative stress is the leading cause in the pathogenesis of Parkinson's disease. Rutin is a naturally occurring strong antioxidant molecule with wide therapeutic applications. It suffers from the problem of low oral bioavailability which is due to its poor aqueous solubility. METHODS: In order to increase the solubility self-nanoemulsifying drug delivery systems (SNEDDS) of rutin were prepared. The oil, surfactant and co-surfactant were selected based on solubility/miscibility studies. Optimization was done by a three-factor, four-level (34) Box-Behnken design. The independent factors were oil, surfactant and co-surfactant concentration and the dependent variables were globule size, self-emulsification time, % transmittance and cumulative percentage of drug release. The optimized SNEDDS formulation (RSE6) was evaluated for various release studies. Antioxidant activity was assessed by various in vitro tests such as 2,2-diphenyl-1-picrylhydrazyl and reducing power assay. Oxidative stress models which had Parkinson's-type symptoms were used to determine the antioxidant potential of rutin SNEDDS in vivo. Permeation was assessed through confocal laser scanning microscopy. RESULTS: An optimized SNEDDS formulation consisting of Sefsol + vitamin E-Solutol HS 15-Transcutol P at proportions of 25:35:17.5 (w/w) was prepared and characterized. The globule size and polydispersity index of the optimized formulation was found to be 16.08 ± 0.02 nm and 0.124 ± 0.01, respectively. A significant (p < 0.05) increase in the percentage of drug release was achieved in the case of the optimized formulation as compared to rutin suspension. Pharmacokinetic study showed a 2.3-fold increase in relative oral bioavailability. The optimized formulation had significant in vitro and in vivo antioxidant activity. CONCLUSION: Rutin SNEDDS have been successfully prepared and they can serve as an effective tool in enhancing the oral bioavailability and efficacy of rutin, thus helping in ameliorating oxidative stress in neurodegenerative disorders like Parkinson's disease.

Effect of high-pressure homogenization on formulation of TPGS loaded nanoemulsion of rutin - pharmacodynamic and antioxidant studies.

Polyphenolic bioflavonoid, Rutin possesses wide range of pharmacological activities. However, it shows poor bioavailability when administered orally. The aim of this study was to formulate and compare the potential of nanoemulsions for the solubility enhancement of rutin (RU) by using different techniques. RU-loaded nanoemulsions were prepared by spontaneous emulsification method and high-pressure homogenization (HPH) technique using sefsol 218 and tocopheryl polyethylene glycol 1000 succinate (TPGS) (1:1), solutol HS15 andtranscutol P as oil phase, surfactant and co-surfactant, respectively. The prepared formulations were compared for various parameters like droplet size, percentage transmittance, zeta potential, viscosity, refractive index and in vitro release. The HPH nanoemulsions showed smaller droplet size and increased in vitro release when compared to nanoemulsions prepared by spontaneous emulsification method. The optimized formulation showed spherical globules with average globule diameter of 18 nm and zeta potential of -41 mV. Cumulative percentage drug released obtained for RU, PF6 (spontaneous emulsification formulation F6) and HF6 (HPH formulation F6) were 41.5 ± 0.04%, 49.5 ± 0.06% and 94.8 ± 0.03%, respectively, after 6 h. The permeability of RU from HF6 was found to be ≈4.6 times higher than RU suspension during ex vivo everted gut sac studies. Antioxidant activity was determined by using DPPH assay and reducing power assay method. Results showed a high scavenging efficiency toward DPPH radicals by HF6. Anti-inflammatory effect of RU as determined by carrageenan-induced rat paw edema method was found to be higher (75.2 ± 4.8%) when compared to RU suspension (46.56 ± 3.5%). It can be inferred that TPGS-loaded nanoemulsion of RU serve as an effective tool in increasing solubility and permeability of RU.

Vitamin E loaded resveratrol nanoemulsion for brain targeting for the treatment of Parkinson's disease by reducing oxidative stress.

Resveratrol, a potent natural antioxidant, possesses a wide range of pharmacological activities, but its oral bioavailability is very low due to its extensive hepatic and presystemic metabolism. The aim of the present study was to formulate a kinetically stable nanoemulsion (o/w) using vitamin E:sefsol (1:1) as the oil phase, Tween 80 as the surfactant and Transcutol P as the co-surfactant for the better management of Parkinson's disease. The nanoemulsion was prepared by a spontaneous emulsification method, followed by high-pressure homogenization. Ternary phase diagrams were constructed to locate the area of nanoemulsion. The prepared formulations were studied for globule size, zeta potential, refractive index, viscosity, surface morphology and in vitro and ex vivo release. The homogenized formulation, which contained 150 mg ml(-1) of resveratrol, showed spherical globules with an average globule diameter of 102 ± 1.46 nm, a least poly dispersity index of 0.158 ± 0.02 and optimal zeta potential values of -35 ± 0.02. The cumulative percentage drug release for the pre-homogenized resveratrol suspension, pre-homogenized nanoemulsion and post-homogenized nanoemulsion were 24.18 ± 2.30%, 54.32 ± 0.95% and 88.57 ± 1.92%, respectively, after 24 h. The ex vivo release also showed the cumulative percentage drug release of 85.48 ± 1.34% at 24 h. The antioxidant activity determined by using a DPPH assay showed high scavenging efficiency for the optimized formulation. Pharmacokinetic studies showed the higher concentration of the drug in the brain (brain/blood ratio: 2.86 ± 0.70) following intranasal administration of the optimized nanoemulsion. Histopathological studies showed decreased degenerative changes in the resveratrol nanoemulsion administered groups. The levels of GSH and SOD were significantly higher, and the level of MDA was significantly lower in the resveratrol nanoemulsion treated group.

Resveratrol: review on therapeutic potential and recent advances in drug delivery.

INTRODUCTION: Natural products have seen a wide range of acceptability for the prevention and treatment of diseases throughout history. Resveratrol, a member of the stilbene family, has been found to potentially exhibit anticancer, antiangiogenic, immunomodulatory and cardioprotective activities as well as being an antioxidant. This is in addition to its usefulness in the treatment of neurodegenerative disease, diabetes and cardiac ailments. Currently, various studies have revealed that resveratrol is a potential drug candidate with multi-spectrum therapeutic application. AREAS COVERED: This review aims to describe the various studies supporting the wide range of pharmacological activities of resveratrol. In addition, it includes a section devoted to discussing the challenges associated with the drug and strategies to improve the properties of resveratrol such as solubility, stability and bioavailability. EXPERT OPINION: Resveratrol demonstrated its ability to be a potential drug candidate for the treatment of different ailments due to its potent antioxidant properties. To improve the drug stability, increase the bioavailability and minimize side-effects of resveratrol, novel drug delivery systems have been formulated to bring this potential candidate to the first line of disease treatment.

Rutin : therapeutic potential and recent advances in drug delivery.

INTRODUCTION: Natural compounds such as bioflavonoids have found application in health care system due to their wide biological activities, high safety margins and lower cost. Rutin , a polyphenolic bioflavonoid has shown wide range of pharmacological applications due to its significant antioxidant properties. Conventionally, it is used as antimicrobial, antifungal, and antiallergic agent. However, current research has shown its multispectrum pharmacological benefits for the treatment of various chronic diseases such as cancer, diabetes, hypertension and hypercholesterolemia. Its use is advantageous over other flavonoids as it is a nontoxic and nonoxidizable molecule. AREAS COVERED: This review focus on various studies done on rutin explaining its broad spectrum pharmacological activities. In addition, this review will also focus on the challenges associated with the drug and various approaches to improve the oral bioavailability of rutin. EXPERT OPINION: Rutin is a highly potent molecule due to its strong antioxidant properties. In the near future, enhancing its bioavailability using novel drug delivery methods having minimum side effects will bring this promising natural molecule to the forefront of therapy for the treatment of various chronic human diseases.

Nanocarrier-based hydrogel of betamethasone dipropionate and salicylic acid for treatment of psoriasis.

INTRODUCTION: Betamethasone dipropionate (BD) has anti-inflammatory, immunomodulatory, and antiproliferative activity. The aim of the current work was to test the hypothesis that the addition of corticosteroid such as BD and a keratolytic agent such as salicylic acid in nanocarrier based microemulsions formulation would result in enhancement and sustaining of corticosteroid delivery rate leading to better anti-psoriatic activity. Clinical use of BD is restricted to some extent due to its poor permeability across the skin. So to increase its permeation across the skin, microemulsion-based gel formulations were prepared and characterised. MATERIALS AND METHODS: Microemulsions were prepared by aqueous phase titration method, using oleic acid:sefsol (1.5:1), Tween 20, isopropyl alcohol, and distilled water as the oil phase, surfactant, cosurfactant and aqueous phase, respectively. Selected formulations were subjected to physical stability studies and consequently in vitro skin permeation studies. Surface studies of optimized formulation were done by transmission electron microscopy. In vivo anti-inflammatory activity was done by carageenan-induced raw paw edema method. RESULTS: The droplet size of microemulsions ranged from 60 to 190 nm. The optimized formulation exhibited viscosity 28.55 ± 2.03 mP, refractive index 1.409, pH 6.4, and conductivity 10(-4) scm(-1). The optimized microemulsion was converted into hydrogel using carbopol 934, and salicylic acid was incorporated into it. Drug deposition in skin was found to be 29.73 µg/mg. Assessment of skin permeation was done by histopathology studies which indicated changes in the structure of epidermal membrane of skin. In vivo anti-inflammatory activity indicated 72.11% and 43.96% inhibition of inflammation in case of developed microemulsion gel and marketed gel, respectively. CONCLUSIONS: The developed microemulsion gel containing BD and salicylic acid provided sustained and good anti-inflammatory activity for the treatment of psoriasis.