Intratracheally Inhalable Nifedipine-Loaded Chitosan-PLGA Nanocomposites as a Promising Nanoplatform for Lung Targeting: Snowballed Protection via Regulation of TGF-β/β-Catenin Pathway in Bleomycin-Induced Pulmonary Fibrosis

Pulmonary fibrosis is a serious ailment that may progress to lung remodeling and demolition, where the key participants in its incidence are fibroblasts responding to growth factors and cellular calcium swinging. Calcium channel blockers, like nifedipine (NFD), may represent auspicious agents in pulmonary fibrosis treatment. Unfortunately, NFD bears complicated pharmacodynamics and a diminished systemic bioavailability. Thus, the current study aimed to develop a novel, non-invasive nanoplatform for NFD for direct/effective pulmonary targeting via intratracheal instillation. A modified solvent emulsification–evaporation method was adopted for the fabrication of NFD-nanocomposites, integrating poly(D,L-lactide-co-glycolide) (PLGA), chitosan (CTS), and polyvinyl alcohol, and optimized for different physiochemical properties according to the 32 full factorial design. Additionally, the aerodynamic behavior of the nanocomposites was scrutinized through cascade impaction. Moreover, the pharmacokinetic investigations were conducted in rats. Furthermore, the optimum formulation was tested in bleomycin-induced pulmonary fibrosis in rats, wherein fibrotic and oxidative stress parameters were measured. The optimum nanocomposites disclosed a nanosized spherical morphology (226.46 nm), a high entrapment efficiency (61.81%) and a sustained release profile over 24 h (50.4%). As well, it displayed a boosted in vitro lung deposition performance with a mass median aerodynamic diameter of 1.12 µm. Pharmacokinetic studies manifested snowballed bioavailability of the optimal nanocomposites by 3.68- and 2.36-fold compared to both the oral and intratracheal suspensions, respectively. The intratracheal nanocomposites revealed a significant reduction in lung fibrotic and oxidative stress markers notably analogous to normal control besides repairing abnormality in TGF-β/β-catenin pathway. Our results conferred a compelling proof-of-principle that NFD-CTS-PLGA nanocomposites can function as a promising nanoparadigm for pulmonary fibrosis management.

Improved Bioavailability of Poorly Soluble Drugs through Gastrointestinal Muco-Adhesion of Lipid Nanoparticles

Gastrointestinal absorption remains indispensable in the systemic delivery of most drugs, even though it presents several challenges that, paradoxically, may also provide opportunities that can be exploited to achieve maximal bioavailability. Drug delivery systems made from nanoparticle carriers and especially, lipid carriers, have the potential to traverse gastrointestinal barriers and deploy in the lymphatic pathway, which aptly, is free from first pass via the liver. Several poorly soluble drugs have presented improved systemic bioavailability when couriered in lipid nanoparticle carriers. In this review, we propose an additional frontier to enhancing the bioavailability of poorly soluble drugs when encapsulated in lipid nano-carriers by imparting muco-adhesion to the particles through application of appropriate polymeric coating to the lipid carrier. The combined effect of gastrointestinal muco-adhesion followed by lymphatic absorption is a promising approach to improving systemic bioavailability of poorly soluble drugs following oral administration. Evidence to the potential of this approach is backed-up by recent studies within the review.

Is curcumin at the threshold of therapeutic effectiveness on patients with colon cancer? – A systematic review

Curcumin, obtained from Curcuma longa, has been the subject of decades of scientific investigation on its therapeutic usefulness. It is reported to possess several therapeutic properties, of which anti-colon cancer is of interest in this review. Clinically, however, curcumin has yet to firm up its place among established anti-colon cancer therapeutic contenders. We aimed to systematically review the prevailing clinical evidence on the role of curcumin in colon cancer treatment. The review drawing from literature on clinical studies indicates fairly long-term tolerability. No regression of tumor was reported when curcumin was the sole intervention. An increase in p53 level expression was reported in a placebo-controlled study but no reduction in PGE2 or 5HETE. Pharmacokinetic data on healthy humans indicate that formulated curcumin delivery systems present significantly higher systemic bioavailability. It appears therefore that the clinical use of curcumin can potentially be realized only through appropriate formulation interventions

Mometasone furoate in the treatment of allergic rhinitis: a complex therapeutic effect

The review examines the role of mometasone furoate (NSMF) intranasal spray (Nasonex) in the treatment of allergic rhinitis (AR). There is a wide prevalence of AR both among children and adults, its adverse effect on the quality of life of patients. It is emphasized that the main means of therapy for moderate and severe course in accordance with international and Russian recommendations for the diagnosis and treatment of AR are intranasal glucocorticosteroids (INGKS). The pharmacological features of the MF molecule that underlie its efficacy and safety, including the affinity, lipophilicity and viscosity of the drug, as well as low systemic bioavailability, are discussed in detail. The therapeutic effects of NSMF in the treatment of seasonal and perennial AR, its effect on nasal symptoms are discussed in detail. The beneficial effect of NSMF therapy on nasal congestion is emphasized separately. The beneficial effect of NSMF treatment on other clinical manifestations of AR, including ocular symptoms, effects on sleep, and olfactory function, has been noted. The safety issues of NSMF use are discussed in detail, including systemic effects, such as effects on adrenal function, eye, and growth retardation in children, and local adverse effects on the nasal mucosa; there is a high profile of local and systemic safety of long-term use of NSMF in the treatment of AR in both adults and children.

Curcumin and Nano-Curcumin Mitigate Copper Neurotoxicity by Modulating Oxidative Stress, Inflammation, and Akt/GSK-3β Signaling

Copper (Cu) is essential for multiple biochemical processes, and copper sulphate (CuSO4) is a pesticide used for repelling pests. Accidental or intentional intoxication can induce multiorgan toxicity and could be fatal. Curcumin (CUR) is a potent antioxidant, but its poor systemic bioavailability is the main drawback in its therapeutic uses. This study investigated the protective effect of CUR and N-CUR on CuSO4-induced cerebral oxidative stress, inflammation, and apoptosis in rats, pointing to the possible involvement of Akt/GSK-3β. Rats received 100 mg/kg CuSO4 and were concurrently treated with CUR or N-CUR for 7 days. Cu-administered rats exhibited a remarkable increase in cerebral malondialdehyde (MDA), NF-κB p65, TNF-α, and IL-6 associated with decreased GSH, SOD, and catalase. Cu provoked DNA fragmentation, upregulated BAX, caspase-3, and p53, and decreased BCL-2 in the brain of rats. N-CUR and CUR ameliorated MDA, NF-κB p65, and pro-inflammatory cytokines, downregulated pro-apoptotic genes, upregulated BCL-2, and enhanced antioxidants and DNA integrity. In addition, both N-CUR and CUR increased AKT Ser473 and GSK-3β Ser9 phosphorylation in the brain of Cu-administered rats. In conclusion, N-CUR and CUR prevent Cu neurotoxicity by attenuating oxidative injury, inflammatory response, and apoptosis and upregulating AKT/GSK-3β signaling. The neuroprotective effect of N-CUR was more potent than CUR.

Is Curcumin at the Threshold of Therapeutic Effectiveness on Patients with Colon Cancer?—A Systematic Review

Curcumin, obtained from curcuma longa, has been the subject of decades of scientific investigation on its therapeutic usefulness. It is reported to possess several therapeutic properties, of which anti-colon cancer is of interest in this review. Clinically however, curcumin has yet to firm up its place among established anti-colon cancer therapeutic contenders. We aimed to systematically review prevailing clinical evidence on the role of curcumin in colon cancer treatment. The review drawing from literature on clinical studies indicates fairly long term tolerability. No regression of tumor was reported when curcumin was the sole intervention. Increase in p53 level expression was reported in a placebo controlled study but no reduction in PGE2 or 5HETE. Pharmacokinetic data on healthy humans indicate that formulated curcumin delivery systems present significantly higher systemic bioavailability. It appears therefore that the clinical use of curcumin can potentially be realized only through appropriate formulation interventions.Systematic Review Registration: [website], identifier [registration number]

Prescribing intranasal steroids in HIV-positive patients: systematic review of the literature

Background There are significant drug–drug interactions between human immunodeficiency virus antiretroviral therapy and intranasal steroids, leading to high serum concentrations of iatrogenic steroids and subsequently Cushing's syndrome. Method All articles in the literature on cases of intranasal steroid and antiretroviral therapy interactions were reviewed. Full-length manuscripts were analysed and the relevant data were extracted. Results A literature search and further cross-referencing yielded a total of seven reports on drug–drug interactions of intranasal corticosteroids and human immunodeficiency virus protease inhibitors, published between 1999 and 2019. Conclusion The use of potent steroids metabolised via CYP3A4, such as fluticasone and budesonide, are not recommended for patients taking ritonavir or cobicistat. Mometasone should be used cautiously with ritonavir because of pharmacokinetic similarities to fluticasone. There was a delayed onset of symptoms in many cases, most likely due to the relatively lower systemic bioavailability of intranasal fluticasone.

Overexpression of MRP3 in HeLa-UGT1A9 Cells Enhances Glucuronidation Capability of the Cells

Background: The interplay between phase II enzymes and efflux transporters leads to extensive metabolism and low systemic bioavailability of flavonoids. Objective: The study aims to investigate the dynamic interplay between multiple UGTs and multiple efflux transporters inside the cells. Methods: A new HeLa-UGT1A9-MRP3 cell was established to overexpress two dominant efflux transporters MRP3 and BCRP, and two UGT isoforms UGT1A9 and UGT1A3. The metabolism and glucuronides excretion for a model flavonoid genistein were determined in HeLa-UGT1A9-MRP3 cells and HeLa-UGT1A9-Con cells that overexpressed one UGT (1A9) and one efflux transporter (BCRP). Results: The excretion rate grew nearly 6-fold, cellular clearance of glucuronides increased about 3-fold, and a fraction of genistein metabolized (fmet) increased (14%, p<0.01) in the new cells. Small interfering (siRNA)-mediated MRP3 functional knockdown resulted in markedly decreases in the excretion rates (26%-78%), intracellular amounts (56%-93%), cellular clearance (54%-96%) in both cells, but the magnitude of the differences in HeLa-UGT1A9-Con cells were relatively small. Reductions in fmet values were similarly moderate (11%-14%). In contrast, UGT1A9 knockdown with siRNA caused large decreases in the excretion rates (46%-88%), intracellular amounts (80%-97%), cellular clearance (80%-98%) as well as fmet value (33%-43%, p<0.01) in both UGT1A9 cells. Comparisons of the kinetic parameters and profiles of genistein glucuronidation and UGT mRNA expression suggest that HeLa-UGT1A9-MRP3 has increased expression of both MRP3 and UGT1A3. Conclusion: The newly engineered HeLa-UGT1A9-MRP3 cells are an appropriate model to study the kinetic interplay between multiple UGTs and efflux transporters. It's a promising biosynthetic tool to obtain flavonoids glucuronides of high purity.

Enhanced Pharmacological Efficacy of Berberine Hydrochloride Loaded Lipid Based Pellets for the Treatment of Metabolic Diseases

Numerous researchers in past have reported the diversified therapeutic effects of Berberine hydrochloride (BERH) for the management of metabolic diseases, however due to poor systemic bioavailability these effects are dose dependant and desired effects were reported at high dose levels. The objective of present investigation is to evaluate and establish the enhancement in pharmacological efficacy of the designed BERH formulation at low oral dose level for the treatment of metabolic diseases constituting metabolic syndrome (MS). In the present investigation, BERH formulation in the dose level of (25 and 50mg/kg/day) was evaluated in cafeteria diet (CD) induced MS model in male Wistar rats for 42 days and compared with available marketed preparation in similar dose level using orlistat as reference drug. Among the studied dose level of BERH formulation the 25 mg/kg/day dose was adequate to produce significant reduction in calorie intake (P < 0.01), body weight, BMI, (P<0.001), organ weight viz. (stomach; P<0.05, liver; P<0.001, heart; P<0.01) and serum biochemical parameters (P<0.001). A significant improvement in lipid peroxidation (P<0.001), catalase (CAT), reduced glutathione (GSH) and superoxide dismutase (SOD) contents (P<0.001) was observed. The histopathological examinations indicated amelioration of liver, heart and pancreas tissues. The current study indicated significant glucose-lowering, hypophagic, anti-obesity, anti-hyperlipidemic and cardio protective activity of the BERH formulation even in much low oral dose level compared to previously reported studies. The observed behavior is attributed due to the enhanced bioavailability of BERH formulation which could be effectively used for metabolic diseases treatment.