Dexmedetomidine inhibits the invasion,migration, and inflammation of rheumatoid arthritis fibroblast-like synoviocytes by reducing the expression of NLRC5

Rheumatoid arthritis (RA) is a chronic, autoimmune disease characterized by inflammatory synovitis, but its pathogenesis remains unclear. NLRC5 is a newly discovered member of the NLR family that is effective in regulating autoimmunity, inflammatory responses, and cell death processes. Dexmedetomidine (DEX) has been reported to have a variety of pharmacological effects, including anti-inflammatory and analgesic effects. However, the role of DEX in RA has not been explored. In adjuvant-induced arthritis (AA) rat models, DEX (10 μg/kg and 20 μg/kg) reduced the pathological score, the arthritis score, paw swelling volume, and the serum levels of IL-1β, IL-6, IL-17A, and TNF-α. Moreover, by using Western blot and real-time quantitative PCR (RT-qPCR), it was demonstrated that DEX can inhibit the expression of IL-1β, IL-6, MMP-3, MMP-9 and P-P65 in the synovial tissue of AA rats. In human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs), DEX (250 nM and 500 nM) was found to inhibit the expression of IL-1β, IL-6, MMP-3, MMP-9, and P-P65 following stimulation with TNF-α. Moreover, DEX can inhibit the invasion and migration of RA-FLSs stimulated by TNF-α. Finally, the expression of NLRC5 in RA-FLSs and AA rat models was also reduced by DEX. After silencing NLRC5 in RA-FLSs, the expression of IL-1β, IL-6, MMP-3, MMP-9, and P-P65, as well as the invasion and migration of cells, were significantly reduced. These results indicate that DEX inhibits the invasion, migration, and inflammation of RA-FLSs by reducing the expression of NLRC5 and inhibiting the NF-κB activation.     

ASIC1a promotes synovial invasion of rheumatoid arthritis via Ca2+/Rac1 pathway

Acid-sensitive ion channels (ASICs) as Ca²⁺ and Na⁺ cation channels are activated by changing in extracellular pH, which expressed in various diseases and participated in underlying pathogenesis. ASIC1a is involved in migration and invasion of various tumor cells. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) located at the edge of the synovium were identified as key players in the pathophysiological process of rheumatoid arthritis and reported to have many similar properties to tumor cells. Here, we investigated the roles of ASIC1a in synovial invasion in vivo and the migration and invasion of RA-FLSs in vitro.Our results showed ASIC1a highly expressed in RA synovial tissues and RA-FLSs. Inhibition of ASIC1a by PCTX-1 reduces synovial invasion and the expressions of MMP2, MMP9, p-FAK to protect articular cartilage in AA rats. Moreover, the acidity-promoted invasion and migration as well as the expressions of MMP2, MMP9, p-FAK of RA-FLSs were down-regulated by ASIC1a-RNAi and PCTX-1 while they were increased by overexpression-ASIC1a. ASIC1a mediated Ca²⁺ influx and the activation of Ras-related C3 botulinum toxin substrate 1(Rac1), which was decreased by the intracellular calcium chelating agent BAPTA-AM. Meanwhile, the migration and invasion as well as the expressions of MMP2, MMP9, p-FAK of RA-FLSs were decreased by Rac1 specific blocker NSC23766. In conclusion, this study indicated that ASIC1a may be a master regulator of synovial invasion via Ca²⁺/Rac1 pathway.     

Total glucosides of paeony for the treatment of rheumatoid arthritis: A methodological and reporting quality evaluation of systematic reviews and meta-analyses

ObjectiveTo assess the methodological, reporting and evidence quality of systematic reviews and meta-analyses of total glucosides of paeony (TGP) for rheumatoid arthritis (RA).MethodsWe comprehensively searched the literature in numerous databases from inception to July 29th, 2020. Two appraisers collected data and assessed the methodological and reporting quality of the included reviews by revised A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2) tool and the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA), respectively. The level of evidence quality was evaluated by employing the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) scale.ResultsEleven relevant articles were collected. The results from AMSTAR-2 showed that the methodological quality of all included reviews was critically low; no authors met the standard of those critical domains (0%), particularly in item 2, item 4 and item 7. The PRISMA scores ranged from 16.5 to 25, and one meta-analysis almost conformed to the PRISMA structure. According to GRADE, the 11 studies included 59 outcomes: 27 had very low quality, 22 had low quality, 10 had moderate quality, and none had high quality evidence. The most prominent downgrading factors were risk of bias, followed by publication bias, inconsistency, imprecision, and indirectness.ConclusionsAlthough included studies summarized that TGP was effective and safe in the treatment of RA, the methodological and reporting quality and the quality of evidence was poor overall; decision-makers should be prudent when using TGP in treating RA patients. High-quality and multicenter studies investigating TGP for RA are urgently needed.     

Prevalence of complementary and alternative medicine use among rheumatoid arthritis patients in Saudi Arabia

Background and aimThe use of complementary and alternative medicine (CAM) is unexplored among Saudi rheumatoid arthritis (RA) patients. The aim of this study was to estimate the prevalence and types of CAM used among patients with RA and factors associated with their use.Experimental procedureA cross-sectional study was conducted at rheumatology clinics in two tertiary hospitals located in Riyadh, Saudi Arabia. The data was collected between May 2017 and February 2018. Unpaired Student's t-tests, Chi-square tests, and Pearson correlation tests were used to compare users vs nonusers.ResultsA total of 438 patients (mean age = 49, SD ± 15 years; 89.7% females) were included in this study. Sixty seven percent of included patients had used CAM for their RA. The majority of CAM users were female (92.1%). The most frequently used CAM products were vitamin D (47%), calcium (37%), honey (15%), ginger (13%), turmeric (11%), black seeds (8%), and fenugreek (8%). One hundred ninety-six (45%) patients believe that CAM is safe, and 287 (96%) patients took it because they believed that CAM had “added benefits”. Statistically significant differences were found for gender, RA duration, erythrocyte sedimentation rate (ESR) level, and seropositivity between CAM users and nonusers (P = 0.019, P = 0.011, P = 0.022, and P < 0.0001, respectively). A significant correlation was found between the Erythrocyte Sedimentation Rate (ESR) level, RA duration and CAM use (r = 0.110, P = 0.022 and r = 0.121, P = 0.012, respectively). These data indicated that patients who used CAM had higher ESR level and longer disease duration than patients didn’t use CAM.ConclusionThere is a high prevalence of CAM use among RA patients. CAM use was perceived to add benefit and patients using it had higher ESR. Larger studies are needed to assess the use of CAM and its impact on RA and its management.     

Medicarpin prevents arthritis in post-menopausal conditions by arresting the expansion of TH17 cells and pro-inflammatory cytokines

Autoimmune diseases are characterized by alteration in balance of various cytokines. Rheumatoid arthritis is a well-known inflammatory disease leading to destruction of cartilage at knee and hands. Collagen-induced arthritis (CIA) is a common autoimmune model for rheumatoid arthritis study. Here, we have investigated the therapeutic role of medicarpin, a natural pterocarpan with known anti-osteoclastogenic activities, in postmenopausal polyarthritis model of DBA/1J mice. For this, mice were ovariectomized and CIA was induced in OVx animals with primary immunization. After 21 days, booster dose was injected in Ovariectomy (OVx) mice to develop postmenopausal poly-arthritis mice model. Medicarpin treatment in mice at dose of 10.0 mg/kg/body wt was started after 21 days of primary immunization for one month of time period every day orally. We found that medicarpin prevented alteration of TH-17/Treg ratio in CIA model leading to reduced osteoclastogenesis. Micro Computed Tomography (Micro-CT) analysis demonstrated that medicarpin prevents cartilage erosion in joints and restores loss of trabeculae parameters in distal tibia. Treatment with medicarpin also prevented alteration of various cytokines level by down-regulating various pro-inflammatory cytokines like TNF-α, IL-6 and IL-17A, while up-regulating anti-inflammatory cytokine IL-10 in CIA model of mice. Biological marker of arthritis is cartilage oligomeric matrix protein (COMP). COMP level was up-regulated in CIA induced mice while treatment with medicarpin significantly restored the serum level of COMP compared with untreated groups. Cartilage staining by Safranin-O also indicates that cartilage destruction in joints of CIA mice was prevented by medicarpin treatment. From this study, we can conclude that medicarpin is effective in preventing arthritis in post-menopausal conditions.     

c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 is a critical regulator for arthritis progression by meditating inflammation in mice model

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. However, the pathogenesis of RA is not fully understood. Here, we reported that c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1, also known as JNK-interacting protein 3 (JIP3)) was significantly important for collagen-induced arthritis (CIA) in mice. Mice with JIP3 knockout (JIP3^−/−) showed a significant decrease in arthritis index and swollen joint count in CIA mice. The histopathology of spleen and joint was markedly alleviated by JIP3 deficiency in CIA mice. Excessive macrophage activation in CIA mice was also inhibited by JIP3 deletion. CIA-induced RANKL/RANK/OPG system mRNA expression was blocked in JIP3-knockout mice. In addition, CIA-triggered cytokine secretion and TLRs/NF-κB activation was inactivated by JIP3-deficiency. In line with the inhibition of inflammation by JIP3-knockout, it also significantly suppressed JNK pathway activation induced by CIA, as evidenced by the down-regulation of p-JNK, p-c-Jun, AFT-2 and Elk-1 in joints. In vitro, RANKL-exposed RAW264.7 cells showed a significant reduction of osteoclast formation using TRAP staining. Moreover, JIP3 inhibition reduced the RANKL-caused expression of osteoclastic genes and inflammatory regulators, as well as activation of TLRs/NF-κB and JNK signaling pathways. Importantly, we found that promoting JNK activity could abrogate JIP3 knockdown-suppressed osteoclastic genes expression, inflammatory response and NF-κB activation. These findings suggested that JIP3 could significantly impede osteoclast formation and function by regulating JNK activation, illustrating a novel therapeutic strategy for managing arthritis and preventing bone destruction.     

Nanoparticles of cisplatin augment drug accumulations and inhibit multidrug resistance transporters in human glioblastoma cells

BackgroundCisplatin (CSP) is a potent anticancer drug widely used in treating glioblastoma multiforme (GBM). However, CSP's clinical efficacy in GBM contrasted with low therapeutic ratio, toxicity, and multidrug resistance (MDR). Therefore, we have developed a system for the active targeting of cisplatin in GBM via cisplatin loaded polymeric nanoplatforms (CSP-NPs).MethodsCSP-NPs were prepared by modified double emulsion and nanoprecipitation techniques. The physiochemical characterizations of CSP-NPs were performed using zeta sizer, scanning electron microscopy (SEM), drug release kinetics, and drug content analysis. Cytotoxicity, induction of apoptosis, and cell cycle-specific activity of CSP-NPs in human GBM cell lines were evaluated by MTT assay, fluorescent microscopy, and flow cytometry. Intracellular drug uptake was gauged by fluorescent imaging and flow cytometry. The potential of CSP-NPs to inhibit MDR transporters were assessed by flow cytometry-based drug efflux assays.ResultsCSP-NPs have smooth surface properties with discrete particle size with required zeta potential, polydispersity index, drug entrapment efficiency, and drug content. CSP-NPs has demonstrated an ‘initial burst effect’ followed by sustained drug release properties. CSP-NPs imparted dose and time-dependent cytotoxicity and triggered apoptosis in human GBM cells. Interestingly, CSP-NPs significantly increased uptake, internalization, and accumulations of anticancer drugs. Moreover, CSP-NPs significantly reversed the MDR transporters (ABCB1 and ABCG2) in human GBM cells.ConclusionThe nanoparticulate system of cisplatin seems to has a promising potential for active targeting of cisplatin as an effective and specific therapeutic for human GBM, thus eliminating current chemotherapy's limitations.     

Assessment of the acute and subacute toxicity of the aqueous extract of Moroccan Ferula communis fruit in a mouse model

Ferula communis L. is thought to possess a wide range of therapeutic qualities. This plant's safety is critical regarding its potential uses as a medicine. Using the techniques outlined in the OECD recommendations, the present study aimed to assess the acute and subacute toxicity profiles of Ferula communis aqueous extract (FC-Ext) in mice. In the acute study, the FC-Ext was administered to adult male and female Swiss albino mice through oral and intraperitoneal routes at doses of 0–4 g/kg. The general behavioral effects, mortality rates, and latency of mortality were evaluated for a period of 14 days. For the sub-acute dose study, the FC-Ext was administered orally to adult mice at doses of 125, 250, and 500 mg/kg on a daily basis for 28 days. Body weight and selected biochemical and hematological parameters were measured, and histological examinations of the liver, kidney, and spleen were conducted to assess any signs of organ damage at the end of the treatment period. The results of the acute toxicity study demonstrated that the LD₅₀ values for the oral and intraperitoneal administration of FC-Ext were 3.6 g/kg and 2.3 g/kg, respectively. In the subacute toxicity study of FC-Ext, no significant changes in body weight were observed. However, a substantial increase in the weights of the liver, kidney, and spleen was observed in male mice. The administration of FC-Ext to mice at doses higher than 250 mg/kg resulted in a decrease in white blood cells and platelets in both sexes and a reduction in red blood cells and mean corpuscular hemoglobin concentration in males and hemoglobin in females. No changes in biochemical parameters were observed. Microscopic examination of vital organs such as the liver, kidney, and spleen revealed no significant injuries. Based on the current results, the aqueous extract of Ferula communis has low toxicity. These findings provide important information about the toxicity profile of the traditional medicine plant Ferula communis.     

Chronotherapy targeting cytokine secretion attenuates collagen-induced arthritis in mice

ObjectiveDiurnal variation of symptoms are observed in rheumatoid arthritis, especially in productions of cytokines that show peak concentrations during mid night. In contrast, cytokines of collagen-induced arthritis (CIA) mice increase in daytimes under Mid-light condition. By using chronotherapy, differences in drug efficacies according to administration time of Baricitinib, a wide ranged cytokine blocker, were examined in CIA mice.MethodsCIA mice were administered a dose of 3 mg/kg of Baricitinib once a day at zeitgeber time (ZT) 0 or ZT12 for 21 days. Arthritis scores, histopathology and factors related to joint destruction in sera were examined. Phosphorylation of STAT3 in liver, expressions of cytokines in spleen, and Interleukin (IL)-6 and tumor necrosis factor (TNF)-α in sera were measured.ResultsIn CIA mice, diurnal variations were observed both in expressions of cytokines and phosphorylation of STAT3. Arthritis scores of ZT0/12 group decreased from day3 as compared to untreated mice, and those of ZT0 group significantly decreased as compared to ZT12 group from day12. Pathological findings, immunohistochemistry of cytokines and Receptor activator of nuclear factor kappa-Β ligand (RANKL)/osteoprotegerin ratio in sera well reflected results of arthritis scores. Diurnal variation of STAT3 phosphorylation was suppressed in ZT0 group. At ZT2, expressions of IL-6/Interferon-γ/TNF/granulocyte–macrophage colony-stimulating factor in ZT0 group were significantly decreased as compared to untreated mice, though not in ZT12 group. In ZT0 group, IL-6 and TNF-α in sera were decreased for longer time than that in ZT12 group.ConclusionChronotherapy using Baricitinib targeting cytokine secretions is effective in CIA mice. Clinical applications of chronotherapy can be expected to enhance the drug efficacy.     

Anti-rheumatoid arthritis effects of flavonoids from Daphne genkwa

ObjectiveThis study aims to select the most effective anti-Rheumatoid Arthritis (RA) component of flavonoids from Daphne genkwa Sieb. et Zucc. by anti-inflammatory and immunomodulatory effects in vitro, and to elucidate the mechanism.MethodsThe anti-inflammatory and immunomodulatory effects of total flavonoids (TF) and four flavonoid components (genkwanin, hydroxygenkwanin, luteolin and apigenin) were determined by pharmacological approach in LPS-induced RAW 264.7 macrophages and ConA-induced T lymphocytes. Principal component analysis (PCA) was used to obtain the optimal anti-RA component in vitro. Western blot and real-time quantitative PCR (q-PCR) were used to explore the mechanisms. Finally, the in vitro anti-RA effect was verified by human rheumatoid arthritis fibroblast-like synoviocytes (FLSs).ResultsTF and four flavonoids significantly reduced the expressions of NO, iNOS, TNF-α, IL-6, IFN-γ and IL-2. PCA showed that genkwanin was the most effective anti-RA component in vitro. Genkwanin inhibited nuclear factor-κB (NF-κB) pathway by decreasing the phosphorylation levels of IKK, IκB and NF-κB, and down-regulated the expressions of iNOS, COX-2 and IL-6 mRNA. Genkwanin also inhibited the abnormal proliferation of FLSs and down-regulated the secretions of NO and IL-6.ConclusionThe most effective anti-RA component was genkwanin. Genkwanin exerts anti-RA effect through down-regulating the activation of NF-κB pathway and mRNA expressions of inflammatory mediators, and also by inhibiting the abnormal proliferation of FLSs and its NO and IL-6 secretion levels.     

Influence of anti-thymocyte globulin plasma levels on outcome parameters in stem cell transplanted children

IntroductionAllogenic hematopoietic stem cell transplantation is a curative option for malignant and non-malignant pediatric diseases. Serotherapy is often employed to avoid graft-versus-host disease (GvHD) on one hand and graft rejection on the other hand. Therapeutic drug monitoring is increasingly used to allow for more precise dosing especially in pediatric patients due to their specific pharmacological characteristics. Application of T-cell directed antibodies is not routinely monitored, but may benefit from more precise dosing regimens.MethodsTwo different preparations of rabbit anti-thymocyte globulin (rATG), Thymoglobuline® and ATG-F (Grafalon®), are frequently used to prevent GvHD in pediatric patients by in vivo T-cell depletion. Total rATG levels and active rATG levels were analyzed prospectively in pediatric patients undergoing HSCT. Clinical and laboratory outcome parameters were recorded.ResultsrATG levels were measured in 32 patients, 22 received thymoglobuline and 10 received ATG-F. The median total peak plasma level was 419.0 µg/ml for ATG-F and 60.4 µg/ml for thymoglobuline. For ATG-F, exposure could be predicted from the calculated dose more precisely than for thymoglobuline. Active peak plasma levels neither of ATG-F, nor of thymoglobuline correlated significantly with the number of lymphocytes prior to serotherapy. There was no significant difference in incidence of aGvHD, cGvHD, rejection, mixed chimerism or viral infections in the two cohorts. However, in our cohort, patients with high thymoglobuline exposure showed a compromised reconstitution of T cells.ConclusionsATG-F and thymoglobuline show different pharmacological and immunological impact in children, whose clinical significance needs to be investigated in larger cohorts.     

Cardioprotective effects of sinomenine in myocardial ischemia/reperfusion injury in a rat model

BackgroundIschemia reperfusion (I/R) play an imperative role in the expansion of cardiovascular disease. Sinomenine (SM) has been exhibited to possess antioxidant, anticancer, anti-inflammatory, antiviral and anticarcinogenic properties. The aim of the study was scrutinized the cardioprotective effect of SM against I/R injury in rat.MethodsRat were randomly divided into normal control (NC), I/R control and I/R + SM (5, 10 and 20 mg/kg), respectively. Ventricular arrhythmias, body weight and heart weight were estimated. Antioxidant, inflammatory cytokines, inflammatory mediators and plasmin system indicator were accessed.ResultsPre-treated SM group rats exhibited the reduction in the duration and incidence of ventricular fibrillation, ventricular ectopic beat (VEB) and ventricular tachycardia along with suppression of arrhythmia score during the ischemia (30 and 120 min). SM treated rats significantly (P < 0.001) altered the level of antioxidant parameters. SM treatment significantly (P < 0.001) repressed the level of creatine kinase MB (CK-MB), creatine kinase (CK) and troponin I (Tnl). SM treated rats significantly (P < 0.001) repressed the tissue factor (TF), thromboxane B2 (TXB2), plasminogen activator inhibitor 1 (PAI-1) and plasma fibrinogen (Fbg) and inflammatory cytokines and inflammatory mediators.ConclusionOur result clearly indicated that SM plays anti-arrhythmia effect in I/R injury in the rats via alteration of oxidative stress and inflammatory reaction.     

An update on the current status and prospects of nitrosation pathways and possible root causes of nitrosamine formation in various pharmaceuticals

Over the last two years, global regulatory authorities have raised safety concerns on nitrosamine contamination in several drug classes, including angiotensin II receptor antagonists, histamine-2 receptor antagonists, antimicrobial agents, and antidiabetic drugs. To avoid carcinogenic and mutagenic effects in patients relying on these medications, authorities have established specific guidelines in risk assessment scenarios and proposed control limits for nitrosamine impurities in pharmaceuticals. In this review, nitrosation pathways and possible root causes of nitrosamine formation in pharmaceuticals are discussed. The control limits of nitrosamine impurities in pharmaceuticals proposed by national regulatory authorities are presented. Additionally, a practical and science-based strategy for implementing the well-established control limits is notably reviewed in terms of an alternative approach for drug product N-nitrosamines without published AI information from animal carcinogenicity testing. Finally, a novel risk evaluation strategy for predicting and investigating the possible nitrosation of amine precursors and amine pharmaceuticals as powerful prevention of nitrosamine contamination is addressed.     

The pro-inflammatory cytokine IL-Iβ alteration by deer (Rusa unicolor) antler extract on osteoarthritis rat model

Osteoarthritis is a disease associated with articular cartilage degradation, intra-articular area inflammation, and subchondral bone replacement. Cytokine IL-1β has a prominent function in the inflammations process that passes in the joints. The 70% ethanol extracts of deer antler (250 and 500 mg/kg BW) and glucosamine sulfate (250 kg/BW) were evaluated for four weeks in reducing cytokine IL-1β to rat model OA-induced Monosodium iodoacetate. Measurements of joint diameter in rat’s knee and hyperalgesia were performed on weeks 0, 1, 2, 3, 4, 5, 6, and 7. The presence of a significant difference in the stimulation thermal latency (p = 0.00) and the resulting increase in swelling of joint diameter (p = 0.00) are evidence that MIA has successfully induced the rat modeling of OA. A significant decrease in cytokine IL-Iβ levels was shown on week 3 after MIA injection (p = 0.00). Both concentrations of deer extracts significantly reduced knee joint diameter (p = 0.00), latency thermal stimulation (p = 0.00), and cytokine IL-1β levels (p = 0.00). Based on the results, it can be concluded that the 70% ethanol extract of deer antler is a potential medicine for OA therapy.     

Safety and tolerability of Empagliflozin use during the holy month of Ramadan by fasting patients with type 2 diabetes: A prospective cohort study

BackgroundType 2 Diabetes Mellitus (T2DM) patients are exposed to a 7.5 times higher risk of hypoglycemia while fasting during Ramadan. Relevant diabetes guidelines prioritize the use of SGLT2 inhibitors over other classes. There is a great need to enrich data on their safe and effective use by fasting patients at greater risk of hypoglycemia. Therefore, this study aims to assess the safety and tolerability of Empagliflozin in T2DM Muslim patients during Ramadan.MethodologyA prospective cohort study was conducted for adult Muslim T2DM patients. Patients who met the inclusion criteria were categorized into two sub-cohorts based on Empagliflozin use during Ramadan (Control versus Empagliflozin). The primary outcomes were the incidence of hypoglycemia symptoms and confirmed hypoglycemia. Other outcomes were secondary. All patients were followed up to eight weeks post-Ramadan. A propensity score (PS) matching and Risk Ratio (RR) were used to report the outcomes.ResultsAmong 1104 patients with T2DM who were screened, 220 patients were included, and Empagliflozin was given to 89 patients as an add-on to OHDs. After matching with PS (1:1 ratio), the two groups were comparable. The use of other OHDs, such as sulfonylurea, DPP4 inhibitors, and Biguanides, was not statistically different between the two groups. The risk of hypoglycemia symptoms during Ramadan was lower in patients who received Empagliflozin than in the control group (RR 0.48 CI 0.26, 0.89; p-value = 0.02). Additionally, the risk of confirmed hypoglycemia was not statistically significant between the two groups (RR 1.09 CI 0.37, 3.22; p-value = 0.89).ConclusionEmpagliflozin use during Ramadan fasting was associated with a lower risk of hypoglycemia symptoms and higher tolerability. Further randomized control trials are required to confirm these findings.     

Preparation and Evaluation of Quinapyramine Sulphate-Docusate Sodium Ionic Complex Loaded Lipidic Nanoparticles and Its Scale Up Using Geometric Similarity Principle

The objective of the present work is to prepare and evaluate ionically complexed Quinapyramine sulphate (QS) loaded lipid nanoparticles and its scale up using geometric similarity principle. Docusate sodium (DS), at a molar ratio of 1:2 of QS to DS, was used to prepare hydrophobic Quinapyramine sulphate-Docusate sodium (QS-DS) ionic complex. Based on the difference in total solubility parameter and polarity of QS-DS complex and different lipids, precirol was selected as a lipid for the preparation of lipidic nanoparticles. The particle size, zeta potential, and % entrapment efficiency (%EE) of QS-DS ionic complex loaded solid lipid nanoparticles (QS-DS-SLN) was found to be 250.10 ± 26.04 nm, ?27.41 ± 4.18 mV and 81.26 ± 4.67% respectively. FTIR studies confirmed the formation of QS-DS ionic complex. DSC and XRD studies revealed the amorphous nature of QS in QS-DS-SLN. The spherical shape of nanoparticles was confirmed by scanning electron microscopy. QS-DS-SLN showed sustained release of QS for up to 60 h. No significant difference was observed in particle size, zeta potential, and % entrapment efficiency of pilot-scale batch prepared by using rotational speed of 700 rpm. In conclusion, ionic complexation approach can be used to increase % EE of charged drugs into lipid nanoparticles.     

Preclinical study for the ameliorating effect of l-ascorbic acid for the oxidative stress of chronic administration of organic nitrates on myocardial tissue in high sucrose/fat rat model

BackgroundThe therapeutic activity of Glyceryl trinitrate (GTN) is mainly regulated by liberating nitric oxide (NO) and reactive nitrogen species (RNS). During this biotransformation, oxidative stress and lipid peroxidation inside the red blood cells (RBCs) occur. Hemoglobin tightly binds to NO forming methemoglobin altering the erythrocytic antioxidant defense system.AimThe principal objective of our research is to show the ameliorating effect of l-ascorbic acid for the deleterious effects of chronic administration of nitrovasodilator drugs used in cardiovascular diseases such as oxidative stresses and tolerance.MethodWe studied some biochemical parameters for the oxidative stress using groups of high sucrose/fat (HSF) diet Wistar male rats chronically orally administered different concentrations of Isosorbide-5-mononitrate (ISMN) 0.3 mg/kg, 0.6 mg/kg and 1.2 mg/kg. Afterwards, we evaluated the role of l-ascorbic acid against these biochemical changes in cardiac tissues.ResultsChronic treatment with organic nitrates caused elevated serum levels of lipid peroxidation, hemoglobin derivatives as methemoglobin and carboxyhemoglobin, rate of hemoglobin autoxidation, the cellular levels of the pro-inflammatory cytokines marker (NF-κB) and apoptosis markers (caspase-3) in the myocardium muscles in a dose-dependent manner. Meanwhile, such exposure caused a decline in the enzymatic effect of SOD, GSH and CAT accompanied by a decrease in the level of mitochondrial oxidative stress marker (nrf2) in the myocardium muscles and a decrease in the serum iron and total iron-binding capacity (TIBC) in a dose-dependent manner. Concomitant treatment with l-ascorbic acid significantly diminished these changes for all examined parameters.ConclusionChronic administration of organic nitrates leads to the alteration of the level of oxidative stress factors in the myocardium tissue due to the generation of reactive oxygen species. Using l-ascorbic acid can effectively ameliorate such intoxication to overcome nitrate tolerance.