Self-nanomicellizing solid dispersion of edaravone: part I – oral bioavailability improvement

Background: Edaravone (EDR) is known for its free radical scavenging, antiapoptotic, antinecrotic, and anticytokine effects in neurological and non-neurological diseases. It is currently available clinically as Radicava® and Radicut®, intravenous medications, recently approved for the treatment of amyotrophic lateral sclerosis and cerebral infarction. However, the oral use of EDR is still restricted by its poor oral bioavailability (BA) due to poor aqueous solubility, stability, rapid metabolism, and low permeability. The present study reports the development of novel EDR formulation (NEF) using self-nanomicellizing solid dispersion (SNMSD) strategy with the aim to enable its oral use. Materials and methods: The selection of a suitable carrier for the development of NEF was performed based on the miscibility study. The optimization of EDR-to-carrier ratio was conducted via kinetic solubility study after preparing SNMSDs using solvent evaporation technique. The drug–polymer carrier interaction and self-nanomicellizing properties of NEF were investigated with advanced characterization studies. In vitro permeation, metabolism, and dissolution study was carried out to examine the effect of the presence of a carrier on physicochemical properties of EDR. Additionally, the dose-dependent pharmacokinetic study of NEF was conducted and compared with the EDR suspension. Results: Soluplus® (SOL) as a carrier was selected based on the potential for improving aqueous solubility. The NEF containing EDR and SOL (1:5) resulted in the highest enhancement in aqueous solubility (17.53-fold) due to amorphization, hydrogen bonding interaction, and micellization. Moreover, the NEF demonstrated significant improvement in metabolism, permeability, and dissolution profile of EDR. Furthermore, the oral BA of NEF showed 10.2-, 16.1-, and 14.8-fold enhancement compared to EDR suspension at 46, 138, and 414 µmol/kg doses. Conclusion: The results demonstrated that SNMSD strategy could serve as a promising way to enhance EDR oral BA and NEF could be a potential candidate for the treatment of diseases in which oxidative stress plays a key role in their pathogenesis.Ankit Parikh, Krishna Kathawala, Chun Chuan Tan, Sanjay Garg, Xin-Fu Zho

Effects of Exogenous Cellulase Source on In Vitro Fermentation Characteristics and Methane Production of Crop Straws and Grasses

In vitro fermentation experiments were conducted to investigate the effects of 3 sources of exogenous cellulase products (EC) at 4 dose rates (DR) (0, 12, 37 and 62 IU/g of DM) on degradation of forage and methane production by mixed rumen micro-organisms of goats. The maximum gas production (Vf) of grasses was higher (P<0.001) in Neocallimastix patriciarum (NP) group than those in Trichoderma reesei (TR) and Trichoderma longibrachiatum (TL) groups. Quadratic increases in dry matter degradation (DMD) of forage and neutral detergent fiber (NDFD) of straw were observed for all EC, with optimum DR in the low range. Supplementation of EC originated from TR and NP increased (P<0.001) DMD of forage compared to that from TL. Addition of EC originated from TR and NP also decreased pH value, ammonia nitrogen (NH3-N) and methane (CH4) production compared to that from TL. Quadratic decreases in pH value, NH3-N and CH4 of forage were noted for EC of TR and NP, and with optimum DR in the low range. For short chain fatty acid, the EC of NP increased total volatile fatty acid (TVFA) and acetate concentration and the ratio of acetate to propionate of forage compared with EC of TL and TR, and with optimum DR in the low to medium range. It was concluded that the source of EC differed in fiber degradation and methane emission, and with optimum DR of TR in the low range (from 12 to 37 U/g DM) in improving fiber degradation and decreasing methane emission

Knockout of p75 neurotrophin receptor attenuates the hyperphosphorylation of Tau in pR5 mouse model

p75 neurotrophin receptor (p75NTR) has been implicated in Alzheimer's disease (AD). However, whether p75NTR is involved in Tau hyperphosphorylation, one of the pathologies observed in AD, remains unclear. In our previous study, the extracellular domain of p75NTR blocked amyloid beta (Aβ) toxicity and attenuated Aβ-induced Tau hyperphosphorylation. Here we show that, in the absence of Aβ, p75NTR regulates Tau phosphorylation in the transgenic mice with the P301L human Tau mutation (pR5). The knockout of p75NTR in pR5 mice attenuated the phosphorylation of human Tau. In addition, the elevated activity of kinases responsible for Tau phosphorylation including glycogen synthase kinase 3 beta; cyclin-dependent-kinase 5; and Rho-associated protein kinase was also inhibited when p75NTR is knocked out in pR5 mice at 9 months of age. The increased caspase-3 activity observed in pR5 mice was also abolished in the absence of p75NTR. Our study also showed that p75NTR is required for Aβ- and pro-brain derived neurotrophin factor (proBDNF)-induced Tau phosphorylation, in vitro. Overall, our data indicate that p75NTR is required for Tau phosphorylation, a key event in the formation of neurofibrillary tangles, another hallmark of AD. Thus, targeting p75NTR could reduce or prevent the pathologic hyperphosphorylation of Tau.Noralyn B. Mañucat-Tan, Lin-Lin Shen, Larisa Bobrovskaya, Mohammed Al-hawwas, Fiona H. Zhou, Yan-Jiang Wang, Xin-Fu Zho

High Altitude test of RPCs for the ARGO-YBJ experiment

A 50 m**2 RPC carpet was operated at the YangBaJing Cosmic Ray Laboratory (Tibet) located 4300 m a.s.l. The performance of RPCs in detecting Extensive Air Showers was studied. Efficiency and time resolution measurements at the pressure and temperature conditions typical of high mountain laboratories, are reported.Comment: 16 pages, 10 figures, submitted to Nucl. Instr. Met

Effects of an ethanollic extract of Gynura procumbens on serum glucose, cholesterol and triglyceride levels in normal and streptozotocin-induced diabetic rats

Singapore Medical Journal4119-13SIMJ

Tight-binding recursion calculations of step energetics on the GaAs(110) surface

Journal of Chemical Physics107155914-5917JCPS

Development of a novel oral delivery system of edaravone for enhancing bioavailability

Edaravone (EDR), a strong free radical scavenger, is known for its promising therapeutic potential in oxidative stress (OS) associated diseases, however poor oral bioavailability is the major obstacle in its potential use. Oral liquid dosage form is the most preferred delivery method in paediatric, geriatric and specialised therapies. The present research discusses the development of a Novel Oral Delivery System (NODS) of EDR to enhance oral bioavailability. From preformulation study, solubility, and stability were identified as key challenges and the requirement of an acidic environment and protection against oxidation were found to be critical. The NODS made up of a mixture of Labrasol (LBS) and an acidic aqueous system, was optimized on the basis of solubility and stability study. It can be stored ≤40°C for at least one month. Drug release from NODS was slow, sustained and significantly better as compared to suspension. The significant reduction in metabolism and improvement in permeability across the small intestine were observed with NODS compared to free EDR. The oral pharmacokinetic study showed 571% relative bioavailability with NODS compared to EDR suspension. From the results obtained, NODS is a promising candidate for use in OS associated diseases.Ankit Parikh, Krishna Kathawala, Chun Chuan Tan, Sanjay Garg, Xin-Fu Zho