Increased dissolution rates of tranilast solid dispersions extruded with inorganic excipients

The purpose of this study was to evaluate the performance of Neusilin® (NEU) a synthetic magnesium aluminometasilicate as inorganic drug carrier co-processed with the hydrophilic surfactants Labrasol and Labrafil to develop Tranilast (TLT) based solid dispersions using continuous melt extrusion (HME) processing. Twin – screw extrusion was optimized to develop various TLT/excipient/surfactant formulations followed by continuous capsule filling in the absence of any downstream equipment. Physicochemical characterisation showed the existence of TLT in partially crystalline state in the porous network of inorganic NEU for all extruded formulations. Furthermore, the in line NIR studies revealed a possible intermolecular H–bonding formation between the drug and carrier resulting in the increase of dissolution of TLT. The capsules containing TLT extruded solid dispersions showed enhanced dissolution rates and compared with the marketed Rizaben® product

Sedimentation record in the Konkan-Kerala Basin: implications for the evolution of the Western Ghats and the Western Indian passive margin

The Konkan and Kerala Basins constitute a major depocentre for sediment from the onshore hinterland of Western India and as such provide a valuable record of the timing and magnitude of Cenozoic denudation along the continental margin. This paper presents an analysis of sedimentation in the Konkan-Kerala Basin, coupledwith a mass balance study, and numerical modelling of flexural responses to onshore denudational unloading and o¡shore sediment loading in order to test competing conceptual models for the development of high-elevation passive margins. The Konkan-Kerala Basin contains an estimated 109,000 km<sup>3</sup>; of Cenozoic clastic sediment, a volume difficult to reconcile with the denudation of a downwarped rift flank onshore, and more consistent with denudation of an elevated rift flank. We infer from modelling of the isostatic response of the lithosphere to sediment loading offshore and denudation onshore that flexure is an important component in the development of the Western Indian Margin.There is evidence for two major pulses in sedimentation: an early phase in the Palaeocene, and a second beginning in the Pliocene. The Palaeocene increase in sedimentation can be interpreted in terms of a denudational response to the rifting between India and the Seychelles, whereas the mechanism responsible for the Pliocene pulse is more enigmatic

Landau Analog Levels for Dipoles in the Noncommutative Space and Phase Space

In the present contribution we investigate the Landau analog energy quantization for neutral particles, that possesses a nonzero permanent magnetic and electric dipole moments, in the presence of an homogeneous electric and magnetic external fields in the context of the noncommutative quantum mechanics. Also, we analyze the Landau--Aharonov--Casher and Landau--He--McKellar--Wilkens quantization due to noncommutative quantum dynamics of magnetic and electric dipoles in the presence of an external electric and magnetic fields and the energy spectrum and the eigenfunctions are obtained. Furthermore, we have analyzed Landau quantization analogs in the noncommutative phase space, and we obtain also the energy spectrum and the eigenfunctions in this context.Comment: 20 pages, references adde

Time-Space Noncommutativity in Gravitational Quantum Well scenario

A novel approach to the analysis of the gravitational well problem from a second quantised description has been discussed. The second quantised formalism enables us to study the effect of time space noncommutativity in the gravitational well scenario which is hitherto unavailable in the literature. The corresponding first quantized theory reveals a leading order perturbation term of noncommutative origin. Latest experimental findings are used to estimate an upper bound on the time--space noncommutative parameter. Our results are found to be consistent with the order of magnitude estimations of other NC parameters reported earlier.Comment: 7 pages, revTe

Population genomic structure and adaptation in the zoonotic malaria parasite Plasmodium knowlesi

Malaria cases due to the zoonotic parasite P. knowlesi are being increasingly reported throughout Southeast Asia and in travelers returning from the region. To test for evidence of signatures of selection or unusual population structure in this parasite, we surveyed genome sequence diversity in 48 clinical isolates recently sampled from Malaysian Borneo and 5 lines maintained in laboratory rhesus macaques after isolation in the 1960s from Peninsular Malaysia and the Philippines. Overall genome-wide nucleotide diversity (π = 6.03 x 10-3) was much higher than has been seen in worldwide samples of either of the major endemic malaria parasite species P. falciparum and P. vivax. A remarkable substructure is revealed within P. knowlesi, consisting of two major sympatric clusters of the clinical isolates, and a third cluster comprising the laboratory isolates. There was deep differentiation between the two clusters of clinical isolates (mean genome-wide FST = 0.21, with 9,293 SNPs having fixed differences of FST = 1.0). This showed marked heterogeneity across the genome, mean FST values of different chromosomes ranging from 0.08 to 0.34, with further significant variation across regions within several chromosomes. Analysis of the largest cluster (Cluster 1, 38 isolates) indicated long-term population growth, with negatively skewed allele frequency distributions (genome-wide average Tajima’s D = -1.35). Against this background there was evidence of balancing selection on particular genes, including the circumsporozoite protein (csp gene had the top value of Tajima’s D = 1.57), and scans of haplotype homozygosity implicate several genomic regions to be under recent positive selection

The delivery of personalised, precision medicines via synthetic proteins

Introduction: The design of advanced drug delivery systems based on synthetic and su-pramolecular chemistry has been very successful. Liposomal doxorubicin (Caelyx®), and liposomal daunorubicin (DaunoXome®), estradiol topical emulsion (EstrasorbTM) as well as soluble or erodible polymer systems such as pegaspargase (Oncaspar®) or goserelin acetate (Zoladex®) represent considerable achievements. The Problem: As deliverables have evolved from low molecular weight drugs to biologics (currently representing approximately 30% of the market), so too have the demands made of advanced drug delivery technology. In parallel, the field of membrane trafficking (and endocytosis) has also matured. The trafficking of specific receptors i.e. material to be recycled or destroyed, as well as the trafficking of protein toxins has been well characterized. This, in conjunction with an ability to engineer synthetic, recombinant proteins provides several possibilities. The Solution: The first is using recombinant proteins as drugs i.e. denileukin diftitox (Ontak®) or agalsidase beta (Fabrazyme®). The second is the opportunity to use protein toxin architecture to reach targets that are not normally accessible. This may be achieved by grafting regulatory domains from multiple species to form synthetic proteins, engineered to do multiple jobs. Examples include access to the nucleocytosolic compartment. Herein the use of synthetic proteins for drug delivery has been reviewed

The role of sulfoglucuronosyl glycosphingolipids in the pathogenesis of monoclonal IgM paraproteinemia and peripheral neuropathy

In IgM paraproteinemia and peripheral neuropathy, IgM M-protein secretion by B cells leads to a T helper cell response, suggesting that it is antibody-mediated autoimmune disease involving carbohydrate epitopes in myelin sheaths. An immune response against sulfoglucuronosyl glycosphingolipids (SGGLs) is presumed to participate in demyelination or axonal degeneration in the peripheral nervous system (PNS). SGGLs contain a 3-sulfoglucuronic acid residue that interacts with anti-myelin-associated glycoprotein (MAG) and the monoclonal antibody anti-HNK-1. Immunization of animals with sulfoglucuronosyl paragloboside (SGPG) induced anti-SGPG antibodies and sensory neuropathy, which closely resembles the human disease. These animal models might help to understand the disease mechanism and lead to more specific therapeutic strategies. In an in vitro study, destruction or malfunction of the blood-nerve barrier (BNB) was found, resulting in the leakage of circulating antibodies into the PNS parenchyma, which may be considered as the initial key step for development of disease