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1.  Design of an Interpolyelectrolyte Gastroretentive Matrix for the Site-Specific Zero-Order Delivery of Levodopa in Parkinson’s Disease 
AAPS PharmSciTech  2013;14(2):605-619.
This study focused on developing a gastroretentive drug delivery system employing a triple-mechanism interpolyelectrolyte complex (IPEC) matrix comprising high density, swelling, and bioadhesiveness for the enhanced site-specific zero-order delivery of levodopa in Parkinson’s disease. An IPEC was synthesized and directly compressed into a levodopa-loaded matrix employing pharmaceutical technology and evaluated with respect to its physicochemical and physicomechanical properties and in vitro drug release. The IPEC-based matrix displayed superior mechanical properties in terms of matrix hardness (34–39 N/mm) and matrix resilience (44–47%) when different normality’s of solvent and blending ratios were employed. Fourier transform infrared spectroscopy confirmed the formation of the IPEC. The formulations exhibited pH and density dependence with desirable gastro-adhesion with Peak Force of Adhesion ranging between 0.15 and 0.21 N/mm, densities from 1.43 to 1.54 g/cm3 and swellability values of 177–234%. The IPEC-based gastroretentive matrix was capable of providing site-specific levodopa release with zero-order kinetics corroborated by detailed mathematical and molecular modeling studies. Overall, results from this study have shown that the IPEC-based matrix has the potential to improve the absorption and subsequent bioavailability of narrow absorption window drugs, such as levodopa with constant and sustained drug delivery.
doi:10.1208/s12249-013-9945-1
PMCID: PMC3666024  PMID: 23494468
gastroretention; interpolyelectrolyte complex; levodopa; narrow absorption window drugs; Parkinson’s disease
3.  Management of ischaemic stroke in the acute setting: review of the current status 
Abstract
Acute ischaemic stroke can be treated by clot busting and clot removal. Thrombolysis using intravenous recombinant-tissue plasminogen activator (IV r-TPA) is the current gold standard for the treatment of acute ischaemic stroke (AIS). The main failure of this type of treatment is the short time interval from stroke onset within which it has to be used for any benefit. The evidence is that IV r-TPA has to be used within 4.5 hours.
Other modalities of treatment are not as effective and need more scrutiny and examination. The available modalities are intra-arterial thrombolysis and clot-retrieval devices. Not unexpectedly, recanalisation treatments have flourished at a rapid rate. Although vessel recanalisation is vital to increasing the possibility of significant tissue reperfusion, clinical trials need to emphasise functional outcomes rather than reperfusion/recanalisation rates to adequately assess success of these devices/techniques.
Our view is that until these treatments become proven in large-scale studies, a greater endeavour should be made in resource-limited settings to expand facilities to enable intravenous r-tPA treatment within the 4.5-hour period following onset of stroke. The resources required are small with the main costs being a CT scan of the brain and the cost of r-tPA. This can easily be done in any emergency facility in any part of the world. What is needed is public awareness, and campaigns of ‘stroke attack’ should be revisited, especially in the resource-limited context. This approach at present will halt to some extent the stroke pandemic that we are facing.
doi:10.5830/CVJA-2013-001
PMCID: PMC3721925  PMID: 23736133
stroke; intravenous r-tPA; recanalisation treatments
4.  Composite Polylactic-Methacrylic Acid Copolymer Nanoparticles for the Delivery of Methotrexate 
Journal of Drug Delivery  2012;2012:579629.
The purpose of this study was to develop poly(lactic acid)-methacrylic acid copolymeric nanoparticles with the potential to serve as nanocarrier systems for methotrexate (MTX) used in the chemotherapy of primary central nervous system lymphoma (PCNSL). Nanoparticles were prepared by a double emulsion solvent evaporation technique employing a 3-Factor Box-Behnken experimental design strategy. Analysis of particle size, absolute zeta potential, polydispersity (Pdl), morphology, drug-loading capacity (DLC), structural transitions through FTIR spectroscopy, and drug release kinetics was undertaken. Molecular modelling elucidated the mechanisms of the experimental findings. Nanoparticles with particle sizes ranging from 211.0 to 378.3 nm and a recovery range of 36.8–86.2 mg (Pdl ≤ 0.5) were synthesized. DLC values were initially low (12 ± 0.5%) but were finally optimized to 98 ± 0.3%. FTIR studies elucidated the comixing of MTX within the nanoparticles. An initial burst release (50% of MTX released in 24 hours) was obtained which was followed by a prolonged release phase of MTX over 84 hours. SEM images revealed near-spherical nanoparticles, while TEM micrographs revealed the presence of MTX within the nanoparticles. Stable nanoparticles were formed as corroborated by the chemometric modelling studies undertaken.
doi:10.1155/2012/579629
PMCID: PMC3418700  PMID: 22919501
5.  Novel High-Viscosity Polyacrylamidated Chitosan for Neural Tissue Engineering: Fabrication of Anisotropic Neurodurable Scaffold via Molecular Disposition of Persulfate-Mediated Polymer Slicing and Complexation 
Macroporous polyacrylamide-grafted-chitosan scaffolds for neural tissue engineering were fabricated with varied synthetic and viscosity profiles. A novel approach and mechanism was utilized for polyacrylamide grafting onto chitosan using potassium persulfate (KPS) mediated degradation of both polymers under a thermally controlled environment. Commercially available high molecular mass polyacrylamide was used instead of the acrylamide monomer for graft copolymerization. This grafting strategy yielded an enhanced grafting efficiency (GE = 92%), grafting ratio (GR = 263%), intrinsic viscosity (IV = 5.231 dL/g) and viscometric average molecular mass (MW = 1.63 × 106 Da) compared with known acrylamide that has a GE = 83%, GR = 178%, IV = 3.901 dL/g and MW = 1.22 × 106 Da. Image processing analysis of SEM images of the newly grafted neurodurable scaffold was undertaken based on the polymer-pore threshold. Attenuated Total Reflectance-FTIR spectral analyses in conjugation with DSC were used for the characterization and comparison of the newly grafted copolymers. Static Lattice Atomistic Simulations were employed to investigate and elucidate the copolymeric assembly and reaction mechanism by exploring the spatial disposition of chitosan and polyacrylamide with respect to the reactional profile of potassium persulfate. Interestingly, potassium persulfate, a peroxide, was found to play a dual role initially degrading the polymers—“polymer slicing”—thereby initiating the formation of free radicals and subsequently leading to synthesis of the high molecular mass polyacrylamide-grafted-chitosan (PAAm-g-CHT)—“polymer complexation”. Furthermore, the applicability of the uniquely grafted scaffold for neural tissue engineering was evaluated via PC12 neuronal cell seeding. The novel PAAm-g-CHT exhibited superior neurocompatibility in terms of cell infiltration owing to the anisotropic porous architecture, high molecular mass mediated robustness, superior hydrophilicity as well as surface charge due to the acrylic chains. Additionally, these results suggested that the porous PAAm-g-CHT scaffold may act as a potential neural cell carrier.
doi:10.3390/ijms131113966
PMCID: PMC3509560  PMID: 23203044
neural tissue engineering; polymer composite; polyacrylamidated chitosan; potassium persulphate; polymer grafting; neurodurable scaffold; molecular modeling and simulation
6.  A Review on Composite Liposomal Technologies for Specialized Drug Delivery 
Journal of Drug Delivery  2011;2011:939851.
The combination of liposomes with polymeric scaffolds could revolutionize the current state of drug delivery technology. Although liposomes have been extensively studied as a promising drug delivery model for bioactive compounds, there still remain major drawbacks for widespread pharmaceutical application. Two approaches for overcoming the factors related to the suboptimal efficacy of liposomes in drug delivery have been suggested. The first entails modifying the liposome surface with functional moieties, while the second involves integration of pre-encapsulated drug-loaded liposomes within depot polymeric scaffolds. This attempts to provide ingenious solutions to the limitations of conventional liposomes such as short plasma half-lives, toxicity, stability, and poor control of drug release over prolonged periods. This review delineates the key advances in composite technologies that merge the concepts of depot polymeric scaffolds with liposome technology to overcome the limitations of conventional liposomes for pharmaceutical applications.
doi:10.1155/2011/939851
PMCID: PMC3065812  PMID: 21490759
7.  In Silico Theoretical Molecular Modeling for Alzheimer’s Disease: The Nicotine-Curcumin Paradigm in Neuroprotection and Neurotherapy 
The aggregation of the amyloid-β-peptide (AβP) into well-ordered fibrils has been considered as the key pathological marker of Alzheimer‘s disease. Molecular attributes related to the specific binding interactions, covalently and non-covalently, of a library of compounds targeting of conformational scaffolds were computed employing static lattice atomistic simulations and array constructions. A combinatorial approach using isobolographic analysis was stochastically modeled employing Artificial Neural Networks and a Design of Experiments approach, namely an orthogonal Face-Centered Central Composite Design for small molecules, such as curcumin and glycosylated nornicotine exhibiting concentration-dependent behavior on modulating AβP aggregation and oligomerization. This work provides a mathematical and in silico approach that constitutes a new frontier in providing neuroscientists with a template for in vitro and in vivo experimentation. In future this could potentially allow neuroscientists to adopt this in silico approach for the development of novel therapeutic interventions in the neuroprotection and neurotherapy of Alzheimer‘s disease. In addition, the neuroprotective entities identified in this study may also be valuable in this regard.
doi:10.3390/ijms12010694
PMCID: PMC3039975  PMID: 21340009
amyloid-β protein; Alzheimer‘s disease; molecular mechanics; artificial neural networks; curcumin; nicotine; isobolographic analysis; docking; central composite design; constraint optimization; ligand-protein complexes; synergism
8.  Fabrication, Modeling and Characterization of Multi-Crosslinked Methacrylate Copolymeric Nanoparticles for Oral Drug Delivery 
Nanotechnology remains the field to explore in the quest to enhance therapeutic efficacies of existing drugs. Fabrication of a methacrylate copolymer-lipid nanoparticulate (MCN) system was explored in this study for oral drug delivery of levodopa. The nanoparticles were fabricated employing multicrosslinking technology and characterized for particle size, zeta potential, morphology, structural modification, drug entrapment efficiency and in vitro drug release. Chemometric Computational (CC) modeling was conducted to deduce the mechanism of nanoparticle synthesis as well as to corroborate the experimental findings. The CC modeling deduced that the nanoparticles synthesis may have followed the mixed triangular formations or the mixed patterns. They were found to be hollow nanocapsules with a size ranging from 152 nm (methacrylate copolymer) to 321 nm (methacrylate copolymer blend) and a zeta potential range of 15.8–43.3 mV. The nanoparticles were directly compressible and it was found that the desired rate of drug release could be achieved by formulating the nanoparticles as a nanosuspension, and then directly compressing them into tablet matrices or incorporating the nanoparticles directly into polymer tablet matrices. However, sustained release of MCNs was achieved only when it was incorporated into a polymer matrix. The experimental results were well corroborated by the CC modeling. The developed technology may be potentially useful for the fabrication of multi-crosslinked polymer blend nanoparticles for oral drug delivery.
doi:10.3390/ijms12096194
PMCID: PMC3189777  PMID: 22016653
nanotechnology; nanoparticles; nanocapsules; methacrylate copolymer; chitosan; oral drug delivery; bioavailability; crosslinking; molecular mechanics simulations
9.  Trends in the Molecular Pathogenesis and Clinical Therapeutics of Common Neurodegenerative Disorders 
The term neurodegenerative disorders, encompasses a variety of underlying conditions, sporadic and/or familial and are characterized by the persistent loss of neuronal subtypes. These disorders can disrupt molecular pathways, synapses, neuronal subpopulations and local circuits in specific brain regions, as well as higher-order neural networks. Abnormal network activities may result in a vicious cycle, further impairing the integrity and functions of neurons and synapses, for example, through aberrant excitation or inhibition. The most common neurodegenerative disorders are Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis and Huntington’s disease. The molecular features of these disorders have been extensively researched and various unique neurotherapeutic interventions have been developed. However, there is an enormous coercion to integrate the existing knowledge in order to intensify the reliability with which neurodegenerative disorders can be diagnosed and treated. The objective of this review article is therefore to assimilate these disorders’ in terms of their neuropathology, neurogenetics, etiology, trends in pharmacological treatment, clinical management, and the use of innovative neurotherapeutic interventions.
doi:10.3390/ijms10062510
PMCID: PMC2705504  PMID: 19582217
Parkinson’s disease; Alzheimer’s disease; Amyotrophic Lateral Sclerosis; Huntington’s disease; neuropathology; amyloid-β protein; Tau; Huntingtin; α-Synuclein; neurotherapeutics; drug delivery

Results 1-9 (9)