Solubilisation of drugs within liposomal bilayers:alternatives to cholesterol as a membrane stabilising agent

Objectives The aim of this work was to investigate the effect of cholesterol on the bilayer loading of drugs and their subsequent release and to investigate fatty alcohols as an alternative bilayer stabiliser to cholesterol. Methods The loading and release rates of four low solubility drugs (diazepam, ibuprofen, midazolam and propofol) incorporated within the bilayer of multilamellar liposomes which contained a range of cholesterol (0–33 mol/mol%) or a fatty alcohol (tetradecanol, hexadecanol and octadecanol) were investigated. The molecular packing of these various systems was also investigated in Langmuir monolayer studies. Key findings Loading and release of drugs within the liposome bilayer was shown to be influenced by their cholesterol content: increasing cholesterol content was shown to reduce drug incorporation and inclusion of cholesterol in the bilayer changed the release profile of propofol from zero-order, for phosphatidyl choline only liposomes, to a first-order model when 11 to 33 total molar % of cholesterol was present in the formulation. At higher bilayer concentrations substitution of cholesterol with tetradecanol was shown to have less of a detrimental impact on bilayer drug loading. However, the presence of cholesterol within the liposome bilayer was shown to reduce drug release compared with fatty alcohols. Monolayer studies undertaken showed that effective mean area per molecule for a 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) : cholesterol mixture deviated by 9% from the predicted area compared with 5% with a similar DSPC : tetradecanol mixture. This evidence, combined with cholesterol being a much more bulky structure, indicated that the condensing influence of tetradecanol was less compared with cholesterol, thus supporting the reduced impact of tetradecanol on drug loading and drug retention. Conclusions Liposomes can be effectively formulated using fatty alcohols as an alternative bilayer stabiliser to cholesterol. The general similarities in the characteristics of liposomes containing fatty alcohols or cholesterol suggest a common behavioural influence for both compounds within the bilayer.

Design and development of agent-based procurement system to enhance business intelligence

The purpose of this research is to propose a procurement system across other disciplines and retrieved information with relevant parties so as to have a better co-ordination between supply and demand sides. This paper demonstrates how to analyze the data with an agent-based procurement system (APS) to re-engineer and improve the existing procurement process. The intelligence agents take the responsibility of searching the potential suppliers, negotiation with the short-listed suppliers and evaluating the performance of suppliers based on the selection criteria with mathematical model. Manufacturing firms and trading companies spend more than half of their sales dollar in the purchase of raw material and components. Efficient data collection with high accuracy is one of the key success factors to generate quality procurement which is to purchasing right material at right quality from right suppliers. In general, the enterprises spend a significant amount of resources on data collection and storage, but too little on facilitating data analysis and sharing. To validate the feasibility of the approach, a case study on a manufacturing small and medium-sized enterprise (SME) has been conducted. APS supports the data and information analyzing technique to facilitate the decision making such that the agent can enhance the negotiation and suppler evaluation efficiency by saving time and cost.

Design and development of an agent-based information system for process improvement

To meet changing needs of customers and to survive in the increasingly globalised and competitive environment, it is necessary for companies to equip themselves with intelligent tools, thereby enabling managerial levels to use the tactical decision in a better way. However, the implementation of an intelligent system is always a challenge in Small- and Medium-sized Enterprises (SMEs). Therefore, a new and simple approach with 'process rethinking' ability is proposed to generate ongoing process improvements over time. In this paper, a roadmap of the development of an agent-based information system is described. A case example has also been provided to show how the system can assist non-specialists, for example, managers and engineers to make right decisions for a continual process improvement. Copyright © 2006 Inderscience Enterprises Ltd.

Achieving cost competitiveness with an agent based integrated process planning and production scheduling system

From a manufacturing perspective, the efficiency of manufacturing operations (such as process planning and production scheduling) are the key element for enhancing manufacturing competence. Process planning and production scheduling functions have been traditionally treated as two separate activities, and have resulted in a range of inefficiencies. These include infeasible process plans, non-available/overloaded resources, high production costs, long production lead times, and so on. Above all, it is unlikely that the dynamic changes can be efficiently dealt with. Despite much research has been conducted to integrate process planning and production scheduling to generate optimised solutions to improve manufacturing efficiency, there is still a gap to achieve the competence required for the current global competitive market. In this research, the concept of multi-agent system (MAS) is adopted as a means to address the aforementioned gap. A MAS consists of a collection of intelligent autonomous agents able to solve complex problems. These agents possess their individual objectives and interact with each other to fulfil the global goal. This paper describes a novel use of an autonomous agent system to facilitate the integration of process planning and production scheduling functions to cope with unpredictable demands, in terms of uncertainties in product mix and demand pattern. The novelty lies with the currency-based iterative agent bidding mechanism to allow process planning and production scheduling options to be evaluated simultaneously, so as to search for an optimised, cost-effective solution. This agent based system aims to achieve manufacturing competence by means of enhancing the flexibility and agility of manufacturing enterprises.

Effects of glutathione, N-acetyl-cysteine, α-lipoic acid and dihydrolipoic acid on the cytotoxicity of a 2-pyridylcarboxamidrazone antimycobacterial agent in human mononuclear leucocytes in vitro

A series of antioxidants was used to explore the cytotoxicity of one particularly toxic antimycobacterial 2-pyridylcarboxamidrazone anti-tuberculosis agent against human mononuclear leucocytes (MNL), in comparison with isoniazid (INH) to aid future compound design. INH caused a significant reduction of nearly 40% in cell recovery compared with control (P < 0.0001), although the co-incubation with either glutathione (GSH, 1 mM) or (NAC, 1 mM) showed abolition of INH toxicity. In contrast, the addition of GSH or NAC 1 h after INH failed to protect the cells from INH toxicity (P < 0.0001). The 2-pyridyl-carboxamidrazone 'Compound 1' caused a 50% reduction in cell recovery compared with control (P < 0.001), although this was abolished by the presence of either GSH or NAC. A 1 h post incubation with either NAC or GSH after Compound 1 addition failed to protect the cells from toxicity (P < 0.001). Co-administration of lipoic acid (LA) abolished Compound 1-mediated toxicity, although again, this effect did not occur after LA addition 1 h post incubation with Compound 1 (P < 0.001). However, co-administration of dihydrolipoic acid (DHLA) prevented Compound 1-mediated cell death when incubated with the compound and also after 1 h of Compound 1 alone. Pre-treatment with GSH, then removal of the antioxidant resulted in abolition of Compound 1 toxicity (vehicle control, 63.6 ± 16.7 versus Compound 1 alone 26.1 ± 13.6% versus GSH pre-treatment, 65.7 ± 7.3%). In a cell-free incubation, NMR analysis revealed that GSH does not react with Compound 1, indicating that this agent is not likely to directly deplete membrane thiols. Compound 1's MNL toxicity is more likely to be linked with changes in cell membrane conformation, which may induce consequent thiol depletion that is reversible by exogenous thiols. © 2004 Elsevier B.V. All rights reserved.

Development of a novel magnetic resonance imaging contrast agent for pressure measurements using lipid-coated microbubbles

The aim of this study was to prepare gas-filled lipid-coated microbubbles as potential MRI contrast agents for imaging of fluid pressure. Air-filled microbubbles were produced with phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) in the presence or absence of cholesterol and/or polyethylene-glycol distearate (PEG-distearate). Microbubbles were also prepared containing a fluorinated phospholipid, perfluoroalkylated glycerol-phosphatidylcholine, F-GPC shells encompassing perfluorohexane-saturated nitrogen gas. These microbubbles were evaluated in terms of physico-chemical characteristics such as size and stability. In parallel to these studies, DSPC microbubbles were also formulated containing nitrogen (N2) gas and compared to air-filled microbubbles. By preventing advection, signal drifts were used to assess their stability. DSPC microbubbles were found to have a drift of 20% signal change per bar of applied pressure in contrast to the F-GPC microbubbles which are considerably more stable with a lower drift of 5% signal change per bar of applied pressure. By increasing the pressure of the system and monitoring the MR signal intensity, the point at which the majority of the microbubbles have been damaged was determined. For the DSPC microbubbles this occurs at 1.3 bar whilst the F-GPC microbubbles withstand pressures up to 2.6 bar. For the comparison between air-filled and N2-filled microbubbles, the MRI sensitivity is assessed by cycling the pressure of the system and monitoring the MR signal intensity. It was found that the sensitivity exhibited by the N2-filled microbubbles remained constant, whilst the air-filled microbubbles demonstrated a continuous drop in sensitivity due to continuous bubble damage.

A multi-agent system using iterative bidding mechanism to enhance manufacturing agility

The global market has become increasingly dynamic, unpredictable and customer-driven. This has led to rising rates of new product introduction and turbulent demand patterns across product mixes. As a result, manufacturing enterprises were facing mounting challenges to be agile and responsive to cope with market changes, so as to achieve the competitiveness of producing and delivering products to the market timely and cost-effectively. This paper introduces a currency-based iterative agent bidding mechanism to effectively and cost-efficiently integrate the activities associated with production planning and control, so as to achieve an optimised process plan and schedule. The aim is to enhance the agility of manufacturing systems to accommodate dynamic changes in the market and production. The iterative bidding mechanism is executed based on currency-like metrics; each operation to be performed is assigned with a virtual currency value and agents bid for the operation if they make a virtual profit based on this value. These currency values are optimised iteratively and so does the bidding process based on new sets of values. This is aimed at obtaining better and better production plans, leading to near-optimality. A genetic algorithm is proposed to optimise the currency values at each iteration. In this paper, the implementation of the mechanism and the test case simulation results are also discussed. © 2012 Elsevier Ltd. All rights reserved.