Biomedical subjects

F Fischel-Ghodsian

Publications and source records attributed to F Fischel-Ghodsian.

5 recordsLinked to original sources

PubMed1996

Characterization of glucose-mediated insulin release from implantable polymers.

We characterized a glucose-sensitive, controlled-release insulin delivery system. Insulin release rates increased when glucose was perfused in the release media surrounding the matrix. The system was composed of solid, particulate insulin, incorporated into an ethylene-vinyl acetate copolymer (EVAc) matrix. Feedback control was mediated by the glucose oxidase enzyme immobilized to Sepharose beads, which were incorporated along with insulin into the EVAc matrix. When glucose in solution entered the insulin delivery system, gluconic acid was produced, causing a drop in the microenvironmental pH of the matrix. This fall in pH resulted in a rise in insulin solubility and consequently a rise in the insulin release rate from the matrix. Insulin concentrations increased in vitro and in vivo in response to glucose infusion. The increased insulin release was shown to consist of a finite pulse of insulin that required an optimal recovery period of 1 h to achieve a maximal repeated response to a glucose stimulus. Repeated pulses were demonstrated over a 4 h period. An optimum enzyme ratio was also determined.

Animals↗

PubMed1993

Analysis of drug release kinetics from degradable polymeric devices.

Drug release kinetics from a degradable polymer undergoing surface erosion have been analysed by mathematical modelling and stimulations. This approach considers drug particles homogeneously dispersed in the matrix, and cases of both a single polymer matrix and a matrix surrounded by a membrane are considered. The influence of different polymer, drug, and membrane parameters on long-term performance has been simulated and provides a theoretical basis for the design of degradable drug delivery devices.

Diffusion↗

PubMed1993

Simulation and optimisation of a self-regulating insulin delivery system.

The delivery of insulin is an integral part of the treatment of diabetes. It has been shown that an implantable polymeric system which releases insulin in response to blood glucose levels is feasible. This work aims to guide further experimental development of this system by constructing a mathematical model of the polymer matrix and analysing its functional characteristics by computer simulations. The system is an implantable polymer containing tri-lysyl insulin and the enzyme glucose-oxidase, and the feedback mechanism is based on the enzymatic reaction between glucose and glucose-oxidase. Acid produced from this reaction reduces the pH in the microenvironment of the polymer, which causes an increase in insulin solubility and release rate. The model was developed on the basis of the physical and chemical properties of the system, which were chosen in the light of direct observations with scanning electron microscopy combined with experimental measurements and reported values, and was validated by comparison with experimental results and by verification of some of its assumptions. Optimisation was undertaken by simulating the effect of different parameters of the system on its performance. Enzyme concentration, pore length, particle size and insulin loading were found to have surprisingly little effect. However, performance was significantly improved by using a hypothetical insulin molecule with a different solubility characteristic. The study can therefore provide a rational basis for the experimental development of a polymer-based artificial pancreas.

Algorithms↗

PubMed1990

Alignment of protein sequences using secondary structure: a modified dynamic programming method.

A method for comparison of protein sequences based on their primary and secondary structure is described. Protein sequences are annotated with predicted secondary structures (using a modified Chou and Fasman method). Two lettered code sequences are generated (Xx, where X is the amino acid and x is its annotated secondary structure). Sequences are compared with a dynamic programming method (STRALIGN) that includes a similarity matrix for both the amino acids and secondary structures. The similarity value for each paired two-lettered code is a linear combination of similarity values for the paired amino acids and their annotated secondary structures. The method has been applied to eight globin proteins (28 pairs) for which the X-ray structure is known. For protein pairs with high primary sequence similarity (greater than 45%), STRALIGN alignment is identical to that obtained by a dynamic programming method using only primary sequence information. However, alignment of protein pairs with lower primary sequence similarity improves significantly with the addition of secondary structure annotation. Alignment of the pair with the least primary sequence similarity of 16% was improved from 0 to 37% 'correct' alignment using this method. In addition, STRALIGN was successfully applied to seven pairs of distantly related cytochrome c proteins, and three pairs of distantly related picornavirus proteins.

Amino Acid Sequence↗

PubMed1988

Enzymatically controlled drug delivery.

An approach for providing feedback control for polypeptide drugs in a polymeric controlled-release system uses a trigger molecule and a polymer-bound enzyme that, in the presence of that trigger molecule, will cause an acid or a base to form. When the pH inside the polymer system changes, the solubility of the drug shifts dramatically, which changes the diffusion or dissolution driving force, and hence the release rate changes correspondingly. This concept was tested using a controlled-release system of ethylene/vinyl acetate copolymer containing insulin and immobilized glucose oxidase. The enzymatic reaction of glucose to gluconic acid reduces the pH in the polymer microenvironment. Since insulin solubility increases with decreasing pH (at physiologic pH, this is true for an insulin with an isoelectric point of 7.4 or higher), the release of insulin increases in response to glucose concentration. The feasibility of this concept has been shown using trilysyl insulin with an isoelectric point of 7.4. Multiple exposures to buffered glucose solutions over several weeks caused insulin release to reversibly increase during each exposure. Polymer-implanted diabetic rats infused with glucose solutions showed a significant increase in insulin concentration in 30 min-an effect not observed in three different sets of control rats.

Animals↗