Advanced parenteral drug delivery system in clinical disease management
Ji-Geng Yan
Medical College of Wisconsin, USA
: J Pharm Drug Deliv Res
Abstract
After a nerve injury, calcium concentration in the intra-nerve fiber drastically increases. The purpose of our study was to test an implantable micro-osmotic pump to deliver medications to accelerate calcium absorption, thereby greatly improving nerve regeneration. Twenty-four SD rats were divided into four groups of six each: 1) Sham control: crush injury to sciatic nerve only; 2) Crush injury with a Nifedipine pump; 3) Crush injury with a Calcitonin pump; 4) Crush injury with a saline pump. Each rat’s right sciatic nerve was crushed. The micro-osmotic pump was implanted in the neck, and the dripping tube was routed to the injured nerve. After four weeks of survival time, compound muscle action potential (CMAP), tetanic muscle force (TMF), myelinated nerve fiber area (NFA), nerve calcium concentration (NCC), and calcified spots (CS) were evaluated. The calcium absorption rate (CAR) was also determined. The order from highest to lowest recovery rate was Nifedipine> Calcitonin > Sham control > Saline. Differences among the groups were statistically significant (P<0.001, ANOVA Test), and the difference between Nifedipine/Calcitonin and Saline/ Sham control were all statistically significant (P<0.001, t-test). The correlation rate of NCC with CMAP/TMF and with NFA/CS and CAR were calculated to be 0.99 (all P<0.001, Pearson’s Correlation). We conclude from this study that nerve regeneration strongly correlated with calcium absorption; our new data has shown greatly improved nerve functional recovery, and this can potentially be translated into clinical applications.
Biography
Parkinson’s disease is a common neurodegenerative disorder of the central nervous system. It is characterized by the loss of dopamine-generating neurons in the substantia nigra and corpus striatum (which leads to the decreasing level of dopamine) and accumulation of α-synuclein aggregates in the brain. Presently, commercial drugs in market altogether do not provide complete treatment for neuronal degradation however only treats the disease in a symptomatic way. Dopamine transporter (DAT) plays an important role in the termination of neurotransmission by rapid reuptake of dopamine (DA) from the synaptic cleft into presynaptic terminals where it will be degraded by monoamino oxidase. With the blockade of DAT, level of dopamine in synaptic cleft as well as dopaminergic neurotransmission will increase. We have modelled the human DAT based on a drosophila’s DAT X-ray crystal structure, and minimized it in the environment of the lipid bilayer and solvent water. The transporter was validated with known inhibitors downloaded from CHEMbl database, in Auto Dock 4.2 and GOLD 5 docking software. The obtained results correlated positively with the existing experimental results. The binding free energy for DA, according to preexistent experiments, is ΔGexperimental= -7.4 kcal/mol; while ΔGcalculated= -6.4 kcal/mol was obtained through our studies. The binding position of DA, also, coincides with previous literatures: interaction with Phe320, Asp79, Ser149, Ser422, and Thr156 amino acids. Thus, with the results collected, a new model was designed for potential inhibitors approached through de novo and fragment based drug design. Novel selective DAT inhibitors, when alone or in combination with levodopa, may improve the quality of life in patients suffering from Parkinson’s disease.
yelekci@khas.edu.tr
