| Background and Objective:Since 1980,Willson first studied in control and randomly, and confirmed the oral steroid treatment of sudden deafness certainly effect, the United States and some other countries (including China) use oral steroids as the first line of treatment for sudden deafness. However, as a result of systemic steroid treatment, there are still a considerable number of individuals have not been improved. Even many patients can not treated by systemic steroids application because of side effects and contraindications reasons. So a new therapeutic approach attention-steroids intratympanic infusion of local application. Compared with the general administration, local administration of the main advantages are: 1. Goal-oriented and drug-target location is good; 2. be able to avoid the blood - labyrinth barrier directly into the inner ear 3. Much higher perilymph drug concentration; 4. No systemic adverse reactions. Furthermore, some clinical studies show that among the patients of sudden deafness who failed by systemic corticosteroid therapy, the auditus have improved in some patients treated by local administration. But, there are many concrete problems are not entirely clear for local administration, such as steroids choice; Local administration of specific strategies -- micro-injection pump drum administered,drug dose,facilitation agent and the frequency of administration needs time to further study and accumulate data.Hyaluronic acid is a macromolecular compound, commonly used in middle ear surgery to prevent adhesion formation. Animal experiments proved that hyaluronic acid on the inner ear structure and function of no significant impact. Another study shows that hyaluronic acid extend contact time and increase permeability of small molecules for round window membrane. To enhance perilymph steroid levels and to maintain the role of a longer time, we are using hyaluronic acid as a facilitation agent, and observe the steroid pharmacokinetic characteristics in perilymph, and the function of gelatin sponge with the role of comparison.The purpose of this study : 1. Investigate the Dexamethasone pharmacokinetics in guinea pig's perilymph lymph, blood and cerebrospinal fluid after intratympanic dexamethasone application, and compared with systemic application. 2. Compared the concentration and time course of dexamethasone in perilymph after intratympanic-dexamethasone,intratympanic-dexamethasone/hyaluronic acid and the dexamethasone/gelatin sponge filled into tympana.Method:60 eardrum and Pryor will be reflective of normal weight 500-600g the albino guinea pigs were randomly divided into 6 groups: oral dexamethasone group (Oral),intraveneous dexamethasone group (IV),intratympanic-injection dexamethasone (ITI-DEX),intratympanic-injection dexamethasone with hyaluronic acid group (ITI-DEX/HA),intratympanic-filled dexamethasone group (ITF-DEX), and 10 animal in each group. Separate group of Oral and IV were administrate dexathesone (8mg/ml) via intragastric administration and intracardiac injection respectively, 8mg/kg; measures for the control,ITI-DEX,ITI-DEX/HA groups, administrated normal saline,dexamethasone(8mg/ml),dexamethasone(8mg/ml)/hyaluronic acid(2mg/ml) via intratympanic-injection application respectively. For ITF-DEX group, filled the gelatin sponge infused with dexamethasone( 8mg/ml) into tympana. All of the groups in 0.5-,1-,2-,4- and 6-h after administration for perilymplu cerebrospinal fluid and blood samples respectively, each sampling point in time have 2 animals (4 ears). Order: blood,perilymph and cerebrospinal fluid. high-performance liquid chromatography(HPLC) analyses: Preparaed the standard solution of 0.1-, 0.5-, 5-, 25-, 50-(mg/L), and established standard curve. After the test of precision and, all the samples have been detected one by one, Empower PDA Software by data processing software to calculate sample concentrations of dexamethasone. Statistical analysis: the average concentration of dexamethasone on each sampling time point were recorded by mean±SD, using SPSS 10.0 software for statistical analysis. comparisons were made between modes of administration by Analysis of Variance (ANOVA). The P value<0.05 was assigned for significance.Result:Dexamethasone Pharmacokinetics in Perilymph1. Comparisons among level peaks after administration①The three IT groups all resulted in higher perilymph DEX level peaks than IVgroup (0.251±0.018mg/L)(P<0.05)②ITI-DEX/HA group resulted in a higher level peak(2.601±0.067mg/L) than the other two groups especially for ITI-DEX group(1.803±0.155mg/L)(P<0.05).2. Comparisons among last levels after administration①Except for the ITI-DEX group, the other two IT groups all resulted in higher perilymph levels than IV group(0.031±0.014mg/L)(P<0.05).②ITI-DEX group resulted in a lower perilymph level(0.051±0.009mg/L) than the other two IT groups(P<0.05). The level of ITI-DEX/HA group (1.010±0.188mg/L) was higher than ITF-DEX group(0.701±0.066mg/L) but there was no significance(P > 0.05).3. Comparisons among the mean levels after administration①The three IT groups all resulted in higher mean perilymph levels than IVgroup(0.131±0.080mg/L) (P<0.05).②ITI-DEX/HA group resulted in a higher mean levels (1.572±0.621mg/L) than the ITF-DEX group(1.208±0.528mg/L) and ITI-DEX group(0.829±0.625mg/L) (P<0.05).Dexamethasone Pharmacokinetics in CSF and PlasmaIn control and IT groups (ITI-DEX, ITI-DEX/HA, ITF-DEX), DEX has not been detected in CSF and plasma. For system groups, it has been detected successfully in both samples of IV group and in plasma sample of Oral group. Especially for IV group, the average concentration was significantly higher than the other groups (P <0.05) Conclusion1. IT-DEX administration achieves higher inner ear drug concentration within all 6h after dose and does not result in systemic absorption, but to maintain a relatively short time, repeated administration was needed.2. ITI-DEX/HA and ITF-DEX all can be improve the concentration and time course of dexamethasone in perilymph. But ITI-DEX/HA is more suitable for clinical use.
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