Transport Characteristics And Mechanism On Efficient Components Of Salviae Miltiorrhizae Radix Et Rhizoma-Notoginseng Radix Et Rhizoma And Their Combination Via Inner Ear Administration

At present, the inner ear and brain diseases are bothering people. Treatment of thesetwo diseases is mainly dependent on systemic drug delivery, but drugs are difficult to enterthe inner ear and brain because of the presence of the blood inner ear barrier (BIB) andblood brain barrier (BBB). However, previous studies have demonstrated that a commoninner ear drug delivery method——intratympanic administration, which can deliver drugsto the inner ear perilymph, and further transport to the cerebrospinal fluid avoiding thehandicap of BBB and BIB, has been applied in clinical. Radix Salvia miltiorrhiza andRadix Panaxnotoginseng, which are usually combined in multiple Chinese medicinalformulaes widely used in sudden deafness, noise deafness and protecting brain injurycaused by cerebral ischemia and cerebral ischemia-reperfusion, promoting recovery ofneurological function etcetera central nervous system diseases, are traditional Chinesecouplet medicine. Studies of their active components are clear, but the bioavailability ofPNS which is the major component of Radix Panaxnotoginseng is low because ofsusceptible to be degraded by acid and enzymatic from gastrointestinal secretion anddifficult to acess the intestinal mucosa. SalB and TSIIA are metabolized rapidly in vivo, sotheir half life are short. For above reasons, their curative effect is not well worked.Accordingly, this study take the classical drug pair Danshen-Sanqi as model drug and R1,Rg1, Rb1, SalB and TsIIA as index content to study the pharmacokinetics and transportmechanism of multi-compoent and compound traditional Chinese medicine transport intobrain via the inner ear.The HPLC method was established to determine SalB and TsIIA in guinea pig in vivosimultaneously. The concentrations in tissues were measured after IT and IV. Then thepharmacokinetic software was used to calculate the pharmacokinetic parameters. The self-defined weighting coefficients based on area under curve (AUC) of each component werecreated to obtain the holistic pharmacokinetic parameters of Danshen. The results show thatcomparing with IV, the two components can be effectively transmissioned to the PL and CSF via IT. The Cmaxand AUC were higher1236.64,19.82and30752.42,106.80times inPL and CSF.Animal tissues (PL, CSF, plasma and brain) were collected in different time after ITPNS, while establish the high-performance liquid chromatography (HPLC) method of theindex content R1, Rg1and Rb1to determine their concentration in tissues. Then thepharmacokinetic software was used to calculate the pharmacokinetic parameters. The self-defined weighting coefficients based on area under curve (AUC) of each component werecreated to obtain the holistic pharmacokinetic parameters of PNS. The integratedpharmacokinetic parameters were then calculated from non-compartmental model analysis.Results showed that after IT PNS can be effectively transferred to the inner ear andbrain.Namely, compared with IV, the Cmaxand AUC were higher12.33,1.46,0.59and12.38,0.46,0.20times in PL, CSF and brain.HPLC-DAD method was established to determine concentrations of R1, Rg1, Rb1,SalB and TsIIA in tissues and their pharmacokintic parameters were calculated by DAS.Using the above method to obtain the the holistic pharmacokinetic parameters of thecompound. Results show that after IT, the Cmaxand AUC were higher62.38,3.86,1.67and37.13,1.08,1.32times in PL, CSF and brain comparing with IV. Compound compatibilityafter IT, the Cmaxand AUC of SalB and TsIIA were increased5.21,0.18and4.73,7.72times than alone, suggesting that PNS was more effectively to promote the effectivecomponents of Danshen to transport into brain.Male guinea pigs were randomly divided into a sham-operation, aischemia-reperfusion model, a positive drug group, IT and IV group. The model of globalchemia-reperfusion was established by ligaturing bilateral common carotid artery andreducing blood pressure. Superoxide dismutase(SOD), nitricoxide(NOS) andmalondialdehyde(MDA) contents in brain and serum were detected by Kit. Single factoranalysis of variance in multiple groups and pairwise t-test between groups were analysisedby SPPS16.0. Results show that comparing with the model group and sham operationgroup, the content of SOD was increased while NOS and MDA were decreasedsignificantly after IV and IT. They can both improve the brain injury caused by cerebral ischemia and cerebral ischemia-reperfusion, but the effect of IT group is significantly betterthan IV group.The results of pharmacokinetics and distribution of above chapters indicate that theeffective components of Danshen and Sanqi can be diffused through the round windowmembrane into PL of the inner ear, and then transported to the brain after IT. IT can beeffectively transferred drugs to the inner ear and brain; it may become a new method todeliver traditional Chinese medicines into brain via the inner ear. According to the researchresuilts，we obtained the relationship of transmission rate and oil water partition coefficient,molecular size, drug dosing in tympanic cavity, the area and height of round windowmembrane as following:logJ0.2231logK-0.6471logD2.2209logCs1.3534This can provide certain basis to predicate the absorption of drugs through the roundwindow membrane.