Objective To explore the effect of Dexmedetomidine (Dex) on acute brain edema in mice in condition with targeted temperature management (TTM) following traumatic brain injury (TBI).Methods A total of 180 male C57BL/6J mice were divided into control group,sham operation group,TBI group,TBI + Dex group,TBI + TTM group,and TBI + Dex + TTM group according to the random number table (n =30 per group).The sham operation group only opened the bone window but did not hit it,and the control group did not open the bone window.The TBI + Dex,TBI + TIM,and TBI + Dex + TTM groups were intraperitoneally injected with Dex (60 μg/kg once every 2 h for 3 times) and/or hypothermia after TBI.The brain tissue injury volume,EB extravasation and brain water content of each group were determined by toluidine blue,Evans blue staining and dry-wet weight method at 24 hours after injury.Real-time quantitative PCR and Western blot were used to detect the expression of Claudin-5 in the injured brain tissue.At 24,48,and 72 hours after injury,the neurological deficiency degree was assessed using the modified neurological severity scores (mNSS).Results Compared with the sham operation group,TBI mice showed significant increase in brain tissue injury volume [(0.49 ± 0.04)mm3 vs.(1 1.57 ± 1.01)mm3],blood-brain barrier permeability [(16.4 ± 0.8) μg/g vs.(54.3 ± 1.7) μg/g],brain tissue water content [(76.7 ± 0.9) ％ vs.(83.1 ± 0.8) ％],and mNSS score [(1.6 ± 0.7) points vs.(13.4 ± 0.7) points] at 24 hour after TBI (all P ＜ 0.01).However,Dex or TTM treatment reduced brain tissue injury volume [(7.20±0.18)mm3 and (5.94 ±0.18)mm3],blood-brain barrier permeability [(32.7 ± 1.2) μg/g and (27.6 ± 1.0) μg,/g],brain tissue water content [(78.5 ± 0.4) ％ and (78.2 ± 0.6) ％],and neurological function [mNSS:(7.3 ± 1.1) points and (5.8 ± 1.3) points] (all P＜0.01).Moreover,Dex + TTM group showed better neuroprotection [reduced brain tissue injury volume:(3.92 ± 0.05) mm3,reduced BBB permeability:(21.6 ± 0.7) μg/g,reduced brain water content:(77.7 ±0.3)％,and reduced mNSS:(4.3 ± 1.2) points] compared with Dex or TTM alone (all P ＜ 0.01).Additionally,the mRNA expression of Claudin-5 (0.23 ± 0.01) decreased significantly at 24 hours after TBI compared with sham group (0.93 ± 0.04,P ＜ 0.01),but Dex or TTM could increase the expression of Claudin-5 (0.47 ± 0.01,and 0.54 ± 0.09) compared with TBI group (P ＜0.01),especially that of TBI + Dex + TTM group (0.64 ± 0.02,P ＜ 0.01).Furthermore,the protein expression of Claudin-5 was in accordance with the result of its mRNA expression.Conclusion Dex in condition with targeted temperature management can up-regulate Claudin-5 expression in early TBI,protect the integrity of blood-brain barrier,attenuate acute brain edema and neurological damage,and improve neurological function recovery.

OBJECTIVETo investigate in vivo distribution and pharmacokinetics of ginsenoside Rb1 (Rb1), ginsenoside Rg1 (Rg1 ) and sanchinoside R1 (R1) after intratympanic administration (IT) or intravenous administration (IV) of Panax notoginseng saponions (PNS) solution, and provide a novel route for delivering traditional Chinese medicine (TCM) to the brain.

METHODThe guinea pigs were employed as experimental animal. Perilymph (PL), cerebrospinal fluid (CSF), brain tissue and plasma were collected periodically after IT and IV of PNS solution. The concentrations of Rb1, Rg1 and R1 were measured by high performance liquid chromatography (HPLC), and statistic program DAS was applied to the calculation of pharmacokinetic parameters. The self-defined weighting coefficients based on area under curve (AUC) of each component were created to obtain the holistic pharmacokinetic profiles of PNS. The integrated pharmacokinetic parameters were then calculated from non-compartmental model analysis.

RESULTRb1, Rg1 and R1 diffused through the round window membrane into PL of the inner ear, and then transported to the brain after IT of PNS solution. However, the pharmacokinetic parameters showed significant differences between the three components. Based on the self-defined AUC weighting coefficients integration approach, the holistic pharmacokinetic profiles of PNS were obtained, from which the integrated pharmacokinetic parameters were calculated. The C(max) in CSF and brain tissues following IT were respectively 1.5 and 0.4-fold higher than those following IV. After IT, the AUC in CSF and brain tissues increased by 0.5 and 1.2 times compared with IV. Furthermore, the C(max) and AUC in plasma following IT were respectively 45.9% and 33.1% lower than those following IV.

CONCLUSIONThis novel intra-cochlear administration might serve as a potential and promising alternative to TCM delivery with enhanced brain-targeted efficiency.

Animals ; Brain ; metabolism ; Drug Administration Routes ; Ear, Middle ; metabolism ; Female ; Ginsenosides ; administration & dosage ; blood ; cerebrospinal fluid ; pharmacokinetics ; Guinea Pigs ; Male ; Medicine, Chinese Traditional ; Panax notoginseng ; chemistry ; Perilymph ; metabolism ; Plants, Medicinal ; chemistry ; Saponins ; administration & dosage ; blood ; cerebrospinal fluid ; pharmacokinetics

OBJECTIVETo prepare pulsed-release tablet (PTS) according to the rhythm of coronary heart disease based on efficacy material and the mechanism of compound Danshen.

METHODPTS were achieved by coating the core which contains drugs, CMS-Na, lactose, succinic acid and MCC with separation layer (Eudragit RL), swelling layer (HPMC E5), and controlled-release membrane (Eudragit RS-RL-EC).

RESULTThe results of in vitro experiments showed that no difference was observed among the profiles of Danshensu, protocatechuic aldehyde, ginsenoside Rg1, Rb1, notoginsenoside R1 release from the two-step release system. And it indicated that swelling was the basis and prerequisite for drug release from PTS, and the diffusion, organic acid-induced, and osmotic pumping mechanism were involved in drug release, but the latter they were the dominant factors.

CONCLUSIONSuccessfully obtained the PTS of a certain lag-time behind the rapid release which indicate that after bed time administration of such device, the drug plasma concentration-time curve CAN meet the requirements of chronotherapy of cardiovascular disease.

Benzaldehydes ; metabolism ; Catechols ; metabolism ; Chromatography, High Pressure Liquid ; Coronary Disease ; drug therapy ; Diffusion ; Drug Compounding ; methods ; Drug Delivery Systems ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; metabolism ; therapeutic use ; Ginsenosides ; metabolism ; Osmosis ; Salvia miltiorrhiza ; chemistry ; Tablets ; Time Factors

This study was intended to assess the therapeutic effect and toxicity of Compound vincristine liposome on breast cancer in nude mice. The mammary cancer models of BALB/c nude mice were set up using MCF-7 cells, and were divided into seven groups: MTO-VCR-LP, MTO-VCR-Soln, VCR-LP, VCR-Soln, MTO-LP, MTO-Soln and 0.9% NaCl. After the first treatment in the same day of transplantation, different treatments were given respectively. According to the design, the BLAB/c nude mice were given the therapy, the weight of nude mice and tumor volume were measured, and the tumor growth inhibitory rate was calculated. Bone marrow smears and extravasation injury were observed. The tumor growth inhibitory rates were higher in MTO-VCR-LP and MTO-VCR-Soln groups than in other groups. MTO-VCR-Soln, VCR-Soln and MTO-Soln led to severe local extravasation injury. MTO-VCR-Soln cause serious bone marrow inhibition of nude mice. The average weight of nude mice in the three liposome groups was higher than that in the three solution groups. So the use of liposome as the carriers of the two anticancer drugs could improve the cure rate of cancer and decrease the side-effects. This work, which not only expanded the research field of liposome but also brought in new ideas and new methods to treat cancer. Furthermore, the findings in this research may have the potential for use in clinical practice.
Animals ; Drug Carriers ; Drug Synergism ; Female ; Liposomes ; administration & dosage ; Mammary Neoplasms, Experimental ; drug therapy ; pathology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitoxantrone ; administration & dosage ; adverse effects ; Neoplasm Transplantation ; Random Allocation ; Vincristine ; administration & dosage ; adverse effects

OBJECTIVETo compare the influence on the dissolution of tanshinone IIA (TS IIA) solid dispersions in complex carriers and single, which used in preparation of TS IIA solid dispersions, and further enhance the dissolution of TS IIA.

METHODThe TS IIA solid dispersions were prepared by solvent technique with polyvinylpyrrolidone K30 (PVPK30), poloxamer188 (F68) and combination of PVPK30 and F68 as carriers, respectively. The physical characteristics of TS IIA solid dispersions was studied using differential scanning calorimetry (DSC). Dissolution rates were studied using small cup method (CHP XC III). The solubility of TS IIA with the solid dispersions and pure drug form were determined by HPLC method.

RESULTThe DSC analysis suggested that TS IIA was dispersed as an amorphous form in the combination of PVPK30 and F68. Dissolution profile of the prepared solid dispersions could be described by Weibull equation (R>0.99). For tested three carries, Td value (calculated time to 63.2% of total drug release according to Weibull equation) were (90.40 +/- 2.82) min, (204.5 +/- 8.20) min and (25.83 +/- 0.13) min, respectively. The PVPK30/F68-TS IIA solid dispersion resulted in a significant increase of TS IIA solubility compared with prepared PVPK30-TS IIA and F68-TS IIA solid dispersions (P<0.01).

CONCLUSIONAs compared to single use of PVPK30 or F68, the combination of PVPK30 and F68 improve the dissolution rate and solubility of TS IIA significantly in the prepared solid dispersions (P<0.01). The application of complex carriers in solid dispersion technology should be paid more attention to improvement of poorly soluble drugs dissolution in the future.

Diterpenes, Abietane ; Phenanthrenes ; chemistry ; Solubility ; Temperature

OBJECTIVETo prepare effervescent osmotic pump tablet (EOPTs) according to the rhythm of coronary heart disease based on efficacy material and the mechanism of compound Danshen and to study the mechanism of drug released of that tablets.

METHODSince compound Danshen consist of compounds with polyphenolic groups or carboxyl groups, such as phenolic acids, flavonoids, and triterpenoids that they were acidic. EOPTs were prepared from tablet cores which containing NaHCO3 as effervescent, NaCL and manitol as osmotic agents, HPMC as retarding agents coating with CA membrane. And study the mechanism of drug released according to the change of tablet osmotic pressure.

RESULTThe results of in vitro experiments showed that no difference was observed among the profiles of Danshensu, protocatechuic aldehyde, ginsenoside Rg1, Rb1, notoginsenoside R1 release EOPTs. The drug was completely released from the device with a zero-order release rate over 12 h.

CONCLUSIONEOPTs are Successfully obtained EOPT which the drug is released from the device over 12 h and the release mechanism of EOPTs is explained.

Coronary Disease ; physiopathology ; Drug Compounding ; Drugs, Chinese Herbal ; administration & dosage ; metabolism ; Infusion Pumps ; Osmosis ; Salvia miltiorrhiza ; metabolism ; Tablets ; Time Factors

This study sought to clarify the molecular location and the interaction between mitoxantrone and mitoxantrone transforsomes. The anthraquinone of mitoxantrone, a heterocyclic ring that intercalates in the lipid of bilayer, was determined by UV-spectrophotometry and electron probes scan microscopy. Two aminoethylamino side-chains of the drugs fit to the phosphates of lecithin were determined by 8-value, thus the interaction with lecithin was substantiated. Differential scanning calorimetry confirmed that mitoxantrone has remarkable stabilizing effect on the mitoxantrone transforsomes membrane. The mitoxantrone binds tightly to lecithin. So a high degree of encapsulation efficiency and the sustained-release character of mitoxantrone transforsomes are verified.
Anthraquinones ; chemistry ; Calorimetry, Differential Scanning ; Delayed-Action Preparations ; chemistry ; Lecithins ; chemistry ; Mitoxantrone ; chemistry ; Spectrophotometry

Bovine serum albumin nanoparticles(BSANP) were prepared by desolvation method. The activated folic acid (N-hydroxysuccinimide ester of folic acid) was conjuated to the surface of BSANP via the amino groups. Then the folate-conjugated BSANPs (folate-BSANP) were purified with Sephadex G-50 column and completely separated from unreacted folic acid. After chymotryptic hydrolysis, the extent of folate conjugation on the BSANP was determined by quantitative ultraviolet(UV) spectrophotometric analysis. It was found that the spectrum of trypsin digest of folate-conjugate BSANP is basically identical with that of folate, thus indicating folate is successfully expressed on the surface of BSANP. The folate-BSANP was averagely 66 nm in diameter and was spherical in shape. Folate-conjugated BSANP was achieved, which represents a potential new drug carrier for tumor cell-selective targeting.
Animals ; Antineoplastic Agents ; administration & dosage ; Carrier Proteins ; chemistry ; Cattle ; Drug Delivery Systems ; methods ; Folate Receptors, GPI-Anchored ; Folic Acid ; chemistry ; Immunotoxins ; Microspheres ; Nanotechnology ; Receptors, Cell Surface ; chemistry ; Serum Albumin, Bovine ; chemistry

The valaciclovir was used as the model drug, the bovine serum albumin nanoparticles (BSA-NP) were prepared by desolvation process. Glycyrrhizin (GL) was oxidized by sodium periodate to be conjugated to surface reactive amino groups (SRAG) of the VACV-BSA-NP. Gel filtration method combined with HPLC method verified that GL was covalent coupling to the surface of VACV-BSA-NP with mean 9 GL residues per albumin molecule. The mean diameter of the VACV-BSA-NP-GL was 268 +/- 23 nm, the drug loading was 1.35%, and embedding ratio was 68.76%. The characteristics of release in vitro were in accord with two-phase kinetics. The uptake amount of VACV-BSA-NP-GL by primary cultured rat hepatocytes in vitro was higher, compared to the control-VACV-BSA-NP. 69.89% and 64.82% of the VACV were concentrated in liver at 15 min after i.v. VACV-BSA-NP-GL and VACV-BSA-NP, respectively. There is a significant difference between surface-modified group and control group (P<0.10). VACV-BSA-NP-GL was successfully prepared, which is considered to be a novel drug delivery system for targeting to hepatocytes.
Acyclovir ; analogs & derivatives ; pharmacology ; Cells, Cultured ; Drug Delivery Systems ; Glycyrrhizic Acid ; pharmacology ; Hepatocytes ; cytology ; metabolism ; Humans ; Microspheres ; Nanostructures ; Nanotechnology ; Particle Size ; Serum Albumin, Bovine ; pharmacology ; Technology, Pharmaceutical ; methods ; Valine ; analogs & derivatives ; pharmacology

Recent studies in the realm of metabolic chemistry of traditional Chinese drugs (TCD),appeared in literature were reviewed. Methods for such study were enumerated and commented upon.Some problems that arised in the study were discussed. It was suggested that the study of metabolic chem-istry on TCD and its compounded preparations should be further pursued.