Salvianolic acid A (SAA) is a water-soluble component from the root of Salvia Miltiorrhiza Bge, a traditional Chinese medicine, which has been used for the treatment of cerebrovascular diseases for centuries. The present study aimed to determine the brain protective effects of SAA against cerebral ischemia reperfusion injury in rats, and to figure out whether SAA could protect the blood brain barrier (BBB) through matrix metallopeptidase 9 (MMP-9) inhibition. A focal cerebral ischemia reperfusion model was induced by middle cerebral artery occlusion (MCAO) for 1.5-h followed by 24-h reperfusion. SAA was administered intravenously at doses of 5, 10, and 20 mg·kg. SAA significantly reduced the infarct volumes and neurological deficit scores. Immunohistochemical analyses showed that SAA treatments could also improve the morphology of neurons in hippocampus CA1 and CA3 regions and increase the number of neurons. Western blotting analyses showed that SAA downregulated the levels of MMP-9 and upregulated the levels of tissue inhibitor of metalloproteinase 1 (TIMP-1) to attenuate BBB injury. SAA treatment significantly prevented MMP-9-induced degradation of ZO-1, claudin-5 and occludin proteins. SAA also prevented cerebral NF-κB p65 activation and reduced inflammation response. Our results suggested that SAA could be a promising agent to attenuate cerebral ischemia reperfusion injury through MMP-9 inhibition and anti-inflammation activities.
Animals ; Anti-Inflammatory Agents ; administration & dosage ; Blood-Brain Barrier ; drug effects ; enzymology ; immunology ; Brain ; Brain Ischemia ; drug therapy ; enzymology ; genetics ; Caffeic Acids ; administration & dosage ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Lactates ; administration & dosage ; Male ; Matrix Metalloproteinase 9 ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; enzymology ; genetics ; immunology ; prevention & control ; Salvia miltiorrhiza ; chemistry ; Tissue Inhibitor of Metalloproteinase-1 ; genetics ; metabolism ; Transcription Factor RelA ; genetics ; immunology

BACKGROUND/AIMS: To prevent hypocalcemia after parathyroidectomy (PTX), parenteral calcium is required in addition to oral calcitriol and calcium. After switching to oral calcium, patients can be discharged from the hospital. The aim of this study was to analyze the clinical characteristics and outcomes of PTX performed at a single Korean center and to investigate the associated laboratory factors used to analyze the total amount of postoperative calcium required. METHODS: We enrolled 91 hemodialysis patients undergoing PTX from November 2003 to December 2011. We collected clinical and laboratory data preoperatively, 12 and 48 hours postoperatively, at discharge, and 3 and 6 months postoperatively. RESULTS: In total, 59 patients underwent PTX with autotransplantation (AT), 6 underwent total PTX without AT, 11 underwent subtotal PTX, and 15 underwent limited PTX. Total PTX without AT showed the lowest recurrence rate. At all postoperative time points, the mean levels of serum calcium, phosphorus, and intact parathyroid hormone (iPTH) decreased significantly, compared with preoperative levels; however, alkaline phosphatase (ALP) increased significantly from 48 hours postoperatively to discharge (p < 0.001). On multiple linear regression analysis, the total amount of injected calcium during hospitalization showed a significant correlation with preoperative ALP (p < 0.001), preoperative iPTH (p = 0.037), and Deltaphosphorus at 48 hours (p < 0.001). We developed an equation for estimating the total calcium requirement after PTX. CONCLUSIONS: Preoperative ALP, preoperative iPTH, and Deltaphosphorus at 48 hours may be significant factors in estimating the postoperative calcium requirement. The formula for postoperative calcium requirement after PTX may help to predict the duration of postoperative hospitalization.
Administration, Intravenous ; Administration, Oral ; Adult ; Aged ; Biomarkers/blood ; Calcium/blood ; Calcium Carbonate/*administration & dosage ; Calcium Compounds/*administration & dosage ; Calcium Gluconate/*administration & dosage ; *Decision Support Techniques ; *Dietary Supplements ; Female ; Humans ; Hyperparathyroidism, Secondary/blood/diagnosis/*surgery ; Hypocalcemia/diagnosis/etiology/*prevention & control ; Lactates/*administration & dosage ; Linear Models ; Male ; Middle Aged ; Models, Biological ; Multivariate Analysis ; Parathyroid Hormone/blood ; Parathyroidectomy/*adverse effects ; Phosphorus/blood ; Recurrence ; Republic of Korea ; Retrospective Studies ; Risk Factors ; Time Factors ; Treatment Outcome ; Young Adult

Salvianolic acid A (Sal A) is one of the most effective compounds isolated from the root of Salvia miltiorrhiza. Up to now, several studies regarding the pharmacokinetic profiles of Sal A have been reported, however there is no such study reported in monkeys, the species which is more similar to human. The aim of this study is to develop a LC-MS method for the determination of Sal A in monkey plasma and apply it to the pharmacokinetic studies of monkeys. After single intravenous administration of Sal A, the plasma concentration-time curves were observed and the main pharmacokinetic parameters were calculated. The plasma concentration at 2 min (C2 (min)) values were (28.343 ± 6.426), (45.679 ± 12.301) and (113.293 ± 24.360) mg x L(-1) for Rhesus monkeys treated with Sal A at 2.5, 5 and 10 mg x kg(-1). The area under the concentration-time curve (AUC(0-∞)) values were (3.316 ± 0.871), (5.754 ± 2.150) and (13.761 ± 2.825) μg x L(-1) x h, respectively. Furthermore, this method was improved and applied to the simultaneous determination of Sal A, Sal B and Sal C, which provided useful information for preclinical studies and clinical trials of Sal A, Sal B and Sal C.
Administration, Intravenous ; Animals ; Caffeic Acids ; pharmacokinetics ; Chromatography, Liquid ; Drugs, Chinese Herbal ; pharmacokinetics ; Lactates ; pharmacokinetics ; Macaca mulatta ; Mass Spectrometry ; Plant Roots ; chemistry ; Salvia miltiorrhiza ; chemistry

To develop a LC-MS/MS method for the determination of protocatechuic acid, protocatechuic aldehyde, salvianolic acid A, salvianolic acid B, cryptotanshinone and tanshinone II(A) in rat plasma and brain. The plasma and brain samples were precipitated with ethyl acetate, then were separated on an Agilent eclipse plus-C18 column (2.1 mm x 50 mm, 3.5 microm) using acetonitrile (consisting of 0.1% formic acid) and water (consisting of 0.1% formic acid) as mobile phase in gradient elution mode. The mass spectrometer was operated under both positive and negative ion mode with the ESI source, and the detection was performed by MRM. The transition of 154.3/153.1 m/z for protocatechuic acid, 137.3/108 m/z for protocatechuic aldehyde, 493.0/295.2 m/z for Salvianolic acid A, 718.0/520.0 m/z for salvianolic acid B, 321.4/152.3 m/z for chloramphenicol, 297.4/254.3 m/z for cryptotanshinone, 295.5/249.3 m/z for tanshinone II(A) and 285.2/154.0 m/z for Diazepam. The calibration curves in the range of 0.625-1 000 microg x L(-1) for protocatechuic acid and protocatechuic aldehyde, 1.25-1 000 microg x L(-1) for salvianolic acid A, 2.5-1 000 microg x L(-1) for salvianolic acid B, 0.15-1 000 microg x L(-1) for cryptotanshinone, 0.625-1 000 microg x L(-1) for tanshinone II(A) are with good linearityin rat plasma and brain. The analysis method is sensitive, simple, and suitable enough to be applied in the pharmacokinetic study of the 6 main components. Animal testing gives the lgBB of the drugs and further studies of the 6 components cross the blood-brain barrier can be carried out.
Animals ; Benzaldehydes ; administration & dosage ; blood ; pharmacokinetics ; Benzofurans ; administration & dosage ; blood ; pharmacokinetics ; Blood-Brain Barrier ; metabolism ; Brain ; metabolism ; Caffeic Acids ; administration & dosage ; blood ; pharmacokinetics ; Catechols ; administration & dosage ; blood ; pharmacokinetics ; Chromatography, Liquid ; methods ; Diterpenes, Abietane ; administration & dosage ; blood ; pharmacokinetics ; Hydroxybenzoates ; administration & dosage ; blood ; pharmacokinetics ; Injections, Intravenous ; Lactates ; administration & dosage ; blood ; pharmacokinetics ; Phenanthrenes ; administration & dosage ; blood ; pharmacokinetics ; Plant Preparations ; administration & dosage ; blood ; pharmacokinetics ; Rats ; Reproducibility of Results ; Salvia miltiorrhiza ; chemistry ; Tandem Mass Spectrometry ; methods

As a novel targeting drug delivery system, acid-sensitive micelles have many advantages, such as increasing solubility of lipophilic drugs, acid-sensitive release, high drug loading, etc. They can load drugs though non-covalent encapsulation and covalent conjugation methods. In tumor tissues, drugs are released quickly from the depolymerized micelles with lipophilic copolymer protonation or lypohydrophilic copolymer hydrolysis and covalent conjugated drugs are released when the acid-sensitive covalent linkage breaks. This review mainly advances acid-sensitive micelles for the tumor targeting drug delivery systems from drug-loaded methods and release mechanisms.
Animals ; Antibiotics, Antineoplastic ; administration & dosage ; pharmacology ; Antineoplastic Agents, Phytogenic ; administration & dosage ; pharmacology ; Cell Line, Tumor ; Doxorubicin ; administration & dosage ; pharmacology ; Drug Carriers ; chemistry ; Drug Delivery Systems ; Humans ; Hydrogen-Ion Concentration ; Lactates ; chemistry ; Micelles ; Paclitaxel ; administration & dosage ; pharmacology ; Polyethylene Glycols ; chemistry ; Polymers

After oral administration of Salvia miltiorrhiza (Danshen in Chinese), Panax notoginseng (Sanqi in Chinese) and Danshen Sanqi combination suspensions to Beagle dogs, the plasma concentration-time profiles of danshensu, tanshinone II(A), cryptotanshinone, notoginsenoside R1, ginsenoside Rg1 and Rb1 were analyzed by LC-MS/MS. Pharmacokinetic parameters were calculated and analyzed with BAPP 2.0 software. The results showed that the Cmax and AUC of danshensu, notoginsenoside R1, ginsenoside Rg1 and Rb1 in Danshen Sanqi combination group all decreased in comparison with those of Danshen or Sanqi given alone, while the CLz/F and Vz/F increased to some extent. No significant differences of the pharmacokinetics of tanshinone II(A) and cryptotanshinone were observed between groups.
Administration, Oral ; Animals ; Area Under Curve ; Diterpenes, Abietane ; blood ; pharmacokinetics ; Dogs ; Drug Combinations ; Drugs, Chinese Herbal ; administration & dosage ; isolation & purification ; pharmacokinetics ; Female ; Ginsenosides ; blood ; pharmacokinetics ; Lactates ; blood ; pharmacokinetics ; Male ; Panax notoginseng ; chemistry ; Phenanthrenes ; blood ; pharmacokinetics ; Plants, Medicinal ; chemistry ; Salvia miltiorrhiza ; chemistry

This study aimed to investigate the effects of concentration, intestinal section and borneol on the intestinal absorption of salvianolic acids. The experiment not only studied the intestinal absorption properties of three concentrations of rosmarinic acid, salvianolic acid B and salvianolic acid A at duodenum, jejunum and ileum, but also of salvianolic acids compatible with borneol at different concentrations using single-pass intestinal perfusion model in rat with phenol red as the marker. The results showed that salvianolic acids was stable under weak-acid condition and affected by metabolism enzyme; The Peff and Ka significantly different among three concentrations of rosmarinic acid and salvianolic acid B, whose intestinal absorption were saturated in high concentration, suggesting that the transport mechanisms of rosmarinic acid and salvianolic acid B were similar to active transport or facilitated diffusion; However, there was inconspicuousness in the Peff and Ka of salvianolic acid A at different concentrations, whose absorption was not saturated in high concentration, indicating that the transport mechanisms of salvianolic acid A was passive diffusion; The Peff and Ka in the ileum obviously higher than those in the duodenum and jejunum, namely the ileum was the best absorption section; When concentration of borneol increased, the enhancing effect of intestinal absorption of salvianolic acids increased, but significantly decreased when borneol increased to some degree. The enhancing effect of medium borneol concentration was the optimum. This implied that borneol can enhance the intestinal absorption of salvianolic acids, and the capacity of enhancing effect was influenced by the concentration of borneol.
Animals ; Benzofurans ; isolation & purification ; pharmacokinetics ; Bornanes ; administration & dosage ; pharmacokinetics ; pharmacology ; Caffeic Acids ; isolation & purification ; pharmacokinetics ; Cinnamates ; isolation & purification ; pharmacokinetics ; Depsides ; isolation & purification ; pharmacokinetics ; Dose-Response Relationship, Drug ; Duodenum ; metabolism ; Ileum ; metabolism ; Intestinal Absorption ; Jejunum ; metabolism ; Lactates ; isolation & purification ; pharmacokinetics ; Male ; Perfusion ; methods ; Plants, Medicinal ; chemistry ; Rats ; Rats, Sprague-Dawley ; Salvia miltiorrhiza ; chemistry

Biodegradable four-arm star-shaped poly(ethylene glycol)-block-poly(L-lactic acid) copolymer (sPEG-b-PLLA), four-arm star-shaped poly(L-lactic acid) (sPLLA), linearly poly(ethylene glycol)-block-poly(L-lactic acid) copolymer (PEG-b-PLLA) and linearly poly(L-lactic acid) (PLLA) were synthesized from L-lactice acid, pentaerythritol, poly(ethylene glycol) and star-shaped poly(ethylene glycol), using the method of melt polycondensation, and the products were characterized and confirmed by 1H NMR spectroscopy, FT-IR and GPC. Four types of ibuprofen loaded microspheres based on the above four types of polymers, i.e., IBU/PLLA, IBU/sPLLA, IBU/PEG-b-PLLA, and IBU/sPEG-b-PLLA microspheres were prepared using the method of solvent evaporation, and the optimized preparation technology was obtained via orthogonal experiments, and the drug-encapsulating properties and in vitro drug-releasing properties were studied. The results showed that compared with IBU/PLLA and IBU/PEG-b-PLLA microspheres, the drug encapsulate efficiency of IBU/sPLLA and IBU/sPEG-b-PLLA microspheres were higher and the in vitro drug releasing rate slowed down, which mainly due to the faster degradation of sPLLA and sPEG-b-PLLA for the star-shaped structure and the block copolymerization of sPEG. The drug releasing curves of these three types of microspheres could be fit by first-order equation, and the releasing mechanism was non-Fickian diffusing, i.e., the synergetic effect of polymer degradation and drug diffusion.
Analgesics, Non-Narcotic ; administration & dosage ; chemistry ; Anti-Inflammatory Agents, Non-Steroidal ; administration & dosage ; chemistry ; Delayed-Action Preparations ; Drug Carriers ; Ibuprofen ; administration & dosage ; chemistry ; Lactates ; chemistry ; Lactic Acid ; chemistry ; Magnetic Resonance Spectroscopy ; Microspheres ; Particle Size ; Polyesters ; Polyethylene Glycols ; chemistry ; Polymers ; chemistry ; Spectroscopy, Fourier Transform Infrared

OBJECTIVETo develop a HPLC method for determination of the concentration of Danshensu in rat plasma and undertake comparative pharmacokinetic study of sodium danshensu and Salvia miltiorrhiza injection in rat as well as to assess the effect of other components of Salvia miltiorrhiza injection on the pharmacokinetics of Danshensu.

METHODRats received an iv. infusion of sodium Danshensu or S. miltiorrhiza injection (equal to Danshensu 30 mg x kg(-1)). Blood samples were collected from carotid artery. Plasma concentration of Danshensu extracted with perchloric acid was measured. The pharmacokinetic parameters were calculated with DAS2.0 software.

RESULTA good linear relationship of Danshensu was obtained from the range of 0.5 to 80.0 mg x L(-1), and the lowest limit of determination was 0.2 mg x L(-1). The plasma concentration time curves of Danshensu were best fitted with two-compartment models for Danshensu itself and for Salvia miltiorrhiza injection as well. The pharmacokinetic parameters such as t1/2alpha, AUC, CL had significant differences.

CONCLUSIONThe concomitant components in Salvia miltiorrhiza injection influence the pharmacokinetic properties of Danshensu and speed up its disposition and elimination.

Animals ; Drugs, Chinese Herbal ; administration & dosage ; pharmacokinetics ; Lactates ; pharmacokinetics ; Male ; Rats ; Rats, Sprague-Dawley ; Salvia miltiorrhiza ; chemistry

OBJECTIVESTo investigate the inhibitory effect of danshensu on the activation of JNK signaling in rat hepatic stellate cells (HSCs) induced by IL-1beta.

METHODSThe proliferation of primary rat HSCs treated with different concentration of Danshensu was checked by MTT colorimetric assay. The expression and phosphorylation of JNK and P-JNK was detected by western blotting. Synthesis and secretion of collagen I were detected by the quantitative immunocytochemical assay and ELISA.

RESULTSDanshensu inhibited the proliferation of HSCs in a dose-dependent manner. At the concentration of 0.0625 to 0.25 mmol/L, Danshensu significantly repressed the proliferation of HSC induced by IL-1beta (P < 0.05). Synthesis and secretion of Type I collagen was significantly decreased 24 hours after 0.25 mmol/L Danshensu treatment (P < 0.01). The phosphorylation of JNK induced by IL-1beta was significantly inhibited by Danshensu treatment (P < 0.05), however, the expression of JNK was not regulated by Danshensu.

CONCLUSIONDanshensu represses the activation and proliferation of HSCs, and inhibits the synthesis and secretion of Type I collagen, possibly via the repression of the JNK signal transduction.

Animals ; Blotting, Western ; Cell Proliferation ; drug effects ; Cells, Cultured ; Collagen Type I ; metabolism ; secretion ; Dose-Response Relationship, Drug ; Down-Regulation ; Hepatic Stellate Cells ; drug effects ; metabolism ; Immunohistochemistry ; Interleukin-1beta ; pharmacology ; JNK Mitogen-Activated Protein Kinases ; metabolism ; Lactates ; administration & dosage ; pharmacology ; Liver Cirrhosis ; etiology ; prevention & control ; Male ; Mitogen-Activated Protein Kinases ; metabolism ; Rats ; Rats, Wistar ; Signal Transduction ; drug effects