Triptolide(TP), the main active and toxic component of Tripterygium wilfordii, has the limitations of low bioavailability, poor absorption, low concentration in plasma, and small lethal dose. Microneedle(MN), the hybrid of hypodermic needle and transdermal patch, is a physical penetration-enhancing system. Dissolving microneedles(DMNs) can be tailored to specific needs of degradation rate. In this study, the TP-loaded DMNs(DMNs-TP) were prepared with the two-step centrifugation method. The optimal ratio of PVA to PVP K30, water content in matrix solution, demoulding method, and plasticizer for preparing DMNs were investigated with the indexes of formability and mechanical strength. The drug loading capacity was determined by HPLC and morphological characteristics were observed under an optical microscope. The mechanical properties were investigated by H&E staining and Franz diffusion cell was used to detect the in vitro skin permeation characteristics. Through the experiment, we confirmed that the optimal backing material should be PVA and PVP K30(3∶1) and the optimal ratio of matrix material to water should be 3∶4. The prepared DMNs-TP were pyramidal with smooth surface and length of approximately 550 μm. Each patch(2.75 cm~2) had the drug loading capacity of(153.41±2.29) μg, and TP was located in the upper part of the needle. The results of in vitro skin permeation assay demonstrated that the cumulative penetration of TP in DMNs-TP reached 80% in 24 h, while little TP solution penetrated the skin, which proved that DMNs promoted the transdermal delivery of TP.
Administration, Cutaneous ; Diterpenes ; Drug Delivery Systems ; Epoxy Compounds ; Needles ; Phenanthrenes ; Skin

This study developed a population pharmacokinetic model for sodium tanshinone IIA sulfonate (STS) in healthy volunteers and coronary heart disease (CHD) patients in order to identify significant covariates for the pharmacokinetics of STS. Blood samples were obtained by intense sampling approach from 10 healthy volunteers and sparse sampling from 25 CHD patients, and a population pharmacokinetic analysis was performed by nonlinear mixed-effect modeling. The final model was evaluated by bootstrap and visual predictive check. A total of 230 plasma concentrations were included, 137 from healthy volunteers and 93 from CHD patients. It was a two-compartment model with first-order elimination. The typical value of the apparent clearance (CL) of STS in CHD patients with total bilirubin (TBIL) level of 10 μmol(L was 48.7 L(h with inter individual variability of 27.4%, whereas that in healthy volunteers with the same TBIL level was 63.1 L(h. Residual variability was described by a proportional error model and estimated at 5.2%. The CL of STS in CHD patients was lower than that in healthy volunteers and decreased when TBIL levels increased. The bootstrap and visual predictive check confirmed the stability and validity of the final model. These results suggested that STS dosage adjustment might be considered based on TBIL levels in CHD patients.
Adult ; Aged ; Aged, 80 and over ; Bilirubin ; blood ; Coronary Disease ; drug therapy ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; pharmacokinetics ; Female ; Humans ; Male ; Metabolic Clearance Rate ; Middle Aged ; Models, Biological ; Phenanthrenes ; administration & dosage ; blood ; pharmacokinetics

Cardiac dysfunction, a common consequence of sepsis, is the major contribution to morbidity and mortality in patients. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of Tanshinone IIA (TA), a main active component of Salvia miltiorrhiza Bunge, which has been widely used in China for the treatment of cardiovascular and cerebral system diseases. In the present study, the effect of STS on sepsis-induced cardiac dysfunction was investigated and its effect on survival rate of rats with sepsis was also evaluated. STS treatment could significantly decrease the serum levels of C-reactive protein (CRP), procalcitonin (PCT), cardiac troponin I (cTn-I), cardiac troponin T (cTn-T), and brain natriuretic peptide (BNP) in cecal ligation and puncture (CLP)-induced) septic rats and improve left ventricular function, particularly at 48 and 72 h after CLP. As the pathogenesis of septic myocardial dysfunction is attributable to dysregulated systemic inflammatory responses, several key cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10) and high mobility group protein B1 (HMGB1), were detected to reveal the possible mechanism of attenuation of septic myocardial dysfunction after being treated by STS. Our study showed that STS, especially at a high dose (15 mg·kg), could efficiently suppress inflammatory responses in myocardium and reduce myocardial necrosis through markedly reducing production of myocardial TNF-α, IL-6 and HMGB1. STS significantly improved the 18-day survival rate of rats with sepsis from 0% to 30% (P < 0.05). Therefore, STS could suppress inflammatory responses and improve left ventricular function in rats with sepsis, suggesting that it may be developed for the treatment of sepsis.
Animals ; C-Reactive Protein ; genetics ; immunology ; Cecum ; surgery ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; Female ; Heart ; drug effects ; physiopathology ; Humans ; Interleukin-6 ; genetics ; immunology ; Ligation ; adverse effects ; Male ; Myocardium ; immunology ; Phenanthrenes ; administration & dosage ; chemistry ; Punctures ; adverse effects ; Rats ; Salvia miltiorrhiza ; chemistry ; Sepsis ; drug therapy ; etiology ; immunology ; physiopathology ; Troponin T ; genetics ; immunology ; Tumor Necrosis Factor-alpha ; genetics ; immunology

Benign prostatic hyperplasia (BPH) is an age-related disease of unknown etiology, characterized by prostatic enlargement coincident with distinct alterations in tissue histology. In the present study, we investigated whether triptolide can prevent testosterone-induced prostatic hyperplasia in rats. Castration was performed via the scrotal route after urethane aesthesia. BPH was induced in experimental groups by daily subcutaneous injections of testosterone propionate (TP) for two weeks. Triptolide was administered daily by oral gavage at a dose of 100 and 50 μg·kg for 2 weeks, along with the TP injections. On day 14, the animals were humanely killed by cervical dislocation after aesthesia. Prostates were excised, weighed, and used for histological studies. Testosterone and dihydrotestosterone (DHT) levels in serum and prostate were measured. The results showed that triptolide significantly reduced the prostate weight, and the testosterone and DHT levels in both the serum and prostate. Histopathological examination also showed that triptolide treatment suppressed TP-induced prostatic hyperplasia. In conclusion, triptolide effectively inhibits the development of BPH induced by testosterone in a rat model.
Androgens ; blood ; Animals ; Diterpenes ; administration & dosage ; Drugs, Chinese Herbal ; administration & dosage ; Epoxy Compounds ; administration & dosage ; Humans ; Male ; Phenanthrenes ; administration & dosage ; Prostate ; drug effects ; growth & development ; Prostatic Hyperplasia ; blood ; drug therapy ; physiopathology ; Rats ; Rats, Sprague-Dawley ; Testosterone ; blood ; Tripterygium ; chemistry

Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors and histone deacetylase (HDAC) inhibitors have recently emerged as promising anticancer drugs. The aim of this study was to investigate the effect of combination treatment with the PARP inhibitor PJ34 and HDAC inhibitor SAHA on the proliferation of liver cancer cells. Cell proliferation and apoptosis were assessed in three human liver cancer cell lines (HepG2, Hep3B and HCC-LM3) treated with PJ34 (8 μmol/L) and SAHA (1 μmol/L), alone or combined, by Cell Counting Kit-8 assay and flow cytometry, respectively. The nude mice bearing subcutaneous HepG2 tumors were administered different groups of drugs (10 mg/kg PJ34, 25 mg/kg SAHA, 10 mg/kg PJ34+25 mg/kg SAHA), and the inhibition rates of tumor growth were compared between groups. The results showed that combined use of PJ34 and SAHA could synergistically inhibit the proliferation of liver cancer cell lines HepG2, Hep3B and HCC-LM3. The apoptosis rate of HepG2 cells treated with PJ34+SAHA was significantly higher than that of HepG2 cells treated with PJ34 or SAHA alone (P<0.05). In vivo, the tumor inhibition rates were 53.5%, 61.4% and 82.6% in PJ34, SAHA and PJ34+SAHA groups, respectively. The combined use of PJ34 and SAHA could significantly inhibit the xenograft tumor growth when compared with use of PJ34 or SAHA alone (P<0.05). It was led to conclude that PJ34 and SAHA can synergistically suppress the proliferation of liver cancer cells.
Animals ; Antineoplastic Combined Chemotherapy Protocols ; administration & dosage ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Drug Synergism ; Hep G2 Cells ; Histone Deacetylase Inhibitors ; administration & dosage ; pharmacology ; Humans ; Hydroxamic Acids ; administration & dosage ; pharmacology ; Liver Neoplasms ; drug therapy ; Mice ; Phenanthrenes ; administration & dosage ; pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors ; administration & dosage ; pharmacology ; Xenograft Model Antitumor Assays

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

The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. The antimalarials quinine (QN) and halofantrine (HF) possess moderate antischistosomal properties. The major metabolic pathway of QN and HF is through cytochrome P450 (CYP) 3A4. Accordingly, this study investigates the effects of CYP3A4 inhibitor, ketoconazole (KTZ), on the antischistosomal potential of these quinolines against Schistosoma mansoni infection by evaluating parasitological, histopathological, and biochemical parameters. Mice were classified into 7 groups: uninfected untreated (I), infected untreated (II), infected treated orally with PZQ (1,000 mg/kg) (III), QN (400 mg/kg) (IV), KTZ (10 mg/kg)+QN as group IV (V), HF (400 mg/kg) (VI), and KTZ (as group V)+HF (as group VI) (VII). KTZ plus QN or HF produced more inhibition (P<0.05) in hepatic CYP450 (85.7% and 83.8%) and CYT b5 (75.5% and 73.5%) activities, respectively, than in groups treated with QN or HF alone. This was accompanied with more reduction in female (89.0% and 79.3%), total worms (81.4% and 70.3%), and eggs burden (hepatic; 83.8%, 66.0% and intestinal; 68%, 64.5%), respectively, and encountering the granulomatous reaction to parasite eggs trapped in the liver. QN and HF significantly (P<0.05) elevated malondialdehyde levels when used alone or with KTZ. Meanwhile, KTZ plus QN or HF restored serum levels of ALT, albumin, and reduced hepatic glutathione (KTZ+HF) to their control values. KTZ enhanced the therapeutic antischistosomal potential of QN and HF over each drug alone. Moreover, the effect of KTZ+QN was more evident than KTZ+HF.
Animals ; Anthelmintics/*administration & dosage ; Disease Models, Animal ; Drug Synergism ; Female ; Humans ; Intestines/parasitology ; Ketoconazole/*administration & dosage ; Liver/parasitology/pathology ; Male ; Mice ; Parasite Load ; Phenanthrenes/*administration & dosage ; Quinine/*administration & dosage ; Schistosoma mansoni/isolation & purification ; Schistosomiasis mansoni/*drug therapy/pathology ; Treatment Outcome

Triptolide (TP) is a major active component in Tripterygium root, but its therapeutic window was very narrow due to its severe multi-organ toxicity. In this work, the effect of TP combined with glycyrrhetic acid (GA) on mRNA expression and activity of four cytochrome P450 (CYP) enzymes in rat liver was studied after intragastric administration of TP (0.05, 0.3 and 0.6 mg x kg(-1) x day(-1)) and TP (0.6 mg x kg(-1) x day(-1)) combined with GA (30 mg x kg(-1) x day(-1)) for 7 consecutive days. Compared with the control, the high dose of TP significantly up-regulated the mRNA expression levels of CYP2E1, 1A2, 3A1 and 2C11, the co-administration of TP and GA further up-regulated the mRNA expression levels of CYP3A1, 2C11 and 2E1 as compared with the high dose of TP. Meanwhile, TP at high dose and combined with GA significantly increased CYP3A-associated testosterone 6beta-hydroxylation activity (2.2-fold and 4.1-fold, respectively) as compared with the control. Because TP is mainly metabolized by CYP3A2 in male rats, the present work indicated that TP-induced increase of CYP3A activity might be an important reason for the rapidly metabolic clearance of TP in rat liver, and GA can reduce the hepatotoxicity of TP by promoting its hepatic metabolic clearance. Furthermore, the results also suggest that the drug interactions might be occurred when TP and GA were co-administered with other CYP3A substrate drug.
Animals ; Aryl Hydrocarbon Hydroxylases ; genetics ; metabolism ; Cytochrome P-450 CYP1A2 ; genetics ; metabolism ; Cytochrome P-450 CYP2E1 ; genetics ; metabolism ; Cytochrome P-450 CYP3A ; genetics ; metabolism ; Cytochrome P-450 Enzyme System ; genetics ; metabolism ; Cytochrome P450 Family 2 ; Diterpenes ; administration & dosage ; isolation & purification ; pharmacology ; Dose-Response Relationship, Drug ; Drug Combinations ; Drug Interactions ; Enzyme Activation ; Epoxy Compounds ; administration & dosage ; isolation & purification ; pharmacology ; Glycyrrhetinic Acid ; isolation & purification ; pharmacology ; Liver ; enzymology ; Male ; Phenanthrenes ; administration & dosage ; isolation & purification ; pharmacology ; Plant Roots ; chemistry ; Plants, Medicinal ; chemistry ; RNA, Messenger ; metabolism ; Rats ; Rats, Wistar ; Steroid 16-alpha-Hydroxylase ; genetics ; metabolism ; Tripterygium ; chemistry

OBJECTIVETo explore clinical features the adverse reactions of Tanshinone II(A) Sodium Sulfonate Injection (T II(A) SSI) and their reasons, thus providing reference for rational medication.

METHODSThe literatures on adverse reactions and incompatibilities of T II(A) SSI were retrieved (domestic medical journals from January 2000 to December 2011) and statistically analyzed.

RESULTSIn the 18 cases of adverse drug reaction (ADR), the clinical manifestations of T II(A) SSI induced adverse reactions were various, involving reactions of appendages and the neuromuscular system (each accounting for 50%). The elderly and women were mainly involved. Many organs and systems were involved. There existed more incompatibilities.

CONCLUSIONThe medical workers should pay special attention to T II(A) SSI induced adverse reactions, thus avoiding recurrence of ADR, evading risks, and ensuring safe and rational medication.

Adult ; Aged ; Drug-Related Side Effects and Adverse Reactions ; Female ; Humans ; Injections ; Male ; Middle Aged ; Phenanthrenes ; administration & dosage ; adverse effects

OBJECTIVETo develop a drug delivery system triptolide-polyethylenimine-cyclodextrin and to evaluate its anticancer activity in vitro.

METHODSTriptolide was conjugated to polyethylenimine-cyclodextrin by N, N'-carbonyldiimidazole to form triptolide-polyethylenimine-cyclodextrin. (1)H-NMR, FT-IR and XRD were used to confirm its structure. The anticancer effect of the polymer was assessed by MTT assay, erasion trace test and hematoxylin-eosin staining. The potential to condense siRNA and to delivery siRNA into cytoplasm was demonstrated by gel retardation assay, zeta-potential determination and fluorescence staining.

RESULTSTriptolide was successfully conjugated to polyethylenimine-cyclodextrin and the conjugation rate of triptolide was 10% (w/w). siRNA was effectively condensed by the polymer at the N/P ratio of 5, and its particle size was 300 ±15 nm and zeta potential was 8 ±2.5 mV. MTT assay, erasion trace test and hematoxylin-eosin staining revealed that triptolide-polyethylenimine-cyclodextrin had anticancer effect and low cytotoxicity to normal cells. The polymer was able to deliver siRNA to the cytoplasm effectively as demonstrated by fluorescence staining.

CONCLUSIONTriptolide-polyethylenimine-cyclodextrin is able to inhibit the growth and migration of cancer cells in vitro and to carry siRNA into cells effectively. It is potential to be used as a novel prodrug for co-delivery of gene and drug in cancer treatment.

Antineoplastic Agents ; administration & dosage ; pharmacology ; Cell Line, Tumor ; Cyclodextrins ; Diterpenes ; administration & dosage ; pharmacology ; Drug Carriers ; Epoxy Compounds ; administration & dosage ; pharmacology ; Humans ; Nanoparticles ; Phenanthrenes ; administration & dosage ; pharmacology ; Polyethyleneimine ; Polymers