This study aims to investigate the scientificity and efficacy of the compatibility of Jinlingzi San from pharmacokinetics. Liquid chromatography-tandem mass spectrometry(LC-MS/MS) was utilized to determine the plasma concentrations of the active components: toosendanin, tetrahydropalmatine A, and tetrahydropalmatine B at various time points following the gavage of Jinlingzi San and its single medicines in rats. Subsequently, WinNonlin was employed to calculate pertinent pharmacokinetic parameters. The pharmacokinetic parameters in rat plasma were compared between the single medicines and the compound formula of Jinlingzi San. It was discovered that the area under the curve(AUC_(all)) and peak concentrations(C_(max)) of tetrahydropalmatine A, and tetrahydropalmatine B were significantly elevated in the compound formula group compared with the single medicine groups. Conversely, the AUC_(all )and C_(max) of toosendanin notably decreased. Furthermore, the compound formula group had longer mean residence time(MRT) and lower apparent clearance(CL/F) of all three active ingredients than the single medicine groups(P<0.05). These findings indicated that Jinlingzi San enhanced the absorption of tetrahydropalmatine A and tetrahydropalmatine B in vivo, facilitating their pharmacological actions. Concurrently, it inhibited the absorption of toosendanin, thereby preventing potential toxic reactions. Moreover, the compatibility prolonged the residence time of the active ingredients in the body. This study provides a reference for exploring the compatibility rationality of Jinlingzi San.
Animals ; Rats ; Tandem Mass Spectrometry/methods* ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Rats, Sprague-Dawley ; Chromatography, Liquid/methods* ; Berberine Alkaloids/blood* ; Liquid Chromatography-Mass Spectrometry

Neuropathic pain is one of the common complications of diabetes. Tetrahydropalmatine(THP) is a main active component of Corydalis Rhizoma with excellent anti-inflammatory and pain-alleviating properties. This study aims to investigate the therapeutic effect of THP on diabetic neuropathic pain(DNP) and the underlying mechanism. High-fat and high-sugar diet(4 weeks) and streptozotocin(STZ, 35 mg·kg~(-1), single intraperitoneal injection) were employed to induce type-2 DNP in rats. Moreover, lipopolysaccharide(LPS) was used to induce the activation of BV2 microglia in vitro to establish an inflammatory cellular model. Fasting blood glucose(FBG) was measured by a blood glucose meter. Mechanical withdrawal threshold(MWT) was assessed with von Frey filaments, and thermal withdrawal latency(TWL) with hot plate apparatus. The protein expression levels of OX42, inducible nitric oxide synthase(iNOS), CD206, p38, and p-p38 were determined by Western blot, the fluorescence expression levels of OX42 and p-p38 in the dorsal horn of the rat spinal cord by immunofluorescence, the mRNA content of p38 and OX42 in rat spinal cord tissue by qRT-PCR, and levels of nitric oxide(NO), interleukin-1β(IL-1β), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), interleukin-10(IL-10), and serum fasting insulin(FINS) by enzyme-linked immunosorbent assay(ELISA). RESULTS:: showed that the mo-del group demonstrated significant decrease in MWT and TWL, with pain symptoms. THP significantly improved the MWT and TWL of DNP rats, inhibited the activation of microglia and p38 MAPK signaling pathway in rat spinal cord, and ameliorated its inflammatory response. Meanwhile, THP promoted the change of LPS-induced BV2 microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, suppressed the activation of the p38 MAPK signaling pathway, decreased the expression levels of inflammatory factors NO, IL-1β, IL-6, and TNF-α, and increased the expression level of anti-inflammatory factor IL-10. The findings suggested that THP can significantly ameliorate the pain symptoms of DNP rats possibly by inhibiting the inflammatory response caused by M1 polarization of microglia via the p38 MAPK pathway.
Animals ; Berberine Alkaloids ; Blood Glucose/metabolism* ; Diabetes Mellitus ; Diabetic Neuropathies/genetics* ; Interleukin-10 ; Interleukin-6/metabolism* ; Lipopolysaccharides/pharmacology* ; Microglia ; Neuralgia/metabolism* ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Spinal Cord/metabolism* ; Streptozocin/therapeutic use* ; Tumor Necrosis Factor-alpha/metabolism* ; p38 Mitogen-Activated Protein Kinases/metabolism*

The goal of treatment of metabolic syndrome is the prevention of diabetes and cardiovascular events. A series of novel tetrahydrocoptisine quaternary ammonium compounds were prepared to evaluate their action of hypoglycemia and hypolipidemia for finding the therapeutic agents of metabolic syndrome. Starting from the coptisine hydrochloride (2), fifteen target compounds were synthesized by reduction and substitution of the 7-N position. All of the target compounds were characterized by 1H NMR and HR-MS. Their hypoglycemic activities were evaluated in HepG2 cell and hypolipidemic activities of compounds with better hypoglycemic activity were tested further in vivo. Results indicated that compounds 5, 7, 8 and 9 exhibited better hypoglycemic activities in vitro and compounds 5 and 8 exhibited good hypolipidemic activities in high-fat-diet (HFD) induced hyperlipidemia mice and (or) hamsters. However, the activity is not as good as simvastatin.
Animals ; Berberine Alkaloids ; chemical synthesis ; chemistry ; pharmacology ; Cholesterol ; blood ; Glucose ; metabolism ; Hep G2 Cells ; Humans ; Hyperlipidemias ; blood ; Hypoglycemic Agents ; chemical synthesis ; chemistry ; pharmacology ; Hypolipidemic Agents ; chemical synthesis ; chemistry ; pharmacology ; Mesocricetus ; Mice ; Molecular Structure ; Quaternary Ammonium Compounds ; chemical synthesis ; chemistry ; pharmacology ; Structure-Activity Relationship ; Triglycerides ; blood

OBJECTIVETo evaluate the effect of additives on absorption of Coptis chinensis total alkaloid and their pharmacokinetics in mice.

METHODThe mice were fed with the mixture of C. chinensis total alkaloids and additives (1:1). And then the feces and orbital blood were taken to detect the content of total alkaloids by HPLC and their pharmacokinetics.

RESULTGlutin could make the absorption of jatrorrhizine, coptisine, berberine and total alkaloids increased by 30%. Tween 80 and arabic gum did not affect the absorption of berberine, but inhibit that of other alkaloids. There had no influence of lecithin on the absorption of alkaloids. The peak time of total alkaloids in blood were 2 h (Cmax 1=5.9 mg x L(-1)) and 5.0 h (Cmax 2=3.4 mg x L(-1)), respectively, AUC was 17.6 mg x h x L(-1), the elimination of Half-life t1/2 was 5.2 h. After addition of glutin, the peak time of total alkaloids in blood were 1.5 h (Cmax 1=7.6 mg x L(-1)) and 4.8 h (Cmax 2=8.5 mg x L(-1)), AUC was up to 31.1 mg x h(-1) x L(-1), the elimination of Half-life t1/2 was 6.2 h.

CONCLUSIONGlutin could accelerate the mice on the absorption of C. chinensis total alkaloids, to extend the elimination half-life, increase the blood concentration and bioavailability.

Absorption ; drug effects ; physiology ; Alkaloids ; blood ; pharmacokinetics ; Animals ; Berberine ; analogs & derivatives ; blood ; Chromatography, High Pressure Liquid ; Coptis ; chemistry ; Diterpenes ; pharmacology ; Drug Interactions ; Female ; Food Additives ; pharmacology ; Half-Life ; Male ; Mice

A sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the quantification of tetrahydropalmatine (THP) and dehydrocorydaline (DHC) in rat plasma. The compounds were simply pretreated by protein precipitation using acetone. Chromatographic separation was achieved on a reversed-phase SB-C18 column with the mobile phase of acetonitrile-ammonium acetate (0. 1% acetic acid) and step gradient elution resulted at a flow rate of 0.80 mL x min(-1). A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in the positive ion mode. Quantification was performed using multiple reaction monitoring (MRM) of the transitions m/z 356. 2 --> m/z 191.9 and m/z 366. 2 --> m/z 350.2 for THP and DHC respectively. The method showed excellent linearity over the concentration range 1-1 000 ng x mL(-1) of two components (r = 0.994 for THP and r = 0.992 for DHC). The low limits of quantification were both 1 ng x mL(-1). The extract recoveries of analytes were from 71.71% to 91.59% for THP and from 83.27% to 103.15% for DHC. The precisions, the accuracy and the stability of the analytes meet the requirements. The method was applied to a pharmacokinetic study of THP and DHC after oral administration of the total alkaloid extraction of Rhizoma Corydalis (Yanhusuo). The AUC were (1.90 +/- 0.04), (2.58 +/- 0.08) and (4.34 +/- 0.19) mg x L(-1) h for low, medium and high doses of THP, respectively. While the DHC concentrations in plasma of low dose and medium dose were too lower to be detected, the AUC of high dose was (0.0896 +/- 0.0002) mg x L(-1) h.
Administration, Oral ; Alkaloids ; administration & dosage ; blood ; isolation & purification ; metabolism ; pharmacokinetics ; Animals ; Area Under Curve ; Berberine Alkaloids ; blood ; pharmacokinetics ; Chromatography, Liquid ; Corydalis ; chemistry ; Male ; Plants, Medicinal ; chemistry ; Random Allocation ; Rats ; Rats, Wistar ; Spectrometry, Mass, Electrospray Ionization ; Tandem Mass Spectrometry

OBJECTIVETo study the protective effect of dl-tetrahydropalmatine(dl-THP) on liver injury induced by carbon tetrachloride (CC4) in mice.

METHODMice were administracted with dl-tetrahydropalmatine ip 20, 40 mg x kg(-1) daily for 9 d respectively, and then actue liver injury model was induced by 0.1% carbon tetrachloride ip 20 mL x kg(-1). The mice were killed 17 h after injection ip of CCl4, serum alanine and aspartate aminotransferase (ALT and AST) activity were measured, and maleic dialdehyde (MDA) and superoxide dismutase(SOD) activity in liver were detected.

RESULTdl-THP significantly reduced the level of serum ALT and AST, inhibited lipoperxidation in liver, while increased SOD activity in liver tissue. Degeneration of hepatocytes was obviously prevented in mice treated with dl-THP, and the liver histological structure was well maintained.

CONCLUSIONdl-THP has inhibitory effects on liver injury induced by CCl4 in mice. The mechanisms may be related with its effects of reducing lipid peroxidation product.

Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Berberine Alkaloids ; pharmacology ; Carbon Tetrachloride Poisoning ; Chemical and Drug Induced Liver Injury ; etiology ; metabolism ; pathology ; Female ; Lipid Peroxidation ; drug effects ; Liver ; metabolism ; pathology ; Male ; Malondialdehyde ; metabolism ; Mice ; Protective Agents ; pharmacology ; Random Allocation ; Superoxide Dismutase ; metabolism