Kawasaki disease with peritonsillar abscess as the first symptom: A case report.

BACKGROUND: Kawasaki disease (KD), also known as mucocutaneous lymph node syndrome, is an acute, self-limiting vasculitis of unknown aetiology that mainly involves the medium and small arteries and can lead to serious cardiovascular complications, with a 25% incidence of coronary artery aneurysms. Periton-Sillar abscesses are a rare symptom of KD and is easily misdiagnosed at its early stages. CASE SUMMARY: A 5-year-old boy who presented to a community hospital with a 3-d fever, difficulty in opening his mouth, and neck pain and was originally treated for throat infection without improvement. On the basis of laboratory tests, ultrasound of submandibular and superficial lymph nodes and computed tomography of the neck, the clinician diagnosed the periamygdala abscess and sepsis that did not resolve after antibiotic therapy. On the fifth day of admission, the child developed conjunctival congestion, prune tongue, perianal congestion and desquamation, and slightly stiff and swollen bunions on both feet. A diagnosis of KD was reached with complete remission after intravenous immunoglobulin treatment. CONCLUSION: Children with neck pain, lymph node enlargement, or airway obstruction as the main manifestations are poorly treated with intravenous broad-spectrum antibiotics. Clinicians should not rush invasive operations such as neck puncture, incision, and drainage and should be alert for KD when it cannot be explained by deep neck space infection and early treatment with aspirin combined with gammaglobulin.

Population pharmacokinetics of nalbuphine in patients undergoing general anesthesia surgery.

Purpose: The aim of this study was to build a population pharmacokinetics (PopPK) model of nalbuphine and to estimate the suitability of bodyweight or fixed dosage regimen. Method: Adult patients who were undergoing general anesthetic surgery using nalbuphine for induction of anesthesia were included. Plasma concentrations and covariates information were analyzed by non-linear mixed-effects modeling approach. Goodness-of-fit (GOF), non-parametric bootstrap, visual predictive check (VPC) and external evaluation were applied for the final PopPK model evaluation. Monte Carlo simulation was conducted to assess impact of covariates and dosage regimens on the plasma concentration to nalbuphine. Results: 47 patients aged 21-78 years with a body weight of 48-86 kg were included in the study. Among them, liver resection accounted for 14.8%, cholecystectomy for 12.8%, pancreatic resection for 36.2% and other surgeries for 36.2%. 353 samples from 27 patients were enrolled in model building group; 100 samples from 20 patients were enrolled in external validation group. The results of model evaluation showed that the pharmacokinetics of nalbuphine was adequately described by a two-compartment model. The hourly net fluid volume infused (HNF) was identified as a significant covariate about the intercompartmental clearance (Q) of nalbuphine with objective function value (OFV) decreasing by 9.643 (p < 0.005, df = 1). Simulation results demonstrated no need to adjust dosage based on HNF, and the biases of two dosage methods were less than 6%. The fixed dosage regimen had lower PK variability than the bodyweight regimen. Conclusion: A two-compartment PopPK model adequately described the concentration profile of nalbuphine intravenous injection for anesthesia induction. While HNF can affect the Q of nalbuphine, the magnitude of the effect was limited. Dosage adjustment based on HNF was not recommended. Furthermore, fixed dosage regimen might be better than body weight dosage regimen.

A Validated UHPLC-MS/MS Method for Determination of Nalbuphine in Human Plasma and Application for Pharmacokinetic Study of Patients Undergoing General Anesthesia.

Nalbuphine was a semisynthetic opioid analgesic widely used in the treatment of both acute and chronic pain. We developed and validated a rapid, simple and sensitive method by ultra-performance liquid chromatography-tandem mass spectrometry (MS/MS) for the simultaneous quantitation of nalbuphine in human plasma, and we reported the pharmacokinetic features of patients during general anesthesia for abdominal surgery. Sample separation was achieved on a Kinetex Phenyl-Hexyl column (50 × 2.1 mm, 1.7 µm) after simple protein precipitation with acetonitrile. The mobile phase was composed of acetonitrile and 3 mM of ammonium acetate aqueous solution with 0.1% formic acid. Gradient elution was used in 4.5 min with a flow rate of 0.5 mL/min at 40°C. MS detection using AB Sciex QTRAP 5500 mass spectrometer was characterized by electrospray ionization for positive ions in multiple reaction monitoring mode. Quantitative ion pairs were m/z 358.4 â†’ 340.1 for nalbuphine and m/z 340.0 â†’ 268.3 for nalmefene, which were used as the internal standard (IS). The calibration curves showed good linearity (r2>0.99) over concentration range of 0.1-500 ng/mL. The intra-and inter-batch precisions were within 10.67%, and accuracy ranged from 94.07 to 105.34%. The IS-normalized matrix factors were 1.02-1.03 with RSD% (≤5.82%). The recoveries ranged from 101.09 to 106.30%. In conclusion, a rapid, simple, sensitive and economical analytical method was developed and validated to detect the concentration in plasma samples obtained from patients receiving nalbuphine intravenous injection and was successfully applicated to human pharmacokinetic studies of nalbuphine.

Pharmacokinetic Study of Nalbuphine in Surgical Patients Undergoing General Anesthesia with Varying Degrees of Liver Dysfunction.

Purpose: This study aimed to characterize the pharmacokinetics of nalbuphine in patients undergoing general anesthesia with varying degrees of liver dysfunction. Patients and Methods: Twenty-four patients were enrolled and divided into three cohorts based on liver function: normal liver function (n = 13), mild liver dysfunction (n = 5), and moderate/severe liver dysfunction (n = 6). During the induction of anesthesia, they received 15 mg of nalbuphine intravenously. Venous blood samples were collected from each patient. The plasma concentration of nalbuphine was determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The pharmacokinetic parameters of nalbuphine were calculated by non-compartmental analysis (NCA) using Phoenix WinNonlin software. Results: Compared with the normal liver function group, the plasma elimination half-life (T1/2) of nalbuphine was increased by approximately 33% in the moderate/severe liver dysfunction group (2.66 h vs 3.54 h, P<0.05), and the volume of distribution (Vd) increased by approximately 85% (100.08 L vs 184.95 L, P<0.05). Multivariate analysis revealed that weight and platelet were associated with clearance (CL); total bilirubin as an independent factor was associated with T1/2, and weight associated with area under the curve (AUC(0→∞)) independently. Conclusion: The T1/2, mean residence time, and Vd of nalbuphine in patients with moderate/severe liver dysfunction were prolonged or increased significantly compared with those in the normal liver function group. These data suggest that it may need to be used with caution when nalbuphine is administered to patients with moderate or severe liver dysfunction.

Mechanisms and Molecular Targets of BuShenHuoXue Formula for Osteoarthritis.

The aim was to identify latent mechanism of BuShenHuoXue (BSHX) formula for the management of osteoarthritis (OA) through the network pharmacology approach and experimental validation. We obtained OA-related targets through the Gene Expression Omnibus database and bioactive ingredients with corresponding targets in the formula via the Traditional Chinese Medicine Systems Pharmacology database. Subsequently, networks of the protein-protein interaction and compound-disease target were created and enrichment analysis was implemented. Furthermore, in vitro, IL-1ß was applied to rat chondrocytes to mediate apoptosis through inflammation and the Alcian blue and type II collagen staining was used to observe cell morphology. The TUNEL and DAPI staining was performed to observe chondrocyte apoptosis, and the apoptosis rates were gauged via flow cytometry. In addition, we utilized Western blot and PCR to detect the protein and mRNA expression, respectively. A total of 104 potential chemicals and 42 intersecting targets were screened out. Quercetin and luteolin from BSHX formula were principal ingredients. The experiment validated quercetin might suppress chondrocyte apoptosis mediated by IL-1ß and reduce SELE, MMP2, and COL1 expression. Via the AGE-RAGE signaling pathway in diabetic complications, quercetin could aim at SELE, MMP2, and COL1 and exert antagonistic effects against OA.

A Validated HPLC-MS/MS Method for Quantification of Methotrexate and Application for Therapeutic Drug Monitoring in Children and Adults with Non-Hodgkin Lymphoma.

PURPOSE: A simple, rapid and reliable method to quantify methotrexate (MTX) in human plasma by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was established and validated in two laboratories. PATIENTS AND METHODS: Sample separation was achieved on a Synergi Hydro-RP column (50 mm×2.0 mm, 2.5 µm) with a gradient elution program in 3.5 min after a simple protein precipitation with methanol (MeOH) and acetonitrile (ACN) (1:1). About 5 mM ammonium formate aqueous solution with 0.2% formic acid and ACN were used as mobile phase with a flow rate of 0.5 mL/min at 40 °C. Mass spectrometry detection using AB Sciex Triple Quad 4500 mass spectrometer (4500 QQQ) and Qtrap 5500 mass spectrometer (5500 Q-trap) were both characterized by electrospray ionization (ESI) for positive ions in multiple reaction-monitoring (MRM) mode. Quantitative ion pairs were m/z 455.1→m/z 308.0 for MTX and m/z 248.1→m/z 121.0 for tinidazole (TNZ) used as internal standard (IS). RESULTS: Linear calibration curves were generated over the range of 5-1000 ng/mL (r2> 0.99) on both the 4500 QQQ and 5500 Q-trap, both of the intra- and inter-batch precision were less than 7.67% and accuracy ranged from 96.33% to 108.94%. The recovery and matrix effect were 82.20-93.98% and 102.69-105.28%, respectively. CONCLUSION: An analytical method transfer was achieved by re-verification in two laboratories to ensure stability and reproducibility and this method has been applied for therapeutic drug monitoring (TDM) successfully in children and adults with NHL, and during routine TDM, two delayed elimination of MTX cases were observed and analyzed.

Determining novel candidate anti-hepatocellular carcinoma drugs using interaction networks and molecular docking between drug targets and natural compounds of SiNiSan.

BACKGROUND: SiNiSan (SNS) is an ancient traditional Chinese medicine (TCM) used to treat liver and spleen deficiencies. We studied the unique advantages of using SNS to treat hepatocellular carcinoma (HCC) with multiple components and targets to determine its potential mechanism of action. METHODS: The active compounds from the individual herbs in the SNS formula and their targets were mined from Traditional Chinese Medicine Systems Pharmacology Database (TCMSP). HCC-associated targets were collected from the TCGA and GEO databases and samples were collected from patients with stage III hepatocellular carcinoma. A compound-disease target network was constructed, visualized, and analyzed using Cytoscape software. We built a protein-protein interaction (PPI) network using the String database. We enriched and analyzed key targets using GSEA, GO, and KEGG in order to explore their functions. Autodock software was used to simulate the process of SNS molecules acting on HCC targets. RESULTS: A total of 113 candidate compounds were taken from SNS, and 64 of the same targets were chosen from HCC and SNS. The predominant targets genes were PTGS2, ESR1, CHEK1, CCNA2, NOS2 and AR; kaempferol and quercetin from SNS were the principal ingredients in HCC treatment. The compounds may work against HCC due to a cellular response to steroid hormones and histone phosphorylation. The P53 signaling pathway was significantly enriched in the gene set GSEA enrichment analysis and differential gene KEGG enrichment analysis. CONCLUSIONS: Our results showed that the SNS component has a large number of stage III HCC targets. Among the targets, the sex hormone receptors, the AR and ESR1 genes, are the core targets of SNS component and the most active proteins in the PPI network. In addition, quercetin, which has the most targets, can act on the main targets (BAX, CDK1, CCNB1, SERPINE1, CHEK2, and IGFBP3) of the P53 pathway to treat HCC.

Effects of multidose simvastatin co-administration on pharmacokinetic profile of apatinib in rats by UPLC-MS/MS.

Apatinib, a small molecule anti-angiogenic tyrosine kinase inhibitor is used extensively to treat advanced gastric cancer and simvastatin (SV) is often co-prescribed to treat cardiovascular disease in cancer patients. As both apatinib and SV are metabolized primarily by cytochrome P450 variant CYP3A4, they are likely to interact. Therefore, the potential effect of SV co-administration on pharmacokinetics of apatinib in Sprague-Dawley male rats is demonstrated for the first time.Sixteen rats were randomly divided into two groups (n = 8), 2 mg/kg SV orally co-administrated for seven days (group B) and the corresponding control group (group A). Apatinib concentrations of rat plasma samples were detected by ultra-performance liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were calculated using non compartmental methods.Co-administration of SV for seven days significantly increased area under curve (AUC(0-t)), AUC(0-∞) and maximum plasma concentration of apatinib by 2.4-, 2.4-, and 2.7-fold, respectively while decreasing apparent volume of distribution and clearance by 81.7 and 73.9%, respectively.These findings suggest that concomitant administration of SV with 7 days may have inhibited the metabolism of apatinib in rats.

Efficacy and safety of HER2 inhibitors in combination with or without pertuzumab for HER2-positive breast cancer: a systematic review and meta-analysis.

BACKGROUND: Although the dual anti-HER2 therapy, namely, pertuzumab plus trastuzumab and docetaxel, has shown promising results in HER2+ breast cancer patients, whether the dose, efficacy and safety of this treatment differs from those of other pertuzumab-based dual anti-HER2 therapies remain controversial. This systematic review evaluates the efficacy and safety of H (trastuzumab or trastuzumab emtansine ± chemotherapy) + P (pertuzumab) compared with those of H in HER2+ breast cancer patients. METHODS: A comprehensive search was performed to identify eligible studies comparing the efficacy and safety of H + P versus H. The pathologic complete response (pCR), median progression-free survival (PFS) and overall survival (OS) were the primary outcomes, and safety was the secondary outcome. A subgroup analysis of pCR according to hormone receptor (HR) status was performed. All analyses were conducted using STATA 11.0. RESULTS: Twenty-six studies (9872 patients) were identified. In the neoadjuvant setting, H + P significantly improved the pCR [odds ratio (OR) = 1.33; 95% confidence interval (CI), 1.08-1.63; p = 0.006]. In the metastatic setting, H + P significantly improved PFS [hazard ratios (HRs) = 0.75; 95% CI, 0.68-0.84; p < 0.001]. There was a trend towards better OS but that it did not reach statistical significance (HRs = 0.81; 95% CI, 0.64-1.03; p = 0.082). A subgroup analysis revealed that the HER2+/HR- patients who received H + P showed the highest increase in the pCR. Rash, diarrhea, epistaxis, mucosal inflammation, and anemia were significantly more frequently observed with H + P than with H, whereas myalgia was less frequent (OR = 0.91; 95% CI, 0.82-1.01; p = 0.072), and no significant difference in cardiac toxicity was observed between these therapies (OR = 1.26; 95% CI, 0.81-1.95; P = 0.309). CONCLUSIONS: Our study confirms that H + P is superior to H in the (neo)adjuvant treatment of HER2+ breast cancer, and increase the risk of acceptable and tolerable toxicity (rash, diarrhea, epistaxis, mucosal inflammation, and anemia). TRIAL REGISTRATION: A systematic review protocol was registered with PROSPERO (identification number: CRD42018110415 ).

Quantification of 1D, a novel derivative of curcumin with potential antitumor activity, in rat plasma by liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study in rats.

CONTEXT: 1 D is a novel derivative of curcumin and shows very promising antitumor activities in various cancer cell lines. OBJECTIVE: To characterize its preclinical pharmacokinetic profiles, a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of 1 D in rat plasma. MATERIALS AND METHODS: An aliquot of 50 µL plasma sample was processed by protein precipitation with methanol. Chromatographic separation was accomplished on a Zorbax Eclipse Plus C18 column (2.1 mm × 50 mm, 1.8 µm) with a gradient elution system (water/0.1% formic acid and methanol). Detection was performed by multiple reaction monitoring (MRM) mode using electrospray ionization in the positive ion mode. The optimized fragmentation transition for 1 D was m/z 491.2 â†’ 361.2. RESULTS: The method was linear over the concentration range of 5-1000 ng/mL. The intra- and inter-day precisions were less than 9.8% and the accuracy was within ± 14.5%. The mean recovery of 1 D ranged from 102.5 to 105.9%. No matrix effects and significant sample loss during sample processing were observed. The validated method has been successfully applied to a pharmacokinetic study in rats after intravenous administration of 1 D. Non-compartmental pharmacokinetic parameters, including half-life (t1/2), apparent volume of distribution (Vz), clearance (CLz), and area under the concentration-time curve (AUC(0-t)) were 4.92 h, 46.56 L/kg, 6.33 L/h/kg, and 806.70 µg/L/h, respectively. DISCUSSION AND CONCLUSIONS: Results demonstrated that 1 D displayed favourable pharmacokinetic properties for further in vivo pharmacologic evaluation, which could be facilitated by the validated LC-MS/MS method.

Ceritinib Alone for Crizotinib-naive Versus Crizotinib-pretreated for Management of Anaplastic Lymphoma Kinase-rearrangement Non-Small-cell Lung Cancer: A Systematic Review.

Ceritinib shows a promising efficacy in patients with anaplastic lymphoma kinase (ALK)-rearrangement non-small-cell lung cancer (NSCLC). The present systematic review determined the whole body and intracranial effectiveness and safety of ceritinib in crizotinib-naive versus crizotinib-pretreated regimens in ALK-rearrangement NSCLC. A comprehensive search of databases, including PubMed, EMBASE, Ovid, Web of Science, and COCHRANE, was performed to identify clinical trials in English-language journals. We estimated the pooled progression-free survival (PFS) and overall response rate (ORR) for ceritinib in whole body and intracranial responses to find differences between crizotinib-naive and crizotinib-pretreated regimens. The intracranial disease control rate in both crizotinib-naive and crizotinib-pretreated regimens was also estimated. The pooled efficacy parameters were as follows: ORR, 56.9% (95% confidence interval [CI], 53.6%-60.1%); PFS, 8.26 months (95% CI, 6.18-11.07 months); intracranial ORR, 41.3% (95% CI, 35.3%-47.6%); and intracranial disease control rate, 79.8% (95% CI, 73.8%-84.7%). The pooled ceritinib for crizotinib-naive showed a trend toward greater ORR and longer PFS compared with ceritinib for crizotinib-pretreated (68.9% and 14.62 months vs. 48.2% and 6.32 months, respectively). The intracranial ORR for ceritinib as the initial regimen was 50.6% compared with 33.6% for crizotinib-pretreated. The discontinuation and dose reduction rates were 3.1% and 38.4%, respectively. The most common grade 3/4 adverse effects were increased alanine aminotransferase (25.5%), increased γ-glutamyltransferase (12.6%), and increased aspartate aminotransferase (11.1%). Ceritinib is an effective agent for both crizotinib-naive and crizotinib-pretreated patients with locally advanced or metastatic ALK-rearranged NSCLC. Ceritinib has significant activity in crizotinib-naive patients with brain metastases.

DL0410, a novel dual cholinesterase inhibitor, protects mouse brains against Aß-induced neuronal damage via the Akt/JNK signaling pathway.

AIM: 1,1'-([1,1'-Biphenyl]-4,4'-diyl)bis(3-(piperidin-1-yl)propan-1-one)dihydrochloride (DL0410) is a novel synthetic dual acetylcholinesterase (AChE)/butyrocholinesterase (BuChE) inhibitor, which has shown a potential therapeutic effect on Alzheimer's disease (AD). In this study we examined whether DL0410 produced neuroprotective effects in an AD cellular model and an Aß1-42-induced amnesia mouse model. METHODS: The in vitro inhibitory activities against AChE and BuChE were estimated using Ellman's assay. Copper-induced toxicity in APPsw-SY5Y cells was used as AD cellular model, the cell viability was assessed using MTS assay, and cell apoptosis was evaluated based on mitochondrial membrane potential detection. Aß1-42-induced amnesia mouse model was made in male mice by injecting aggregated Aß1-42 (2 µg in 2 µL 0.1% DMSO) into the right cerebral ventricle. Before and after Aß1-42 injection, the mice were orally administered DL0410 (1, 3, 9 mg·kg-1·d-1) or rivastigmine (2 mg·kg-1·d-1) for 3 and 11 d, respectively. Memory impairments were examined using Morris water maze (MWM) test and passive avoidance test. The expression levels of APP, CREB, BDNF, JNK and Akt in the mouse brains were measured with either immunohistochemistry or Western blotting. RESULTS: DL0410 exhibited in vitro inhibitory abilities against AChE and BuChE with IC50 values of 0.286±0.004 and 3.962±0.099 µmol/L, respectively, which were comparable to those of donepezil and rivastigmine. In APPsw-SY5Y cells, pretreatment with DL0410 (1, 3, and 10 µmol/L) decreased the phosphorylation of JNK and increased the phosphorylation of Akt, markedly decreased copper-stimulated Aß1-42 production, reversed the loss of mitochondrial membrane potential, and dose-dependently increased the cell viability. In Aß1-42-treated mice, DL0410 administration significantly ameliorated learning and memory deficits in MWM test and passive avoidance test. Furthermore, DL0410 administration markedly decreased Aß1-40/42 deposits in mouse cerebral cortices, and significantly up-regulated neurotrophic CREB/BDNF. Meanwhile, Akt/JNK signaling pathway may play a key role in the neuroprotective effect of DL0410. CONCLUSION: DL0410 ameliorates cognitive deficit and exerts neuronal protection in AD models, implicating this compound as a candidate drug for the prevention and therapy of AD.

Determination of salvianolic acid C in rat plasma using liquid chromatography-mass spectrometry and its application to pharmacokinetic study.

A sensitive and reliable LC-ESI-MS method for the determination of salvianolic acid C in rat plasma has been developed and validated. Plasma samples were prepared by liquid-liquid extraction with ethyl acetate and separated on a Zorbax SB-C18 column (3.5 µm, 2.1 × 100 mm) at a flow rate of 0.3 mL/min using acetonitrile-water as mobile phase. The detection was carried out by a single quadrupole mass spectrometer with electrospray ionization source and selected ion monitoring mode. Linearity was obtained for salvianolic acid C ranging from 5 to 1000 ng/mL. The intra- and inter-day precisions (RSD, %) didn't exceed 9.96%, and the accuracy (RE, %) were all within ±3.64%. The average recoveries of the analyte and internal standard were >89.13%. Salvianolic acid C was proved to be stable during all sample storage, preparation and analytic procedures. The validated method was successfully applied to pharmacokinetic study after oral and intravenous administration of salvianolic acid C to rats. The absolute oral bioavailability of salvianolic acid C was 0.29 ± 0.05%. This method was further applied to simultaneous determination of salvianolic acid A, salvianolic acid B and salvianolic acid C in rat plasma and showed good practicability.

Pharmacokinetic study of salvianolic acid D after oral and intravenous administration in rats.

A sensitive, specific and rapid LC-MS method was developed and validated for the determination of salvianolic acid D (SalD) in rat plasma. This method used a single quadrupole mass spectrometer with an electrospray ionization (ESI) source. A single ion monitoring scanning (SIM) mode was employed. It showed good linearity over the concentration range from 3.3 to 666.7 ng/mL for the determination of SalD. The R.S.D.% of intra-day and inter-day precision values were no more than 7.69%, and the accuracy was within 91%-104% at all quality control levels. This LC-MS method was applied to the pharmacokinetic study of SalD in rats. A two-compartmental model analysis was employed. The plasma concentrations at 2 min (C 2min) were 5756.06±719.61, 11,073.01±1783.46 and 21,077.58±5581.97 µg/L for 0.25, 0.5 and 1 mg/kg intravenous injection, respectively. The peak plasma concentration (C max) was 333.08±61.21 µg/L for 4 mg/kg oral administration. The area under curve (AUC0-t ) was 14,384.379±8443.184, 22,813.369±11,860.823, 46,406.122±27,592.645 and 8201.740±4711.961 µg/L·h for intravenous injection (0.25, 0.5 and 1 mg/kg) and oral administration (4 mg/kg), respectively. The bioavailability of SalD was calculated to be 4.159%±0.517%.

Artesunate down-regulates immunosuppression from colorectal cancer Colon26 and RKO cells in vitro by decreasing transforming growth factor ß1 and interleukin-10.

Immunosuppression is the main source of ineffective treatment on tumor, and the study aimed to investigate the effect of artesunate on tumor immunosuppression. Supernatants of re-cultivated murine colorectal cancer cell Colon26 and human colorectal cancer cell RKO after pre-treatment with or without artesunate were enrolled, and their effects on five immune parameters were assessed, including killing activity of natural killer (NK) and lymphocyte proliferation, as measured by MTT, and expressions of interleukin 2 receptor (IL-2R)α, CD3ε(+)ζ(+) and CD3ε(-)ζ(+) on lymphocytes, as analyzed by flow cytometry. Six immunosuppressive factors were measured by ELISA, including transforming growth factor (TGF) ß1, vascular endothelial growth factor (VEGF), IL-4, IL-6, IL-10, and prostaglandin E2 (PGE2). Then, multiple linear regression analysis was applied to reveal the correlation between immunosuppression and immunosuppressive factors, and was used to confirm the findings. It was shown that Colon26 and RKO cells secreted immunosuppressive factors and inhibited these five immune parameters steadily. After pretreatment with artesunate, immunosuppression from the two cells was down-regulated significantly (all P<0.05), and the concentrations of TGF-ß1 and IL-10 decreased greatly (all P<0.001). There were positive correlations between the down-regulation of immunosuppression and the decrease in TGF-ß1 or IL-10. Their combined potency attributed to decreased TGF-ß1 and IL-10 with respect to the down-regulating effect of artesunate on immunosuppression of NK killing, lymphocyte proliferation and expressions of IL-2Rα and CD3ε(+)ζ(+), was about 60%-90%. The present analysis provides clues that artesunate reverses the immunosuppression from Colon26 and RKO colorectal cancer cells by decreasing TGF-ß1 and IL-10. This is probably one of the anti-tumor mechanisms of artesunate.

[Pharmacokinetics of salvianolic acid A after single intravenous administration in Rhesus monkey].

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.

Pharmacokinetic study of salvianolic acid A in beagle dog after oral administration by a liquid chromatography-mass spectrometry method: a study on bioavailability and dose proportionality.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvianolic acid A (SAA) is one of the main water-soluble components isolated from Salvia miltiorrhiza Bunge. Pharmacological researches revealed that it had various curative activities after oral and intravenous administration, including beneficial effects on diabetes and its complications, cardioprotective effect, anti-platelet aggregation, and so on. However, there is no report regarding the pharmacokinetics of SAA in beagle dogs after oral administration up to now. AIM OF THE STUDY: To study the pharmacokinetics of different doses of SAA in beagle dogs and figure out the absolute bioavailability and dose proportionality of SAA after oral administration. MATERIALS AND METHODS: Male and female beagle dogs were orally administered SAA 5, 10 and 20mg/kg randomly. The plasma drug concentration was detected by a rapid, sensitive and reproducible liquid chromatography-mass spectrometry (LC-MS) method. The pharmacokinetic parameters were calculated from plasma concentration-time data using the DAS pharmacokinetic software Data Analysis System Version 3.0 program. RESULTS: After single-dose oral administration of SAA, the mean peak plasma concentration (Cmax) values for groups treated with 5, 10 and 20 mg/kg doses ranged from 14.38 to 38.18 µg/L, and the mean area under the concentration-time curve (AUC(0-t)) values ranged from 38.77 to 130.33 (µg/L·h). SAA showed lack of dose proportionality over the dose range 5-20mg/kg, based on the power model. However, the increase in systemic exposure with dose appeared linear. The absolute bioavailability was calculated to range from 1.47% to 1.84%. CONCLUSION: The pharmacokinetic properties of SAA in beagle dogs after oral administration were characterized as rapid oral absorption, quick clearance, and poor absolute bioavailability. Systemic exposure exhibited lack of dose proportionality over the dose range 5-20mg/kg. Furthermore, a readily preparative LC-MS method was demonstrated in this study for the research of traditional Chinese medicine.

The role of leptin in obesity and the potential for leptin replacement therapy.

Leptin (from the Greek word "lepto'' meaning "thin") is a 167-amino acid peptide hormone encoded by the obesity (ob) gene and secreted by white adipocytes. Blood leptin concentrations are increased in obese individuals. Leptin is a satiety hormone that provides negative feedback to the hypothalamus, controlling appetite and energy expenditure. Leptin binds to presynaptic GABAergic neurons to produce its effect, raising the distinct possibility that GABAergic axon terminals are the ultimate subcellular site of action for its effects. Released into the circulation, leptin crosses the blood-brain barrier and binds to leptin receptors, influencing the activity of various hypothalamic neurons, as well as encoding orexigenic and anorexigenic neuropeptides. Moreover, leptin affects a wide range of metabolic functions in the peripheral tissue. In this review, we discuss some physiologic functions of leptin, including effects on obesity and some effects of leptin replacement therapy.