Ginkgo diterpene lactones meglumine injection (GDLI) is a commercially available product used for neuroprotection. However, the pharmacokinetic properties of the prototypes and hydrolyzed carboxylic forms of the primary components in GDLI, i.e., ginkgolide A (GA), ginkgolide B (GB), and ginkgolide K (GK), have never been fully evaluated in beagle dogs. In this work, a simple, sensitive, and reliable method based on ultra-fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) was developed, and the prototypes and total amounts of GA, GB, and GK were determined in beagle dog plasma. The plasma concentrations of the hydrolyzed carboxylic forms were calculated by subtracting the prototype concentrations from the total lactone concentrations. For the first time, the pharmacokinetics of GA, GB, and GK were fully assessed in three forms, i.e., the prototypes, the hydrolyzed carboxylic forms, and the total amounts, after intravenous administration of GDLI in beagle dogs. It was shown that ginkgolides primarily existed in the hydrolyzed form in plasma, and the ratio of hydrolysates to prototype forms of GA and GB decreased gradually to a homeostatic ratio. All of the three forms of the three ginkgolides showed linear exposure of AUC to the dosages. GA, GB, and GK showed a constant half-life approximately 2.7, 3.4, and 1.2 h, respectively, which were consistent for the forms at three dose levels (0.3, 1.0, and 3.0 mg·kg) and after a consecutive injection of GDLI for 7 days (1.0 mg·kg).
Animals ; Dogs ; Ginkgo biloba ; chemistry ; Ginkgolides ; administration & dosage ; pharmacokinetics ; Lactones ; administration & dosage ; pharmacokinetics ; Plant Extracts ; administration & dosage ; pharmacokinetics ; Tandem Mass Spectrometry

A HPLC-MS/MS multiple-reaction monitoring (MRM) quantitative analysis was made to establish a determination method for drug concentrations of costunolide (Co) and dehydrocostuslactone (De) in blood samples in the positive ion mode, with diazepam as the internal standard substance, in order to study the pharmacokinetic process of sesquiterpene lactones costunolide and dehydrocostuslactone after the oral administration of Weichang'an pills, and provide an theoretical basis for further studies on the substance basis for the anti-diarrhea effect of Weichang'an pills. In the blood samples, Co and De showed a good linearity within concentration ranges 0.700 0-769.7, 2.510-956.0 μg x L(-1), respectively. The results of precision, stability and recovery experiences proved the stability and reliability of the plasma concentration determination method. After the oral administration, the concentrations of Co and De in plasma increased with the increase in dose, with T(max) between 10.65-12.98 h, indicating a long time to reach peak plasma concentrations; C(max) of costunolide and dehydrocostuslactone ranged between 3.750-5.450,15.34-44.52 μg x L(-1), respectively. The in vivo adsorption of Co and De conformed to the one-compartment model, with a longer time to attain the peak plasma concentrations. These results provided an experimental basis for revealing the active substance basis and clinical medication of Weichang'an pills.
Administration, Oral ; Animals ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; pharmacokinetics ; Lactones ; administration & dosage ; blood ; pharmacokinetics ; Male ; Rats ; Rats, Wistar ; Sesquiterpenes ; administration & dosage ; blood ; pharmacokinetics ; Tablets ; administration & dosage ; chemistry ; pharmacokinetics

OBJECTIVETo evaluate the analgesic efficacy and systemic anti-inflammation of preoperative cyclooxygenase-2 nonsteroidal antiinflammatory drug, rofecoxib, after total knee replacement (TKR).

METHODSThirty patients underwent elective knee replacement were randomly given oral rofecoxib 25 mg (group RE, n = 15) or placebo (group E, n = 15) 1 hour prior to surgery. All patients received epidural combined isoflurane anesthesia during surgery and patient-controlled epidural analgesia after surgery for 72 hrs (0.1 mg/ml morphine + 1.2 mg/ml bupivacaine + 0.02 mg/ml droperidol). Modified verbal rate scale was used to evaluate postoperative pain intensity. The outcomes included pain scores during rest and movement of knee joints and analgesia satisfaction. Daily morphine consumption was recorded. Circulation leucocyte and serum cytokine concentrations (including interleukin 6, interleukin 8, interleukin 10, Tumor necrosis factor-alpha) were determined before surgery, at the end of surgery, 2 h, 6 h, 12 h, 24 h and 48 h after surgery in two groups using RIA. The amount of intraoperative blood loss and postoperative drainage from the knees were measured.

RESULTSThe pain scores were significantly less in the group RE than in group E during rest and knee joints movement on the first and second postoperative day, with an improvement in total analgesia satisfaction (P < 0.05). The mean dose of morphine for first 24 h was (8.1 +/- 1.5) mg in the E group and (6.8 +/- 0.7) mg in the RE group (t = -2.71, P < 0.01). Leucocyte and neutrophil counts were much higher in group E than in group RE at 12 h, 24 h post-operatively (P < 0.05). Serum TNF-alpha concentration was significantly lower in group RE than group E at the end of surgery, 6 h, 12 h postoperatively, as well as IL6 at 48 h, IL8 at 24h after surgery (P < 0.05). There were no significant differences in respect to the amount of intraoperative and postoperative blood loss between two groups (P > 0.05).

CONCLUSIONPreoperative cyclooxygenase-2-specific nonsteroidal anti-inflammatory drug rofecoxib increases analgesia satisfaction, reduces opioid requirement and demonstrates a systemic anti-inflammatory effect after TKR.

Administration, Oral ; Aged ; Analgesia, Epidural ; Anti-Inflammatory Agents ; Arthroplasty, Replacement, Knee ; Cyclooxygenase 2 Inhibitors ; administration & dosage ; Drug Therapy, Combination ; Female ; Humans ; Lactones ; administration & dosage ; Male ; Middle Aged ; Morphine ; administration & dosage ; Pain, Postoperative ; drug therapy ; prevention & control ; Premedication ; Sulfones ; administration & dosage

Due to its serious comorbidities and high prevalence, obesity is one of the heaviest burdens for public health. Although diet, exercise and behavioral modification are the first-line treatment for obesity, their outcomes are not satisfactory. The goal of this article is to review currently available anti-obesity drugs so that physicians may apply the principle of pharmacologic treatment for obesity to obese patients in the real clinical situation. Orlistat, phentermine, diethylpropion, mazindol, and phendimetrazine have been approved as anti-obesity drugs by Korea food and drug administration and administered to patients in Korea. Besides, several non-approved drugs, including fluoxetine, bupropion, topiramate and zonisamide, are being used for weight reduction. Among these drugs, orlistat has been studied most and is the only approved drug for long-term weight management. On the other hand, the rest of the approved drugs lack the evidence of safety issues on the long-term administration. Considering that the non-approved drugs have only a small body of clinical trial results for their efficacy and safety as anti-obesity drugs, it is not appropriate to use them as a first-line therapy in obesity. Because several new medicines and combination therapies are under investigations, more drug therapy options seem to be available in this field in coming years. Although the properly executed pharmacologic treatment is a good option for weight reduction, physicians should recognize that diet, exercise, and behavioral modification are essential to all obese patient and that pharmacologic treatment has several limitations until now.
Anti-Obesity Agents ; Bupropion ; Comorbidity ; Diet ; Diethylpropion ; Fluoxetine ; Fructose ; Hand ; Humans ; Isoxazoles ; Korea ; Lactones ; Mazindol ; Morpholines ; Obesity ; Phentermine ; Prevalence ; Public Health ; United States Food and Drug Administration ; Weight Loss

OBJECTIVETo study the pharmacokinetics and bioavailability of ginkgolides sustained-release tablet and conventional tablet in Beagle dogs.

METHODThe concentrations of ginkgolides in plasma were determined by LC-MS. The main pharmacokinetic parameters of ginkgolides sustained-release tablet and conventional tablet in vivo were obtained using Pharmacokinetic software DAS 2.0.

RESULTThe C(max) of grinkgolide A in ginkgolide sustained-release tablet and conventional tablet were 443.51, 1 039.30 microg x L(-1), respecitvely. t(max) were 2.92, 1.08 h, respectively. AUC(0-12h) were 1 808.21, 2 041.37 h x microg(-1) x L(-1), respectively. MRT were 5.18, 3.18 h, respectively. The relative bioavailability of ginkgolides A was 88.58%. The C(max) of ginkgolide B in ginkgolide sustained-release tablet and conventional tablet were 407.13, 547.38 microg x L(-1), respectively. t(max) were 2.92, 1.08 h, respectively. AUC(01-12 h) were 1 987.31, 1 748.04 h x microg(-1) x L(-1), respectively. MRT were 6.05, 4.98 h, respectively. The relative bioavailability of ginkgolides B was 113.69%.

CONCLUSIONThe ginkgolides sustained-release tablets have good sustained release characteristics and are bioequivalent to the reference formulation.

Animals ; Area Under Curve ; Biological Availability ; Chromatography, High Pressure Liquid ; methods ; Delayed-Action Preparations ; administration & dosage ; pharmacokinetics ; Dogs ; Ginkgolides ; administration & dosage ; analysis ; pharmacokinetics ; Lactones ; analysis ; Male ; Mass Spectrometry ; methods ; Quality Control ; Tablets ; administration & dosage ; pharmacokinetics ; Therapeutic Equivalency

AIMTo investigate protective effects of ginkgolide B (GB) in different administration modes on glutamate-induced neuronal damage.

METHODSEssential GB were obtained by supercritical CO2 fluid extraction. Glutamate excitotoxicity were examined in primary cultures from neonatal Wistar rat, by using of Trypan blue dye staining, testing the lactate dehydrogenase leakage from cultured neurons and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) method. The protective effects of GB in different administration modes (pre-treatment and post-treatment) were adopted and compared with the NMDA receptor uncompetitive antagonist-MK-801 in acute-treatment.

RESULTSTreatment with GB in two administration modes both could increase ratio of surviving neuron, decrease LDH efflux and reduce ratio of neuron apoptosis in different degree, depended on dose in certain range. The protective effect of pre-treatment was superior to post-treatment, but inferior to MK-801.

CONCLUSIONGB can protect neurons against glutamate damage, and preventive using has more efficiency. The potential mechanism of its neural protection may be not only related to PAF receptor. If the predominant protection effect of GB in pretreatment is considered, precautionary intervention to high-risk population could have more value.

Animals ; Cells, Cultured ; Dizocilpine Maleate ; pharmacology ; Ginkgolides ; administration & dosage ; pharmacology ; Glutamic Acid ; adverse effects ; Hippocampus ; drug effects ; metabolism ; Lactones ; administration & dosage ; pharmacology ; Neurons ; drug effects ; metabolism ; Rats ; Rats, Wistar

Overexpression of cyclooxygenase-2 (COX-2) has been associated with hepatocarcinogenesis. Inhibitors of COX-2 have proapoptotic and antiproliferative effects on malignant tumors and inhibit tumor invasion to the surrounding tissues. We report here a case of complete regression of advanced hepatocellular carcinoma (HCC) during COX-2 inhibitor administration. An eighty-year-old female was diagnosed as an advanced HCC, which was associated with HCV infection. She received COX-2 inhibitor for 3 months due to degenerative arthritis of both knees. Tumor enhancement on arterial phase CT completely disappeared without specific treatment for the HCC, and the tumor size decreased on the follow-up CT scan.
Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Carcinoma, Hepatocellular/*drug therapy ; Cyclooxygenase 2 Inhibitors/administration & dosage/*therapeutic use ; Diclofenac/administration & dosage/analogs & derivatives/therapeutic use ; Female ; Humans ; Lactones/administration & dosage/therapeutic use ; Liver Neoplasms/*drug therapy ; Pyrazoles/administration & dosage/therapeutic use ; Sulfonamides/administration & dosage/therapeutic use ; Sulfones/administration & dosage/therapeutic use

Obesity is associated with a reduction in life expectancy and an increase in mortality from cardiovascular diseases, cancer, and other causes. The U.S. Preventive Service Task Force (USPSTF) recommends screening all adults for obesity. Clinicians should offer or refer patients with a body mass index of 30 kg/m2 or higher to intensive, multicomponent behavioral interventions. Behavioral interventions can lead to a moderate weight loss and improvement in blood sugar and other risk factors for cardiovascular disease. Behavioral interventions decreased the incidence of diabetes diagnosis by about 50% over 2 to 3 years. Orlistat, phentermine, diethylpropion, phendimetrazine, mazindol have been approved as anti-obesity drugs by Korea Food and Drug Administration. The U.S. Food and Drug Administration approved lorcaserin and phentermine plus topiramate combination for treatment of obesity in 2012.
Adult ; Advisory Committees ; Anti-Obesity Agents ; Benzazepines ; Blood Glucose ; Body Mass Index ; Cardiovascular Diseases ; Diethylpropion ; Fructose ; Humans ; Incidence ; Korea ; Lactones ; Life Expectancy ; Mass Screening ; Mazindol ; Morpholines ; Obesity ; Phentermine ; Risk Factors ; United States Food and Drug Administration ; Weight Loss

OBJECTIVEThis paper reports a method based on liquid chromatography coupled with electrospray mass spectrometry for the analysis of terpenoids in ginkgo laminae.

METHODThe analysis was performed on ZORBAX RX-C18 (2.1 mm x 150 mm) column with methanol-water(with gradient) as mobile phase at a flow rate of 0.25 mL x min(-1), and column temperature of 25 degrees C. Analyses were carried out in the selected ion monitoring (SIM) mode.

RESULTGinkgolides (GA, GB and GC) and bilobalide were quantitatively detected by external standardization with linear in the range of 4.04-1.012 x 10(2) ng, with coefficient and relative standard deviations being 0.993 7-0.999 8 and 2.50%-4.73%. LC-ESI-MS shows a greatly increased sensitivity compared with other methods. The detection limit of this method by SIM was 1.47 x 10(-3)-0.320 microg x mL(-1).

CONCLUSIONThis method is specific, reproducible, rapidly and permits quantitative analyses of ginkgolides and bilobalide in different samples with simple pre-purification steps.

Chromatography, Liquid ; Cyclopentanes ; analysis ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; isolation & purification ; Furans ; analysis ; Ginkgo biloba ; chemistry ; Ginkgolides ; analysis ; Lactones ; analysis ; Plant Leaves ; chemistry ; Plants, Medicinal ; chemistry ; Spectrometry, Mass, Electrospray Ionization ; Tablets

AIMTo study the effect of uvarigrin on mitochondrial dependent pathway during the apoptosis induced by it in MDR KBv200 cells and their parental sensitive KB cells.

METHODSMTT assay was used to detect the cytotoxic effect of uvarigrin on KBv200 and KB cells. Annexin V FITC staining identified uvarigrin-induced apoptosis in KBv200 and KB cells. These cells underwent incubation with DCFH-DA, or DiOC6, followed by flowcytometry for the measurement of reactive oxygen species (ROS) and mitochondrial membrane potential (deltapsim), respectively. The Western blotting analysis was performed on Caspase-9 activation.

RESULTSUvarigrin inhibited the growth of KBv200 cells and KB cells in vitro. Most of the uvarigrin-induced cells death was found to be due to apoptosis, as determined by Annexin V FITC staining. During the apoptosis, the level of ROS increased while the level of deltapsim decreased in a time-dependent manner. Uvarigrin triggered Caspase-9 activation.

CONCLUSIONUvarigrin induced apoptosis in KBv200 cells and KB cells probably through a mitochondria-dependent pathway.

Antineoplastic Agents, Phytogenic ; administration & dosage ; isolation & purification ; pharmacology ; Apoptosis ; drug effects ; Caspase 9 ; metabolism ; Cell Proliferation ; drug effects ; Dose-Response Relationship, Drug ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Furans ; administration & dosage ; isolation & purification ; pharmacology ; Humans ; KB Cells ; Lactones ; administration & dosage ; isolation & purification ; pharmacology ; Membrane Potentials ; drug effects ; Mitochondria ; physiology ; Plants, Medicinal ; chemistry ; Reactive Oxygen Species ; metabolism ; Uvaria ; chemistry