Clonazepam release from poly(DL-lactide-co-glycolide) nanoparticles prepared by dialysis method

Aim of this work is to prepare poly(DL-lactide-co-glycolide) (PLGA) nanoparticles by dialysis method without surfactant and to investigate drug loading capacity and drug release. The size of PLGA nanoparticles was 269.9±118.7 nm in intensity average and the morphology of PLGA nanoparticles was spherical shape from the observation of SEM and TEM. In the effect of drug loading contents on the particle size distribution, PLGA nanoparticles were monomodal pattern with narrow size distribution in the empty and lower drug loading nanoparticles whereas bi- or trimodal pattern was showed in the higher drug loading ones. Release of clonazepam from PLGA nanoparticles with higher drug loading contents was slower than that with lower loading contents.     

A trace component of ginseng that inhibits Ca2+ channels through a pertussis toxin-sensitive G protein.

A crude extract from ginseng root inhibits high-threshold, voltage-dependent Ca2+ channels through an unknown receptor linked to a pertussis toxin-sensitive G protein. We now have found the particular compound that seems responsible for the effect: it is a saponin, called ginsenoside Rf (Rf), that is present in only trace amounts within ginseng. At saturating concentrations, Rf rapidly and reversibly inhibits N-type, and other high-threshold, Ca2+ channels in rat sensory neurons to the same degree as a maximal dose of opioids. The effect is dose-dependent (half-maximal inhibition: 40 microM) and it is virtually eliminated by pretreatment of the neurons with pertussis toxin, an inhibitor of G(o) and Gi GTP-binding proteins. Other ginseng saponins--ginsenosides Rb1, Rc, Re, and Rg1--caused relatively little inhibition of Ca2+ channels, and lipophilic components of ginseng root had no effect. Antagonists of a variety of neurotransmitter receptors that inhibit Ca2+ channels fail to alter the effect of Rf, raising the possibility that Rf acts through another G protein-linked receptor. Rf also inhibits Ca2+ channels in the hybrid F-11 cell line, which might, therefore, be useful for molecular characterization of the putative receptor for Rf. Because it is not a peptide and it shares important cellular and molecular targets with opioids, Rf might be useful in itself or as a template for designing additional modulators of neuronal Ca2+ channels.     

Ginsenoside Rf, a trace component of ginseng root, produces antinociception in mice

Ginseng root, a traditional oriental medicine, contains more than a dozen biologically active saponins called ginsenosides, including one present in only trace amounts called ginsenoside-Rf (Rf). Previously, we showed that Rf inhibits Ca²⁺ channels in mammalian sensory neurons through a mechanism requiring G-proteins, whereas a variety of other ginsenosides were relatively ineffective. Since inhibition of Ca²⁺ channels in sensory neurons contributes to antinociception by opioids, we tested for analgesic actions of Rf. We find dose-dependent antinociception by systemic administration of Rf in mice using two separate assays of tonic pain: in the acetic acid abdominal constriction test, the ED₅₀ was 56±9 mg/kg, a concentration similar to those reported for aspirin and acetaminophen in the same assay; in the tonic phase of the biphasic formalin test, the ED₅₀ was 129±32 mg/kg. Rf failed to affect nociception measured in three assays of acute pain: the acute phase of the formalin test, and the thermal (49°C) tail-flick and increasing-temperature (3°C/min) hot-plate tests. The simplest explanation is that Rf inhibits tonic pain without affecting acute pain, but other possibilities exist. Seeking a cellular explanation for the effect, we tested whether Rf suppresses Ca²⁺ channels on identified nociceptors. Inhibition was seen on large, but not small, nociceptors. This is inconsistent with a selective effect on tonic pain, so it seems unlikely that Ca²⁺ channel inhibition on primary sensory neurons can fully explain the behavioral antinociception we have demonstrated for Rf.     

In Vivo radioprotective effect of Panax ginseng C.A. Meyer and identification of active ginsenosides

This study evaluated the effect of water extracts of Panax ginseng C.A. Meyer (PG), panaxadiol (PD), panaxatriol (PT), ginsenoside Rb(1), Rb(2), Rc, Rd, Re and Rg(1) on jejunal crypt survival, endogenous spleen colony formation and apoptosis in jejunal crypt cells in gamma-irradiated mice. Jejunal crypts were protected by pretreatment with PG, Rc and Rd. Administration of PG, PD, Rd and Re prior to irradiation resulted in an increase in the formation of endogenous spleen colonies. The frequency of radiation-induced apoptosis in intestinal crypt cells was also reduced by pretreatment with PG, PD, Rb(2), Rc, Rd, Re and Rg(1). In experiments on the effects of the individual ginsenosides, the rank order of activity was Rc > Rd > Rg(1) > Rb(2) > Re > Rb(1) on intestinal crypt survival assay, Re > Rb(2) > Rd > Rg(1) > Rb(1) > Rc on the spleen colony formation assay, and Rg(1) > Re > Rd > Rc > Rb(2) > Rb(1) on inhibiting the death of cells caused by apoptosis. The results indicated that Rc, Rd and Re may have a major radioprotective effect in mice irradiated with high and low doses of radiation. When the same experiments were performed using PD and PT, it was observed that most of the inhibitory effects came from PD rather than PT.     

Effect of calmodulin on ginseng saponin-induced Ca2+-Activated CI-channel activation inXenopus laevis oocytes

We previously demonstrated the ability of ginseng saponins (active ingredients of Panax ginseng) to enhance Ca2+-activated Cl- current. The mechanism for this ginseng saponin-induced enhancement was proposed to be the release of Ca2+ from IP3-sensitive intracellular stores through the activation of PTX-insensitive Galpha(q/11) proteins and PLC pathway. Recent studies have shown that calmodulin (CaM) regulates IP3 receptor-mediated Ca2+ release in both Ca2+-dependent and -independent manner. In the present study, we have investigated the effects of CaM on ginseng saponin-induced Ca2+-activated Cl- current responses in Xenopus oocytes. Intraoocyte injection of CaM inhibited ginseng saponin-induced Ca2+-activated Cl- current enhancement, whereas co-injection of calmidazolium, a CaM antagonist, with CaM blocked CaM action. The inhibitory effect of CaM on ginseng saponin-induced Ca2+-activated Cl- current enhancement was dose- and time-dependent, with an IC50 of 14.9 +/- 3.5 microM. The inhibitory effect of CaM on saponin's activity was maximal after 6 h of intraoocyte injection of CaM, and after 48 h the activity of saponin recovered to control level. The half-recovery time was calculated to be 16.7 +/- 4.3 h. Intraoocyte injection of CaM inhibited Ca2+-induced Ca2+-activated Cl- current enhancement and also attenuated IP3-induced Ca2+-activated Cl- current enhancement. Ca2+/CaM kinase II inhibitor did not inhibit CaM-caused attenuation of ginseng saponin-induced Ca2+-activated Cl- current enhancement. These results suggest that CaM regulates ginseng saponin effect on Ca2+-activated Cl current enhancement via Ca2+-independent manner.     

Effects of Korean red ginseng extract on cisplatin-induced nausea and vomiting

Ginseng, the root of Panax ginseng C.A. Meyer, is well known as a tonic medicine for restoring and enhancing human health. In traditional medicine, ginseng is utilized for the alleviation of emesis, which includes nausea and vomiting. However, it has not yet been demonstrated whether ginseng exhibits in vivo anti-nausea and anti-vomiting properties. In this study, we examined the anti-emetic effect of Korean red ginseng total extract (KRGE) on cisplatin-induced nausea and vomiting using ferrets. Intraperitoneal administration (i.p.) of cisplatin (7.5 mg/kg) induced both nausea and vomiting with one-hour latency. The episodes of nausea and vomiting reached a peak after 1.5 h and persisted for 3 h. Treatment with KRGE via oral route significantly reduced the cisplatin-induced nausea and vomiting in a dose-dependent manner. The anti-emetic effect was 12.7 +/- 8.6, 31.8 +/- 6.9, and 67.6 +/- 4.0% with doses of 0.3, 1.0, and 3.0 g/kg of KRGE, respectively. Pretreatment with KRGE via oral route 1 and 2 h before cisplatin administration also significantly attenuated the cisplatin-induced nausea and vomiting. However this did not occur with a pretreatment 4 h before cisplatin administration. These results are supportive of KRGE being utilized as an anti-emetic agent against nausea and vomiting caused by chemotherapy (i.e. cisplatin).     

Effects of ranitidine for exercise induced gastric mucosal changes and bleeding

AIM: To evaluate the effect of ranitidine on gastric mucosal changes and on GI bleeding in long distance runners. METHODS: Twenty-four long distance runners (M:16, F: 8, age: 18.2±1.5 years) participated in this study. A symptom questionnaire, stool hemoccult test, and upper gastrointestinal (GI) endoscopy were performed on the subjects prior to the study. The subjects took oral ranitidine (150 mg, b.i.d.) for two weeks. The upper GI endoscopy and stool Hemoccult tests were repeated after the treatment. RESULTS: Twenty-two of the 24 runners had at least one upper GI mucosal lesion before the medication. The Endoscopic improvements were seen in eleven of the 14 cases of erosive gastritis and four of the 5 cases of esophagitis. Six subjects were Heme occult positive prior to the study, but only one was positive after the medication. CONCLUSION: Gastric mucosal lesions and GI bleeding in long distance runners seem to be associated to acidrelated factors mediated by the high level of regular run- ning. Ranitidine seems to be and effective prophylaxis to prevent gastric mucosal lesions and GI bleeding.     

Induction of apoptotic cell death by synthetic naringenin derivatives in human lung epithelial carcinoma A549 cells

Although flavonoids, which are both qualitatively and quantitatively one of the largest groups of natural products, exhibit a variety of beneficial health effects, the exact molecular mechanism of the cellular activities is still not fully explained and there currently exists a lack of evidence for any relationship between the structure-activity relationship and apoptosis-inducing activity. In order to determine the importance of the OH group or substitution of the 5 or carbon-7 in the diphenylpropane skeleton of flavonoids, we originally synthesized several modified naringenin derivatives, including 7-O-benzyl naringenin (KUF-1) and 7-O-(MeO-L-Leu-D-Pro-carbonylmethyl) naringenin (KUF-7). Treatment with KUF-1 or KUF-7 resulted in significant apoptosis-inducing effects concomitant with chromatin condensation, caspase activation, and intracellular ROS production. Our data indicate that originally synthesized naringenin derivatives, KUF-1 and KUF-7 differentially regulate the apoptosis of A549 cells via intracellular ROS production coupled with the concomitant activation of the caspase cascade signaling pathway, thereby implying that hydroxylation or substitution at Carbon-7 is critical for the apoptosis-inducing activity of flavonoids.     

Ginsenosides: are any of them candidates for drugs acting on the central nervous system?

The last two decades have shown a marked expansion in the number of publications regarding the effects of Panax ginseng. Ginsenosides, which are unique saponins isolated from Panax ginseng, are the pharmacologically active ingredients in ginseng, responsible for its effects on the central nervous system (CNS) and the peripheral nervous system. Recent studies have shown that ginsenosides regulate various types of ion channels, such as voltage-dependent and ligand-gated ion channels, in neuronal and heterologously expressed cells. Ginsenosides inhibit voltage-dependent Ca(2+), K(+), and Na(+) channel activities in a stereospecific manner. Ginsenosides also inhibit ligand-gated ion channels such as N-methyl-d-aspartate, some subtypes of nicotinic acetylcholine, and 5-hydroxytryptamine type 3 receptors. Competition and site-directed mutagenesis experiments revealed that ginsenosides interact with ligand-binding sites or channel pore sites and inhibit open states of ion channels. This review will introduce recent findings and advances on ginsenoside-induced regulation of ion channel activities in the CNS, and will further expand the possibilities that ginsenosides may be useful and potentially therapeutic choices in the treatment of neurodegenerative disorders.