bluuebunny/crossref_metadata_2025 huggingface dataset:
An evaluation of the relative roles of the unstirred water layer and receptor sink in limiting the in-vitro intestinal permeability of drug compounds of varying lipophilicity
Authors: Katneni Kasiram , Charman Susan A , Porter Christopher J H
Published: October 2010

The roles of the unstirred water layer (UWL) and receptor sink on the in-vitro transmembrane permeability of an increasingly lipophilic series of compounds (mannitol (MAN), diazepam (DIA) and cinnarizine (CIN)) have been assessed. Altered carbogen bubbling rates were used as a means to change the UWL thickness and polysorbate-80 (PS-80), bovine serum albumin (BSA) and α-1-acid glycoprotein (AAG) were employed to alter sink conditions. After correction for solubilisation, Papp data for MAN, DIA and CIN were consistent across varying donor PS-80 concentrations suggesting that for the drugs examined here, the donor UWL did not limit in-vitro permeability. Similarly, altered bubbling rates and receptor sink conditions had no impact on the permeability of MAN. In contrast, decreasing the size of the receptor UWL or adding solubilising agents to the receptor sink resulted in modest enhancements to the permeability of the more lipophilic probe DIA. For the most lipophilic compound, CIN, very significant changes to measured permeability (>30 fold) were possible, but were most evident only after concomitant changes to both the UWL and sink conditions, suggesting that the effectiveness of enhanced sink conditions were dependent on a decrease in the width of the UWL.
The anti-arthritic effect of ursolic acid on zymosan-induced acute inflammation and adjuvant-induced chronic arthritis models
Authors: Kang Suk-Yun , Yoon Seo-Yeon , Roh Dae-Hyun , Jeon Mi-Jeong , Seo Hyoung-Sig , Uh Dong-Kyu , Kwon Young-Bae , Kim Hyun-Woo , Han Ho-Jae , Lee Hye-Jung , Lee Jang-Hern
Published: October 2010

Ursolic acid (UA) is pentacyclic triterpenoic acid that naturally occurs in many medicinal herbs and plants. In this study, we examined the possible suppressive effect of UA extracted from Oldenlandia diffusa on zymosan-induced acute inflammation in mice and complete Freund's adjuvant (CFA)-induced arthritis in rats. UA treatment (per oral) dose-dependently (25–200 mg kg−1) suppressed zymosan-induced leucocyte migration and prostaglandin E2 (PGE2) production in the air pouch exudates. Since the maximal effective dose of UA was 50 mg kg−1 in the zymosan experiment, we used this dose of UA in a subsequent study using an adjuvant-induced rheumatoid arthritis model. UA treatment (50 mg kg−1, per oral, once a day for 10 days) was started from day 12 after adjuvant injection. UA dramatically inhibited paw swelling, plasma PGE2 production and radiological changes in the joint caused by CFA injection. Moreover, UA significantly suppressed the arthritis-induced mechanical and thermal hyperalgesia as well as the spinal Fos expression, as determined by immunohistochemistry, which was increased by CFA injection. In addition, overall anti-arthritic potency of UA was comparable with ibuprofen (100 mg kg−1, oral) while UA did not induce significant gastric lesions as compared with the ibuprofen treatment group. These findings strongly suggest that UA is a useful suppressive compound for rheumatoid arthritis treatment with low risk of gastric problems.
Microinjection of morphine into thalamic nucleus submedius depresses bee venom-induced inflammatory pain in the rat
Authors: Feng Jie , Jia Ning , Han Ling-Na , Huang Fen-Sheng , Xie Yu-Feng , Liu Jian , Tang Jing-Shi
Published: October 2010

Previous studies have provided evidence of the existence of a pain modulatory feedback pathway consisting of thalamic nucleus submedius (Sm)–ventrolateral orbital cortex-periaqueductal grey pathway, which is activated during acute pain and leads to depression of transmission of nociceptive information in the spinal dorsal horn. The aim of this study was to test the hypothesis that morphine microinjection into the Sm decreased spontaneous pain and bilateral thermal hyperalgesia, as well as ipsilateral mechanical allodynia, induced by subcutaneous injections of bee venom into the rat hind paw. Morphine (1.0, 2.5 or 5.0 m̀g in 0.5 μL) injected into the Sm, contralateral to the bee venominjected paw, depressed spontaneous nociceptive behaviour in a dose-dependent manner. Furthermore, morphine significantly decreased bilateral thermal hyperalgesia and ipsilateral mechanical allodynia 2 h after bee venom injection. These morphine-induced effects were antagonized by 1.0 μg naloxone (an opioid antagonist) microinjected into the Sm 5 min before morphine administration. The results provided further support for the important role of the Sm and Sm-opioid receptors in inhibiting nociceptive behaviour and indicated for the first time that Sm opioid receptors were also effective in inhibiting the hypersensitivity provoked by bee venom-induced inflammation.
Effect of hesperetin, a citrus flavonoid, on bacterial enzymes and carcinogen-induced aberrant crypt foci in colon cancer rats: a dose-dependent study
Authors: Aranganathan Selvaraj , Selvam Jayabal Panneer , Nalini Namasivayam
Published: October 2010

Hesperetin, an important bioactive compound in Chinese traditional medicine, has antioxidant and anticarcinogenic properties. Hesperetin is found in abundance in orange and grape juices (200–590 mg L−1) consumed in the daily diet. We have investigated the effect of different doses of hesperetin on faecal and colonic mucosal bacterial enzymes and aberrant crypt foci (ACF) in 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in male Wistar rats. The rats were divided into six groups and were fed a modified pellet diet for 16 weeks. Group 1 served as control and group 2 received the modified pellet diet along with hesperetin (30 mg kg−1). The rats in groups 3–6 rats were given a weekly subcutaneous injection of DMH (20 mg kg−1) for the first four weeks. Hesperetin was supplemented orally at different doses (10, 20 or 30 mg kg−1) for a total of 16 weeks. At the end of the experimental period all rats were killed. In DMH-treated rats, the activity of faecal and colonic mucosal bacterial enzymes, such as β-glucuronidase, β-galactosidase, β-glucosidase, nitroreductase, sulfatase and mucinase, were significantly elevated, but in rats supplemented hesperetin along with DMH the activity was significantly lowered (P < 0.05). The total number of aberrant crypts was significantly increased in unsupplemented DMH-treated rats, while hesperetin supplementation to DMH-treated rats significantly reduced the total number of crypts. The results demonstrated that hesperetin supplementation at a dose of 20 mg kg−1 played a potent role in suppressing the formation of aberrant crypt foci and reducing the activity of bacterial enzymes in colon cancer.
Adenosine A2A receptors and their role in drug addiction
Authors: Brown Robyn M , Short Jennifer L
Published: October 2010

The specific events between initial presumably manageable drug intake and the development of a drug- addicted state are not yet known. Drugs of abuse have varying mechanisms of action that create a complex pattern of behaviour related to drug consumption, drug-seeking, withdrawal and relapse. The neuromodulator adenosine has been shown to play a role in reward-related behaviour, both as an independent mediator and via interactions of adenosine receptors with other receptors. Adenosine levels are elevated upon exposure to drugs of abuse and adenosine A2A receptors are enriched in brain nuclei known for their involvement in the processing of drug-related reinforcement processing. A2A receptors are found in receptor clusters with dopamine and glutamate receptors. A2A receptors are thus ideally situated to influence the signalling of neurotransmitters relevant in the neuronal responses and plasticity that underlie the development of drug taking and drug-seeking behaviour. In this review, we present evidence for the role of adenosine and A2A receptors in drug addiction, thereby providing support for current efforts aimed at developing drug therapies to combat substance abuse that target adenosine signalling via A2A receptors.
Pharmacological and local toxicity studies of a liposomal formulation for the novel local anaesthetic ropivacaine
Authors: de Araujo Daniele Ribeiro , Cereda Cintia Maria Saia , Brunetto Giovanna Bruschini , Vomero Viviane Urbini , Pierucci Amauri , Neto Humberto Santo , de Oliveira Alexandre Leite Rodrigues , Fraceto Leonardo Fernandes , Braga Angélica de Fátima de Assunção , de Paula Eneida
Published: October 2010

This study reports an investigation of the pharmacological activity, cytotoxicity and local effects of a liposomal formulation of the novel local anaesthetic ropivacaine (RVC) compared with its plain solution. RVC was encapsulated into large unilamellar vesicles (LUVs) composed of egg phosphatidylcholine, cholesterol and α-tocopherol (4:3:0.07, mole%). Particle size, partition coefficient determination and in-vitro release studies were used to characterize the encapsulation process. Cytotoxicity was evaluated by the tetrazolium reduction test using sciatic nerve Schwann cells in culture. Local anaesthetic activity was assessed by mouse sciatic and rat infraorbital nerve blockades. Histological analysis was performed to verify the myotoxic effects evoked by RVC formulations. Plain (RVCPLAIN) and liposomal RVC (RVCLUV) samples were tested at 0.125%, 0.25% and 0.5% concentrations. Vesicle size distribution showed liposomal populations of 370 and 130 nm (85 and 15%, respectively), without changes after RVC encapsulation. The partition coefficient value was 132 ± 26 and in-vitro release assays revealed a decrease in RVC release rate (1.5 fold, P < 0.001) from liposomes. RVCLUV presented reduced cytotoxicity (P < 0.001) when compared with RVCPLAIN. Treatment with RVCLUV increased the duration (P < 0.001) and intensity of the analgesic effects either on sciatic nerve blockade (1.4–1.6 fold) and infraorbital nerve blockade tests (1.5 fold), in relation to RVCPLAIN. Regarding histological analysis, no morphological tissue changes were detected in the area of injection and sparse inflammatory cells were observed in only one of the animals treated with RVCPLAIN or RVCluv at 0.5%. Despite the differences between these preclinical studies and clinical conditions, we suggest RVCLUV as a potential new formulation, since RVC is a new and safe local anaesthetic agent.
Oroxylin A induces G2/M phase cell-cycle arrest via inhibiting Cdk7-mediated expression of Cdc2/p34 in human gastric carcinoma BGC-823 cells
Authors: Yang Yong , Hu Yang , Gu Hong-Yan , Lu Na , Liu Wei , Qi Qi , Zhao Li , Wang Xiao-Tang , You Qi-Dong , Guo Qing-Long
Published: October 2010

We reported previously that oroxylin A, a natural product isolated from Scutellariae Radix, was a potent apoptosis inducer of human hepatoma HepG2 cells. In this study, cell-cycle arrest of BGC-823 human gastric carcinoma cells caused by oroxylin A has been investigated. Based on our 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay and flow cytometric analysis, treatment of BGC-823 cells with growth suppressive concentrations of oroxylin A caused an irreversible arrest in the G2/M phase of the cell cycle. Western blot analysis demonstrated that oroxylin A-induced cell-cycle arrest in BGC-823 cells was associated with a significant decrease in cdc2/p34, cyclin B1 and cyclin A expression. In addition, oroxylin A-treated cells decreased the expression of Cdk7, which was responsible for the low expression of M phase promoting factor (cyclin B1/Cdc2). The results suggested that oroxylin A induced G2/M phase cell-cycle arrest via inhibiting Cdk7-mediated expression of Cdc2/p34 in human gastric carcinoma BGC-823 cells.
Taxifolin glycoside inhibits dendritic cell responses stimulated by lipopolysaccharide and lipoteichoic acid
Authors: Kim Yun Jeong , Choi Sun Eun , Lee Min Won , Lee Chung Soo
Published: October 2010

Antigen-presenting dendritic cells may play an important role in the pathogenesis of atopic dermatitis. Taxifolin is demonstrated to have anti-inflammatory effects. The present study was designed to assess the effect of taxifolin glycoside against stimulated responses of dendritic cells isolated from mouse bone marrow and spleen. Dendritic cells exposed to lipopolysaccharide, lipoteichoic acid or interleukin (IL)-1β exhibited increased production of IL-12 p70 and tumour necrosis factor alpha, increased formation of reactive oxygen species (ROS) and nitric oxide (NO), and elevation of intracellular Ca2+ levels. Treatment with taxifolin glycoside inhibited responses stimulated by the microbial products or IL-1β in dendritic cells in a dose-dependent manner. Taxifolin glycoside had a significant inhibitory effect on the production of cytokines, formation of ROS and NO, and change in intracellular Ca2+ levels in dendritic cells of bone marrow and spleen. The results show that taxifolin glycoside seems to inhibit the dendritic cell responses stimulated by microbial products and IL-1β, suggesting that taxifolin glycoside may exert an inhibitory effect against dendritic-cell-mediated immune responses.
Cyamemazine metabolites: effects on human cardiac ion channels in-vitro and on the QTc interval in guinea pigs
Authors: Crumb William , Benyamina Amine , Arbus Christophe , Thomas George P , Garay Ricardo P , Hameg Ahcène
Published: October 2010

Monodesmethyl cyamemazine and cyamemazine sulfoxide, the two main metabolites of the antipsychotic and anxiolytic phenothiazine cyamemazine, were investigated for their effects on the human ether-à-go-go related gene (hERG) channel expressed in HEK 293 cells and on native INa, ICa, Ito, Isus or IK1 of human atrial myocytes. Additionally, cyamemazine metabolites were compared with terfenadine for their effects on the QT interval in anaesthetized guinea pigs. Monodesmethyl cyamemazine and cyamemazine sulfoxide reduced hERG current amplitude, with IC50 values of 0.70 and 1.53 μM, respectively. By contrast, at a concentration of 1 μM, cyamemazine metabolites failed to significantly affect INa, Ito, Isus or IK1 current amplitudes. Cyamemazine sulfoxide had no effect on ICa at 1 μM, while at this concentration, monodesmethyl cyamemazine only slightly (17%), albeit significantly, inhibited ICa current. Finally, cyamemazine metabolites (5 mg kg−1 i.v.) were unable to significantly prolong QTc values in the guinea pig. Conversely, terfenadine (5 mg kg−1 i.v.) significantly increased QTc values. In conclusion, cyamemazine metabolite concentrations required to inhibit hERG current substantially exceed those necessary to achieve therapeutic activity of the parent compound in humans. Moreover, cyamemazine metabolites, in contrast to terfenadine, do not delay cardiac repolarization in the anaesthetized guinea pig. These non-clinical findings explain the excellent cardiac safety records of cyamemazine during its 30 years of extensive therapeutic use.
Pharmacological profile of essential oils derived from Lavandula angustifolia and Melissa officinalis with anti-agitation properties: focus on ligand-gated channels
Authors: Huang Liping , Abuhamdah Sawsan , Howes Melanie-Jayne R , Dixon Christine L , Elliot Mark S J , Ballard Clive , Holmes Clive , Burns Alistair , Perry Elaine K , Francis Paul T , Lees George , Chazot Paul L
Published: October 2010

Both Melissa officinalis (Mo) and Lavandula angustifolia (La) essential oils have putative anti-agitation properties in humans, indicating common components with a depressant action in the central nervous system. A dual radioligand binding and electrophysiological study, focusing on a range of ligand-gated ion channels, was performed with a chemically validated essential oil derived from La, which has shown clinical benefit in treating agitation. La inhibited [35S] TBPS binding to the rat forebrain gamma aminobutyric acid (GABA)A receptor channel (apparent IC50 = 0.040 ± 0.001 mg mL−1), but had no effect on N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or nicotinic acetylcholine receptors. A 50:50 mixture of Mo and La essential oils inhibited [3H] flunitrazepam binding, whereas the individual oils had no significant effect. Electrophysiological analyses with rat cortical primary cultures demonstrated that La reversibly inhibited GABA-induced currents in a concentration-dependent manner (0.01–1 mg mL−1), whereas no inhibition of NMDA- or AMPA-induced currents was noted. La elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission, with a net depressant effect on neurotransmission (in contrast to the classic GABAA antagonist picrotoxin which evoked profound epileptiform burst firing in these cells). These properties are similar to those recently reported for Mo. The anti-agitation effects in patients and the depressant effects of La we report in neural membranes in-vitro are unlikely to reflect a sedative interaction with any of the ionotropic receptors examined here. These data suggest that components common to the two oils are worthy of focus to identify the actives underlying the neuronal depressant and anti-agitation activities reported.
Comparison of chitosan nanoparticles and chitosan hydrogels for vaccine delivery
Authors: Gordon Sarah , Saupe Anne , McBurney Warren , Rades Thomas , Hook Sarah
Published: October 2010

In this work the potential of chitosan nanoparticles (CNP) and thermosensitive chitosan hydrogels as particulate and sustained release vaccine delivery systems was investigated. CNP and chitosan hydrogels were prepared, loaded with the model protein antigen ovalbumin (OVA) and characterised. The immunostimulatory capacity of these vaccine delivery systems was assessed in-vitro and in-vivo. Particle sizing measurements and SEM images showed that optimised OVA-loaded CNP had a size of approximately 200 nm, a polydispersity index < 0.2, and a positive zeta-potential of approximately 18 mV. The amount of OVA adsorbed onto CNP was high with an adsorption efficacy of greater than 96%. Raman spectroscopy indicated conformational changes of OVA when adsorbed onto the surface of CNP. Uptake of the dispersions and immunological activation of murine dendritic cells in-vitro could be demonstrated. Investigation of the release of fluorescently-labelled OVA (FITC-OVA) from CNP and chitosan hydrogels in-vitro showed that approximately 50% of the total protein was released from CNP within a period of ten days; release of antigen from chitosan gel occurred in a more sustained manner, with < 10% of total protein being released after 10 days. The slow release from gel formulations may be explained by the strong interactions of the protein with chitosan. While OVA-loaded CNP showed no significant immunogenicity, formulations of OVA in chitosan gel were able to stimulate both cell-mediated and humoral immunity in-vivo.
Modulating effect of polyethylene glycol on the intestinal transport and absorption of prednisolone, methylprednisolone and quinidine in rats by in-vitro and in-situ absorption studies
Authors: Shen Qi , Li Wenji , Lin Yulian , Katsumi Hidemasa , Okada Naoki , Sakane Toshiyasu , Fujita Takuya , Yamamoto Akira
Published: October 2010

The effects of polyethylene glycol 20000 (PEG 20000) on the intestinal absorption of prednisolone, methylprednisolone and quinidine, three P-glycoprotein (P-gp) substrates, across the isolated rat intestinal membranes were examined by an in-vitro diffusion chamber system. The serosal-to-mucosal (secretory) transport of these P-gp substrates was greater than their mucosal-to-serosal (absorptive) transport, indicating that their net movement across the intestinal membranes was preferentially in the secretory direction. The polarized secretory transport of these drugs was remarkably diminished and their efflux ratios decreased in the presence of PEG 20000. In addition, PEG 20000 did not affect the transport of Lucifer yellow, a non-P-gp substrate. The intestinal membrane toxicity of PEG 20000 was evaluated by measuring the release of alkaline phosphatase (ALP) and protein from the intestinal membranes. The release of ALP and protein was enhanced in the presence of 20 mM sodium deoxycholate (NaDC), a positive control, while these biological parameters did not change in the presence of 0.1–5% (w/v) PEG 20000. These findings indicated that the intestinal membrane damage caused by PEG 20000 was not a main reason for the enhanced absorptive transport of these P-gp substrates in the presence of PEG 20000. Furthermore, the transepithelial electrical resistance (TEER) of rat jejunal membranes in the presence or absence of PEG 20000 was measured by a diffusion chamber method. PEG 20000 (0.1–5.0 % w/v) did not change the TEER values of the rat jejunal membranes, indicating that the increase in the absorptive transport of these P-gp substrates might not be due to the increased transport of these P-gp substrates via a paracellular pathway caused by PEG 20000. Finally, the effect of PEG 20000 on the intestinal absorption of quinidine was examined by an in-situ closed-loop method. The intestinal absorption of quinidine was significantly enhanced in the presence of 0.1-1.0% (w/v) PEG 20000. These findings suggest that PEG 20000 might be a useful excipient to improve the intestinal absorption of quinidine, which is mainly secreted by a P-gp-mediated efflux system in the intestine.
Mechanisms involved in the antinociceptive effect caused by diphenyl diselenide in the formalin test
Authors: Savegnago Lucielli , Jesse Cristiano R , Santos Adair R S , Rocha João B T , Nogueira Cristina W
Published: October 2010

This study investigated the mechanisms involved in the antinociceptive action induced by diphenyl diselenide ((PhSe)2) in the formalin test. Mice were pre-treated with (PhSe)2 by the oral route (0.1–100 mg kg−1), 30 min before formalin injection. To address some of the mechanisms by which (PhSe)2 inhibits formalin-induced nociception mice were treated with different drugs. The antinociceptive effect of (PhSe)2 was shown in the first and second phases of the formalin test. The antinociceptive effect caused by (PhSe)2 (10 mg kg−1, p.o.) was prevented by intrathecal injection of K+ channel blockers such as apamin and charybdotoxin (small- and large-conductance Ca2+-activated K+ channel inhibitors, respectively) and tetraethylammonium (TEA, a non-selective voltage-dependent K+ channel inhibitor), but not glib-enclamide (an ATP-sensitive K+ channel inhibitor). The antinociceptive action caused by (PhSe)2 (10 mg kg−1, p.o.) was also blocked by a nitric oxide (NO) synthase inhibitor (Nω-nitro-l-arginine, L-NOARG) and the soluble guanylate cyclase inhibitors 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and methylene blue. These results suggest the participation of NO/cyclic GMP/Ca2+ and K+ channel pathways in the antinociceptive effect caused by (PhSe)2.
Cancer, chitosan nanoparticles and catalytic nucleic acids
Authors: Tan Mei Lin , Choong Peter F M , Dass Crispin R
Published: October 2010

Objectives

The aim of this review was to examine gene therapy involving DNAzyme and siRNA encapsulation into chitosan nanoparticles, discussing the current and future status of this drug delivery system in enhancing drug delivery and cancer therapy.

Key findings

Cancer is a disease state in which the cells in our body undergo mutations at the genetic level and are transformed, acquiring the ability to replicate limitlessly. Conventional cancer treatment involves the use of surgery and cytotoxic chemotherapy and/or radiotherapy, which have the potential of harming normal, otherwise healthy, non-neoplastic cells. Newer forms of therapy such as immunotherapy and gene therapy have shown initial promise, but still require better ways to limit exposure to cancerous lesions in the body. As a result drug delivery systems have been developed in attempts to deliver therapeutics specifically to the target lesion site. One recent drug delivery system has revolved around the use of chitosan nanoparticle technology, where therapeutics are encapsulated into nanoparticles and targeted to tumours.

Though few, attempts at encapsulating therapeutics such as deoxyribozymes and small or short interfering RNA have been optimistic and encouraging.
Hydrogen sulfide protects from intestinal ischaemia–reperfusion injury in rats
Authors: Liu Hao , Bai Xiao-Bin , Shi Song , Cao Yong-Xiao
Published: October 2010

Objectives

Hydrogen sulfide (H2S) is an endogenously gaseous mediator, regulating many pathophysiological functions in mammalian cells. H2S has been shown to inhibit myocardial ischaemia–reperfusion (I/R) injury. However, little is known about whether H2S could modulate intestinal I/R injury. This study aimed to investigate the effect of H2S on intestinal I/R injury and potential mechanism(s) underlying the action of H2S in regulating the development of intestinal I/R injury in rats.

Methods

Following surgical induction of intestinal I/R injury for 1 h, groups of Sprague-Dawley rats were treated with, or without, tetramethylpyrazine (8 mg/kg), or sodium hydrosulfide (NaHS, an H2S donor at 7 or 14 μmol/kg) 30 min after occlusion. All rats were sacrificed immediately after the reperfusion. Their intestinal injury, together with that of sham-control rats, was histologically examined and their sera and intestinal malondialdehyde (MDA), superoxide dismutase (SOD), peroxidase (GSH-Px) activities were characterized by biochemical analysis.

Key findings

The results showed that NaHS significantly reduced intestinal I/R injury and the levels of sera and intestinal MDA activity, and dramatically increased the levels of serum and intestinal SOD and GSH-Px activity.

Conclusions

The results suggest that H2S protects from intestinal I/R injury in rats, which is associated with increase in the activity of antioxidant enzymes.
Effect of Guanxin No.2 decoction on gene expression in different areas of the myocardial infarcted heart of rats using microarray technology
Authors: Zeng Xiaowei , Yang Jun , Yang Xianzhe , Hong Dongsheng , Wu Limao , Yu Jun
Published: October 2010

Objectives

We have used microarray technology to detect the effect of Guanxin No.2 decoction on gene expression in different areas of the myocardial infarcted heart of rats.

Methods

Male Sprague-Dawley rats (180–200 g) were randomly divided into three groups: sham-operated; coronary artery ligation; and coronary artery ligation plus administration of Guanxin No.2 decoction (10.0 g raw materials/kg per day by gavage). The experiment was carried out on day seven after ligation.

Key findings

We found that the gene expression using microarray technology showed many differences in the border infarcted left ventricular area compared with the remote noninfarcted left ventricular area after administration of Guanxin No.2 decoction.

Conclusions

Guanxin No.2 decoction has a long history in treating ischaemic cardiomyopathy in China, but the molecular mechanism has been unclear. In this study we found that some important genes may have contributed to the cardioprotective effect of Guanxin No.2 decoction.
Strontium fructose 1,6-diphosphate alleviates early diabetic testopathy by suppressing abnormal testicular matrix metalloproteinase system in streptozocin-treated rats
Authors: Zhang Qi , Liu Hao-Ran , Ying Han-Jie , Dai De-Zai , Tang Xiao-Yun , Dai Yin
Published: October 2010

Objectives

Male hypogonadism is frequently associated with testopathy in patients with type 2 diabetes and in middle-aged males. We hypothesized that abnormal matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in testis have large roles to play in male hypogonadism. It has been found in diabetic rats that a novel compound, strontium fructose 1,6-diphosphate (FDP-Sr), with extra high energy supply, could reverse male hypogonadism by normalizing MMP-9 and TIMPs in the testis. We investigated whether FDP-Sr could be promising in treating diabetic testopathy.

Methods

Adult male Sprague-Dawley rats were administered a single dose of streptozocin (65 mg/kg, i.p.) to induce diabetes. The diabetic rats were treated with FDP-Sr in three doses or testosterone propionate in the final four weeks during the eight-week study.

Key findings

Serum testosterone, activity of marker enzymes, and mRNA of MMPs and TIMPs and protein of MMP-9 in the testis were detected. After eight weeks, the activity of acid phosphatase, lactate dehydrogenase, succinate dehydrogenase and γ-glutamyl transpeptidase in testis were significantly decreased (P < 0.01), accompanied by down-regulated mRNA and activity of MMP-2 and MMP-9 (P < 0.01) and upregulated mRNA of TIMP-1 and TIMP-2. Downregulated MMP-9 protein and degenerative changes in histology were predominant in diabetic testis.

Conclusions

FDP-Sr or testosterone propionate significantly normalized expression and activity of the MMPs–TIMPs system to attenuate changes in serum testosterone, marker enzymes and histology in testis. Effects of FDP-S-r were dose-dependent and comparable with those of testosterone propionate. By supplying extra energy, FDP-Sr could be promising in treating diabetic testopathy by normalizing abnormal MMP-9 and its endogenous inhibitors in testes.
Antiulcerogenic and anti-inflammatory activities of the essential oil from Pterodon emarginatus seeds
Authors: Dutra Rafael C , Fava Marcelo B , Alves Caio C S , Ferreira Ana P , Barbosa Nádia R
Published: October 2010

Objectives

The objective of this work was to investigate the antiulcerogenic and anti-inflammatory activities of the essential oil from Pterodon emarginatus seeds.

Methods

The following tests were used: ulcers induced by ethanol, indometacin and HCl/ethanol, and pleurisy induced by carrageenan in Swiss albino rats. The rats were treated by the oral route with essential oil of P. emarginatus seeds.

Key findings

The essential oil at 100, 300 and 500 mg/kg exhibited significant protection against ulcers induced by ethanol, indometacin and HCl/ethanol (P < 0.001). The essential oil caused a marked reduction in the exudate volume and inhibited leucocyte and neutrophil influx (P < 0.05) in carrageenan-induced pleurisy. Moreover, the essential oil significantly decreased nitric oxide (NO) and interleukin-1 (IL-1) levels, without affecting tumour necrosis factor-α production.

Conclusions

The results demonstrated the marked antiulcerogenic and anti-inflammatory effects of the essential oil from P. emarginatus, which are, at least in part, a consequence of NO and IL-1 modulation. P. emarginatus or its constituents might represent new therapeutic options to treat gastric ulcers and inflammatory diseases.
Relaxing effects of Valeriana officinalis extracts on isolated human non-pregnant uterine muscle
Authors: Occhiuto Francesco , Pino Annalisa , Palumbo Dora Rita , Samperi Stefania , De Pasquale Rita , Sturlese Emanuele , Circosta Clara
Published: October 2010

Objectives

This study investigated the relaxing effects of Valeriana officinalis L. (Valerianaceae) on human uterine muscle. The major uses of this species in Europe are as a sedative and an anxiolytic; it is also used as a spasmolytic to treat gastrointestinal spasm.

Methods

We evaluated two valerian extracts (ethanolic and aqueous) in comparison with a natural mixture of valepotriates and nifedipine on spontaneous and agonist-induced contractions in non-pregnant human myometrium in vitro. Qualitative and quantitative chemical analysis was used to correlate the chemical composition of extracts with their spasmolytic effects. Myometrial strips were obtained from hysterectomy specimens of premenopausal women. Longitudinal muscle strips were mounted vertically in tissue baths under physiological conditions to record their isometric contraction. The responses of cumulative concentrations of valerian extracts on spontaneous contractions in the presence and absence of the β-adrenoceptor blocker atenolol or the cyclooxygenase inhibitor indometacin, and on agonist-induced contractions, were investigated.

Key findings

Valerian extracts and valepotriates inhibited uterine contra***ctility in a concentration-dependent manner. Pretreatment with either atenolol or indometacin did not affect the uterine responses to valerian extracts. Valerian extract reduced the maximal contractile response induced by acetylcholine, phenylephrine and histamine independent of the stimulus.

Conclusions

Valerian extracts may have direct inhibitory effects on the contractility of the human uterus and this justifies the traditional use of this plant in the treatment of uterine cramping associated with dysmenorrhoea.
Novel formulation of solid lipid microparticles of curcumin for anti-angiogenic and anti-inflammatory activity for optimization of therapy of inflammatory bowel disease
Authors: Yadav Vivek Ramshankar , Suresh Sarasija , Devi Kshama , Yadav Seema
Published: October 2010

Objectives

This project was undertaken with a view to optimize the treatment of inflammatory bowel disease through a novel drug delivery approach for localized treatment in the colon. Curcumin has poor aqueous solubility, poor stability in the gastrointestinal tract and poor bioavailability. The purpose of the study was to prepare and evaluate the anti-inflammatory activity of solid lipid microparticles (SLMs) of curcumin for the treatment of inflammatory bowel disease in a colitis-induced rat model by a colon-specific delivery approach.

Methods

We have developed a novel formulation approach for treating experimental colitis in the rat model. SLMs of curcumin were prepared with various lipids, such as palmitic acid, stearic acid and soya lecithin, with an optimized percentage of poloxamer 188. The SLMs of curcumin were characterized for particle size, drug content, drug entrapment, in-vitro release, surface morphology and infrared, differential scanning calorimetry and X-ray studies. The colonic delivery system of SLM formulations of curcumin were further investigated for their anti-angiogenic and anti-inflammatory activity using chick embryo and rat colitis models.

Key findings

Particle size, drug content, drug entrapment and in-vitro release studies showed that formulation F4 containing one part stearic acid and 0.5% surfactant had the smallest diameter of 108 μm, 79.24% entrapment and exhibited excellent in-vitro release characteristics when compared with other formulations and pure curcumin. SLMs of curcumin (F4) proved to be a potent angio-inhibitory compound, as demonstrated by inhibition of angiogenesis in the chorioallantoic membrane assay. Rats treated with curcumin and its SLM complex showed a faster weight gain compared with dextran sulfate solution (DSS) control rats. The increase in whole colon length appeared to be significantly greater in SLM-treated rats when compared with pure curcumin and DSS control rats. An additional finding in the DSS-treated rats was chronic cell infiltration with predominance of eosinophils. Decreased mast cell numbers in the mucosa of the colon of SLMs of curcumin and pure curcumin-treated rats was observed.

Conclusions

The degree of colitis caused by administration of DSS was significantly attenuated by colonic delivery of SLMs of curcumin. Being a nontoxic natural dietary product, curcumin could be useful in the therapeutic strategy for inflammatory bowel disease patients.
Novel oral fast-disintegrating drug delivery devices with predefined inner structure fabricated by Three-Dimensional Printing
Authors: Yu Deng-Guang , Shen Xia-Xia , Branford-White Chris , Zhu Li-Min , White Kenneth , Yang Xiang Liang
Published: October 2010

Objectives

Novel fast-disintegrating drug delivery devices with special inner structure characteristics were designed and fabricated using Three-Dimensional Printing.

Methods

Based on computer-aided design models, fast-disintegrating drug delivery devices containing loose powders were prepared automatically using the Three-Dimensional Printing system. The inner powder regions were prepared by depositing the binder solutions onto selected regions during the layer-printing process.

Results

The devices showed acceptable pharmacotechnical properties and fine hardness (63.4 N/cm2) due to the synergistic action of several binding mechanisms, but unsatisfactory friability, with 3.55% total mass loss during the friability tests. Scanning electron microscope images clearly showed that the printed regions were well bound, and that the drug particle size was reduced or individual particles could no longer be distinguished. In contrast, the unprinted regions were uncompacted, with cracks and fissures among the loose mixed powder. All the drug delivery devices disintegrated and wetted rapidly in in-vitro tests. The average disintegration and wetting times were 23.4 s and 67.6 s, respectively. Dissolution tests showed that 98.5% of the drug was released within 2 min.

Conclusions

Three-Dimensional Printing offers strategies for the development of novel oral fast-disintegrating drug delivery devices.
Comparison of WHO and US FDA biowaiver dissolution test conditions using bioequivalent doxycycline hyclate drug products
Authors: Strauch Stefanie , Jantratid Ekarat , Dressman Jennifer B
Published: October 2010

Objectives

The dissolution characteristics of immediate-release doxycycline hyclate products with certified in-vivo bioequivalence to the innovator product were tested with a view to possible application of biowaiver-based approval.

Methods

Five products were tested using US Pharmacopeia Apparatus 2: Antodox 100 mg hard gelatin capsules, Doxycyclin AL 100 T tablets, Doxycyclin-ratiopharm 100 soft gelatin capsules, Doxycyclin STADA 100 mg tablets and Doxy-Wolff 100 mg tablets. Three compendial buffers were used as dissolution media: simulated gastric fluid without pepsin, pH 1.2, acetate buffer, pH 4.5, and simulated intestinal fluid without pancreatin, pH 6.8. Results were obtained at two paddle speeds recommended for biowaiver applications: 75 rpm (World Health Organization; WHO) and 50 rpm (US Food and Drug Administration; US FDA).

Key findings

The results for the tablets and hard gelatin capsules indicate that a paddle speed of 75 rpm is more representative than 50 rpm, since 75 rpm generates dissolution profiles corresponding more closely to the in-vivo profiles than those at 50 rpm. For evaluating soft gelatin capsule formulations with lipid fill, both US FDA and WHO methods were found to be over-discriminating.

Conclusions

Bioequivalence of immediate-release doxycycline hyclate tablets and hard gelatin capsules, but not soft gelatin capsules, can be evaluated in vitro using the biowaiver dissolution test conditions specified by the WHO.
Active absorption of ginsenoside Rg1 in vitro and in vivo: the role of sodium-dependent glucose co-transporter 1
Authors: Xiong Jing , Sun Minjie , Guo Jianxin , Huang Luosheng , Wang Shujing , Meng Boyu , Ping Qineng
Published: October 2010

Objectives

Our previous study suggested that adrenaline (epinephrine) could be an effective absorption enhancer for ginsenoside Rg1 (Rg1). This study focused on the transport mechanism of Rg1 and the role of sodium-dependent glucose co-transporter 1 in the regulation of Rg1 uptake after exposure to adrenaline.

Methods

Caco-2 cells were used as an in-vitro model to assess the absorption mechanism of Rg1. Also the effect of D-glucose on adrenaline-induced absorption of Rg1 was investigated in vivo in rats.

Key findings

Results showed that the uptake of Rg1 was temperature-dependent. The transport from the basolateral side to the apical side was significantly lower compared with that from the apical to the basolateral side (P < 0.01). The transport of Rg1 was concentration dependent (Km was 41.60 mM, Vmax was 353.75 mol/cm2/min). Cells incubated with D-glucose-free medium exhibited significantly greater Rg1 uptake (+ 62.6%) compared with cells in D-glucose-containing medium. The data indicated that sodium-dependent glucose co-transporter 1 was involved in the transport of Rg1. Adrenaline-induced uptake of Rg1 was significantly inhibited in the presence of phlorizin and the absence of Na+. In the in-vivo study in rats, it was found that after co-administration with D-glucose, the adrenaline-induced absorption of Rg1 was inhibited. The area under the concentration-time curve (AUC0→∞) value was significantly decreased from 64.57 ± 27.08 to 1.37 ± 0.42 μg/ml h (P < 0.001).

Conclusions

The data suggested that adrenaline enhanced the absorption of Rg1 by regulating sodium-dependent glucose co-transporter 1.
Phycocyanin liposomes for topical anti-inflammatory activity: in-vitro in-vivo studies
Authors: Manconia Maria , Pendás Jehzabel , Ledón Nurys , Moreira Tomás , Sinico Chiara , Saso Luciano , Fadda Anna Maria
Published: October 2010

Objectives

The aim of this work was to investigate the anti-inflammatory activity of C-phycocyanin (C-PC) on skin inflammation after topical administration and the influence of liposomal delivery on its pharmacokinetic properties.

Methods

Liposomes of different size and structure were prepared with different techniques using soy phosphatidylcholine and cholesterol. Vesicular dispersions were characterised by transmission electron microscopy, optical and fluorescence microscopy for vesicle formation and morphology, dynamic laser light scattering for size distribution, and Zetasizer for zeta-potential. C-PC skin penetration and permeation experiments were performed in vitro using vertical diffusion Franz cells and human skin treated with either free or liposomal drug dispersed in a Carbopol gel.

Key findings

The protein was mainly localised in the stratum corneum, while no permeation of C-PC through the whole skin thickness was detected. Two percent C-PC-encapsulating liposomes showed the best drug accumulation in the stratum corneum and the whole skin, higher than that of the corresponding free 2% C-PC gel. Moreover, skin deposition of liposomal C-PC was dose dependent since skin accumulation values increased as the C-PC concentration in liposomes increased. The topical anti-inflammatory activity of samples was evaluated in vivo as inhibition of croton oil-induced or arachidonic acid-induced ear oedema in rats.

Conclusions

The results showed that C-PC can be successfully used as an anti-inflammatory drug and that liposomal encapsulation is effective in improving its anti-inflammatory activity.
Oral bioavailability enhancement of a hydrophilic drug delivered via folic acid-coupled liposomes in rats
Authors: Ling Sharon Sheue Nee , Yuen Kah Hay , Magosso Enrico , Barker Susan Anne
Published: October 2010

Objectives

A liposome preparation that is amenable to receptor-mediated endocytosis has been developed to enhance the oral bioavailability of poorly absorbable peptidomi-metic drugs by use of folic acid as the mediator of liposomal uptake.

Methods

Folic acid was physically coupled to the surface of the liposomes and cefotaxime was used as the model drug. In-vivo evaluation was carried out on eight Sprague-Dawley rats in a two-way crossover study to compare the oral bioavailability of cefotaxime loaded in folic acid-free liposomes and folic acid-coupled liposomes. Blood samples were collected from the tail vein and plasma cefotaxime levels were determined using an HPLC method.

Key findings

Enhanced oral bioavailability (AUC0-∞) of cefotaxime was observed when administered via folic acid-coupled liposomes. The peak plasma concentration (Cmax) of cefotaxime was increased when administered via folic acid-coupled liposomes as compared with folic acid-free liposomes. At 90% confidence interval, the value for AUC0-∞ was 1.4–2-times higher and the value for Cmax was 1.2–1.8-times higher for the folic acid-coupled liposomes compared with folic acid-free liposomes.

Conclusions

Folic acid could enhance the uptake of liposomally entrapped drug. It could be a useful candidate to supplement liposome delivery systems.
Protective effects of coffee-derived compounds on lipopolysaccharide/d-galactosamine induced acute liver injury in rats
Authors: Akashi Iwao , Kagami Keisuke , Hirano Toshihiko , Oka Kitaro
Published: October 2010

Objectives

The protective effects of coffee-derived compounds on lipopolysaccharide/d-galactosamine (LPS/d-GalN) induced acute liver injury in rats were investigated.

Methods

Wistar rats were orally administered saline (control) or one of the test compounds (caffeine, chlorogenic acid, trigonelline, nicotinic acid or eight ***pyrazinoic acids) at a dose of 100 mg/kg, respectively. This was followed by intraperitoneal injection with LPS (100 μg/kg)/d-GalN (250 mg/kg) 1 h after administration of the test compounds. Blood samples were collected up to 12 h after LPS/d-GalN injection, followed by determination of plasma aspartate aminotransferase, alanine aminotransferase, tumour necrosis factor α (TNF-α) and interleukin 10 (IL-10) levels.

Key findings

Plasma aspartate aminotransferase and alanine aminotransferase levels were significantly increased after LPS/d-GalN-treatment, but were suppressed by pretreatment with caffeine (n = 5), nicotinic acid, non-substituted pyrazinoic acid or 5-methylpyrazinoic acid (n = 6, respectively) 12 h after LPS/d-GalN-treatment (P < 0.01, respectively). Moreover, the animals pretreated with these test compounds showed significantly higher survival rates (83–100%) compared with the control (23%). Only pretreatment with caffeine significantly suppressed the LPS/d-GalN induced elevation of plasma TNF-α levels 1 and 2 h after LPS/d-GalN-treatment (P < 0.01, respectively). Pretreatment with caffeine, nicotinic acid or non-substituted pyrazinoic acid activated the LPS/d-GalN induced elevation of plasma IL-10 levels at 1 and 2 h, although there were no statistically significant differences in IL-10 levels between control and nicotinic acid or non-substituted pyrazinoic acid treated rats.

Conclusions

The results suggest that caffeine, nicotinic acid, non-substituted pyrazinoic acid and 5-methylpyrazinoic acid can protect against LPS/d-GalN induced acute liver injury, which may be mediated by the reduction of TNF-α production and/or increasing IL-10 production.
Bis-(3-hydroxyphenyl) diselenide inhibits LPS-stimulated iNOS and COX-2 expression in RAW 264.7 macrophage cells through the NF-kB inactivation
Authors: Shin Kyung-Min , Shen Liulan , Park Seung Jae , Jeong Jin-Hyun , Lee Kyung-Tae
Published: October 2010

Objectives

Previously, we reported that diaryl diselenide compounds have strong inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophages. In this study, we investigated the molecular mechanisms underlying NO suppression and prostaglandin E2 (PGE2) production by diaryl diselenide compounds, bis-(2-hydroxyphenyl) diselenide (DSE-A), bis-(3-hydroxyphenyl) diselenide (DSE-B), bis-(4-hydroxyphenyl) diselenide (DSE-C), dipyridyl diselenide (DSE-D) and diphenyl diselenide (DSE-E).

Methods

The effect of these compounds on NO suppression and PGE2 production was investigated in RAW 264.7 macrophages.

Key findings

Our data indicate that of the above, DSE-B most potently inhibits NO and PGE2 production, and that it also significantly reduces the releases of tumour necrosis factor (TNF)-α, interleukin(IL)-1β and IL-6. Consistent with these observations, DSE-B also reduced the protein levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), and the mRNA levels of iNOS, COX-2, TNF-α, IL-1β and IL-6. Furthermore, DSE-B inhibited LPS-induced nuclear factor-κB (NF-κB) activation, which was associated with the prevention of the inhibitor κB-α (IκB-α) degradation and a subsequent reduction in nuclear p65 protein levels.

Conclusions

Taken together, our data suggest that the anti-inflammatory properties of DSE-B are due to reduction in the expression of iNOS, COX-2, TNF-α, IL-1β and IL-6 through the down-regulation of NF-κB binding activity.