bluuebunny/crossref_metadata_2025_split huggingface dataset:
Application of pressure-controlled colon delivery capsule to oral administration of glycyrrhizin in dogs
Authors: Shibata Nobuhito , Ohno Tomoya , Shimokawa Tatsuharu , Hu Zhaopeng , Yoshikawa Yukako , Koga Kenjiro , Murakami Masahiro , Takada Kanji 
Published: July 2003

Abstract
A colon delivery system has been used to improve the bioavailability of glycyrrhizin, a glycoside of glycyrrhetic acid. The bioavailability of glycyrrhizin is low when administered in conventional oral galenic dosage forms because glycyrrhizin is enzymatically hydrolysed both in the stomach and in the intestine. It was reasoned that if large amounts of glycyrrhizin were directly delivered to the colon, enzymatic activity should be reduced due to saturation so that intact glycyrrhizin could be absorbed into the systemic circulation. Based on this assumption, pressure-controlled colon delivery capsules (PCDCs) were used as a colon delivery system. Eight types of glycyrrhizin solution were prepared and were introduced into PCDCs. After oral administration of the test PCDCs to beagle dogs, blood samples were obtained over 24 h and plasma glycyrrhizin concentrations were measured by an HPLC method. With PCDCs containing aqueous glycyrrhizin and propylene glycol solutions, plasma glycyrrhizin levels were extremely low and the bioavailabilities of glycyrrhizin were 0.6% and 0.4%, respectively. When Labrasol was added to both types of glycyrrhizin solution, the bioavailability was improved to 4.6 % for aqueous solution and 3.8% for propylene glycol solution. When a surfactant, Polysorbate 80, was added in combination with Labrasol, synergistic effects were not obtained. Furthermore, dose-dependent effects of Polysorbate 80 were not obtained. Labrasol, which is a component of self-emulsifying drug delivery systems (SEDDS), has been shown to strongly improve the bioavailability of glycyrrhizin from the colon.
The effect of selective serotonin reuptake inhibitors (SSRIs) on the pharmacokinetics and metabolism of perazine in the rat
Authors: Daniel Władysława A , Syrek Maciej , Haduch Anna , Wójcikowski Jacek 
Published: July 2003

Abstract
The aim of this study was to investigate the effect of three selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine and sertraline, on the pharmacokinetics and metabolism of perazine in a steady state in rats. Perazine (10 mg kg−1, i.p.) was administered twice daily for two weeks, alone or jointly with one of the SSRIs. Concentrations of perazine and its two main metabolites (N-desmethylperazine and 5-sulfoxide) in the plasma and brain were measured 30 min and 6 and 12 h after the last dose of the drugs. Of the investigated SSRIs, fluoxetine and fluvoxamine significantly increased plasma and brain concentrations of perazine (up to 900% and 760% of the control value, respectively), their effect being most pronounced after 30 min and 6 h. Moreover, simultaneous increases in perazine metabolites concentrations and in the perazine/metabolite concentration ratios were observed. Sertraline elevated plasma and brain concentrations of perazine after 30 min. In-vitro studies with liver microsomes of rats treated chronically with perazine, SSRIs or their combinations showed decreased concentrations of cytochrome P-450 after perazine and a combination of perazine and fluvoxamine (vs control), and increased concentration after a combination of perazine and fluoxetine (vs perazine-treated group). Prolonged treatment with perazine did not significantly change the rate of its own metabolism. Chronic administration of fluoxetine or sertraline, alone or in a combination with perazine, accelerated perazine N-demethylation (vs control or perazine group, respectively). Fluvoxamine had a similar effect. The 5-sulfoxidation of perazine was accelerated by fluvoxamine and sertraline treatment, but the process was inhibited by administration of a combination of perazine and fluoxetine or fluvoxamine (vs control). Kinetic studies using control liver microsomes, in the absence or presence of SSRIs added in-vitro, demonstrated competitive inhibition of both N-demethylation and sulfoxidation by the investigated SSRIs. Sertraline was the most potent inhibitor of perazine N-demethylation but the weakest inhibitor of sulfoxidation. Results of in-vivo and in-vitro studies indicate that the observed interaction between perazine and SSRIs mainly involves competition for an active site of perazine N-demethylase and sulfoxidase. Moreover, increases in the concentrations of both perazine and metabolites measured, produced by the investigated drug combinations in-vivo, suggest simultaneous inhibition of another, yet to be investigated, metabolic pathway of perazine (e.g. aromatic hydroxylation).
Reversible binding of the novel anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid to plasma proteins and its distribution into blood cells in various species
Authors: Zhou Shufeng , Paxton James W , Kestell Philip , Tingle Malcolm D , Kestell Philip 
Published: July 2003

Abstract
The plasma protein binding and distribution in blood cells of the novel anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) has been investigated in-vitro using filtration and an HPLC method to measure DMXAA. DMXAA (500 μm) was extensively bound in plasma from all species with an unbound fraction (fu) of 4.61 ± 1.10 (mouse), 2.59 ± 0.32 (rat), 2.02 ± 0.48 (rabbit) and 2.07 ± 0.23% (human). The binding was concentration dependent with DMXAA concentrations ≥ 1000 μm markedly increasing the fu in the plasma from all species. The estimated number of binding sites in plasma were 2.4 ± 0.2 (mouse), 1.7 ± 0.2 (rat), 0.8 ± 0.1 (rabbit) and 2.1 ± 0.2 (human). The major binding protein in human plasma was albumin, with negligible binding to γ-globulin and α1-acid glycoprotein. There was a significant linear relationship between the bound:free DMXAA concentration ratio (Cb/Cu) and albumin concentration in human serum albumin solution (r = 0.955; P &lt; 0.05) and in healthy human plasma (r = 0.998; P &lt; 0.05), but not in plasma from cancer patients (n = 5), nor across species. In cancer patients (n = 5) DMXAA had a significantly higher (P &lt; 0.05) fu (4.60 ± 0.42%) compared with healthy human plasma (2.07 ± 0.23%). In human plasma, the fu of DMXAA (500 μm) was significantly reduced by 500 μm diazepam (P &lt; 0.05), but not by warfarin, phenylbutazone, salicylic acid, ibuprofen or clofibric acid at that concentration. DMXAA significantly reduced the binding of dansylsarcosine (a Site-II binder) to HSA, but significantly increased the binding of dansylamide (a Site-I binder). Within species, the blood:plasma concentration ratio (CBL/CP) of DMXAA was relatively constant (mouse, 0.581 ± 0.005; rat, 0.667 ± 0.025; rabbit, 0.637 ± 0.019; human, 0.673 ± 0.103) over the range 50–1000 μm, but increased significantly at DMXAA concentrations &gt; 1000 μm in all species except the rabbit. These results indicate that significant alterations in DMXAA plasma binding and distribution into blood cells occur with increasing concentrations of DMXAA in all species, and also that significant interspecies differences exist. It would be more appropriate to compare plasma unbound concentrations when assessing DMXAA exposure in cancer patients or when extrapolating across species.
Synthesis and kinetic evaluation of peptide α-keto-β-aldehyde-based inhibitors of trypsin-like serine proteases
Authors: Lynas John F , Martin S Lorraine , Walker Brian 
Published: July 2003

Abstract
New, synthetic peptide analogues bearing a C-terminal basic α-keto-β-aldehyde moiety were prepared as novel inhibitors of the trypsin-like serine proteases. The compounds, Ac-Leu-Leu-Arg-COCHO, Ac-Arg-Gln-Arg-COCHO and Boc-Val-Leu-Lys-COCHO were evaluated kinetically against trypsin and three other trypsin-like serine proteases, tryptase, plasmin and thrombin, all of which are implicated as mediators of important disease processes. Results illustrate that α-keto-β-aldehydes are potent inhibitors, with similar potency to comparable peptide aldehydes, and intriguingly, appear to act, in some instances, by a novel mechanism of action. Ac-Leu-Leu-Arg-COCHO, an analogue of the natural product leupeptin, is a potent, tight-binding inhibitor of trypsin (Ki(final) = 1.9 μm), plasmin (Ki(final) = 4.9 μm) and tryptase (Ki(final) = 1.2 μm) and an irreversible inactivator of thrombin (k2nd 4500 m−1. min−1). Boc-Val-Leu-Lys-COCHO was found to be a tight-binding inhibitor of its target protease plasmin (Ki(final) = 3.1 μm) and was inactive against thrombin. Ac-Arg-Gln-Arg-COCHO was a slow-binding inhibitor of tryptase (Ki(final) = 1.6 μm) and also irreversibly inactivated trypsin (k2nd = 8920 m−1 min−1). Peptides or peptidomimetics with a C-terminal basic α-keto-β-aldehyde function thus provide a useful new molecular template for the development of new therapeutic agents against a wide range of disorders, such as coagulopathies and asthma, which may be mediated by the aberrant activity of trypsin-like serine proteases.
Characterization and purification of the vitamin K1 2,3 epoxide reductase system from rat liver
Authors: Begent Louise A , Hill Anthony P , Steventon Glyn B , Hutt Andrew J , Pallister Christopher J , Cowell David C 
Published: July 2003

Abstract
The enzyme vitamin K1 2,3 epoxide reductase is responsible for converting vitamin K1 2,3 epoxide to vitamin K1 quinone thus completing the vitamin K cycle. The enzyme is also the target of inhibition by the oral anticoagulant, R,S-warfarin. Purification of this protein would enable the interaction of the inhibitor with its target to be elucidated. To date a single protein possessing vitamin K1 2,3 epoxide reductase activity and binding R,S-warfarin has yet to be purified to homogeneity, but recent studies have indicated that the enzyme is in fact at least two interacting proteins. We report on the attempted purification of the vitamin K1 2,3 epoxide reductase complex from rat liver microsomes by ion exchange and size exclusion chromatography techniques. The intact system consisted of a warfarin-binding factor, which possessed no vitamin K1 2,3 epoxide reductase activity and a catalytic protein. This catalytic protein was purified 327-fold and was insensitive to R,S-warfarin inhibition at concentrations up to 5 mm. The addition of the S-200 size exclusion chromatography fraction containing the inhibitor-binding factor resulted in the return of R,S-warfarin inhibition. Thus, to function normally, the rat liver endoplasmic reticulum vitamin K1 2,3 epoxide reductase system requires the association of two components, one with catalytic activity for the conversion of the epoxide to the quinone and the second, the inhibitor binding factor. This latter enzyme forms the thiol-disulphide redox centre that in the oxidized form binds R,S-warfarin.
Molecular and functional identification of large neutral amino acid transporters LAT1 and LAT2 and their pharmacological relevance at the blood-brain barrier
Authors: Kido Yasuto , Tamai Ikumi , Uchino Hiroshi , Suzuki Fumio , Sai Yoshimichi , Tsuji Akira 
Published: July 2003

Abstract
We present here the evidence of molecular and functional expression of LAT1 and LAT2, subunits of the large neutral amino acid transporter system L, in cultured brain capillary endothelial cells of the rat. By means of the RT-PCR method, transcripts of LAT1, LAT2 and heavy chain of 4F2 antigen (4F2hc) were detected in rat primary cultured brain capillary endothelial cells (BCECs) and immortalized subline, RBEC1. The uptake properties of RBEC1, such as [3H]leucine and l-[3H]DOPA uptake, were similar to those of primary cultured BCECs. So, RBEC1 may retain almost native properties of the large neutral amino acid uptake activities. [3H]Leucine uptake by RBEC1 showed two saturable components and the Km values of the high- and low-affinity components were 8.92 ± 3.18 and 119 ± 45 μm, respectively. The Km value of the high-affinity component agreed well with that of LAT1 and the amino acid transport selectivity of RBEC1 was similar to that of LAT1. Therefore, it is suggested that LAT1 is important at the blood-brain barrier of rats. Additionally, the Km value of the low-affinity component was similar to that of LAT2. These observations indicate that LAT1 and LAT2 are involved as transporters for large neutral amino acids at the blood-brain barrier. Additionally, we concluded that RBEC1 is useful as an in-vitro model for evaluation of the pharmacological relevance of system L at the blood-brain barrier.
Ruscogenin glycoside (Lm-3) isolated from Liriope muscari improves liver injury by dysfunctioning liver-infiltrating lymphocytes
Authors: Wu Feihua , Cao Jingsong , Jiang Jieyun , Yu Boyang , Xu Qiang 
Published: July 2003

Abstract
The effects of ruscogenin 1-O-[β-d-glucopyranosyl(1 → 2)] [β-d-xylopyranosyl(1 → 3)]-β-d-fucopyranoside (Lm-3) and its aglycone, ruscogenin, on liver injury induced in mice by delayed-type hypersensitivity to picryl chloride have been investigated. Lm-3 and ruscogenin significantly decreased liver injury when given during the effector phase of the delayed-type hypersensitivity reaction. The pretreatment of nonparenchymal cells, but not hepatocytes, with Lm-3 or ruscogenin in-vitro caused a concentration- and time-dependent inhibition against the damage. Lm-3 showed a stronger inhibition against the damage than ruscogenin (IC50: Lm-3 6.3 times 10−10 m, ruscogenin 3.9 times 10−7 m). However, neither Lm-3 nor ruscogenin blocked the hepatotoxic potential of CCl4, when used to pretreat hepatocytes. Moreover, Lm-3 and ruscogenin inhibited concanavalin A-induced lymphocyte proliferation only at high concentrations. These results suggested that Lm-3 and ruscogenin improved the immunological liver injury by selectively causing dysfunction of the liver-infiltrating cells rather than by protecting hepatocyte membranes. Such characteristics would be significant for treating immunologically related liver diseases as well as for developing new drugs.
The influence of plasma on the disinfecting activity of the new antimicrobial agent N-chlorotaurine-sodium in comparison with chloramine T
Authors: Gottardi Waldemar , Hagleitner Magdalena , Nagl Markus 
Published: July 2003

Abstract
The phenomenon of increasing bactericidal activity of N-chlorotaurine in the presence of chlorine-consuming material has been investigated both on a chemical-analytical and microbiological basis using plasma as substrate and chloramine T for comparison. Chlorine consumption assessed by iodometric titration showed a biphasic time-course with a very fast loss of oxidation capacity within one minute (N-chlorotaurine: — 9.3%, chloramine T: −16.8%) followed by a slow loss which could still be detected after 24 h (total loss −61.7% and −74.1%, respectively). Killing curves revealed that an increase in bactericidal activity, in spite of improved consumption, did not occur with all strains, and could be detected only at a certain degree of consumption. Escherichia coli and Pseudomonas aeruginosa showed the most pronounced effect, Streptococcus pyogenes and Proteus mirabilis a medium-sized one, while it was absent in Staphylococcus aureus. With chloramine T, an increase in bactericidal activity could not be proved. The chemical basis of these consumption effects can be reduced to four reaction types: oxidation of thiols; chlorine substitution of activated C-H compounds; transhalogenation; and hydrolytic degradation of N-chloro-α-amino acids and -peptides emerging by transhalogenation. The initial fast loss of oxidation capacity can be attributed mainly to oxidation of thiols, while the subsequent slower decrease is caused by the other types of reaction. The increase in bactericidal activity, on the other hand, can be explained by transhalogenation, leading to the formation of more bactericidal N-chloro compounds by which the loss of N-chlorotaurine is over-compensated.
Active intestinal secretion of new quinolone antimicrobials and the partial contribution of P-glycoprotein
Authors: Naruhashi Kazumasa , Tamai Ikumi , Inoue Natsuko , Muraoka Hiromi , Sai Yoshimichi , Suzuki Nagao , Tsuji Akira 
Published: July 2003

Abstract
Transport of quinolone antimicrobials and the contribution of the secretory transporter P-glycoprotein were studied in-vivoand in-vitro. In rat intestinal tissue (Ussing chambers method) and human Caco-2 cells (Transwell method), grepafloxacin showed secretory-directed transport. In both experimental systems, the secretory-directed transport was decreased by ciclosporin A, an inhibitor of P-glycoprotein, and probenecid, an inhibitor of anion transport systems. This suggested the contribution of P-glycoprotein and anion-sensitive transporter(s). The involvement of P-glycoprotein was investigated by using a P-glycoprotein over-expressing cell line, LLC-GA5-COL150, and P-glycoprotein-gene-deficient mice (mdr1a(—/—)/1b(—/—) mice). LLC-GA5-COL150 cells showed secretory-directed transport of grepafloxacin, while the parent cell line, LLC-PK1, did not. The secretory-directed transport of sparfloxacin and levofloxacin was also detected in LLC-GA5-COL150 cells. In the mdr1a(—/—)/1b(—/—) mice, the intestinal secretory clearance was smaller than that in wild-type mice after intravenous administration of grepafloxacin. Moreover, the absorption from an intestinal loop in mdr1a(—/—)/1b(—/—) mice was larger than that in wild-type mice. Accordingly, it appears that some quinolones are transported by secretory transporters, including P-glycoprotein. The involved transporters function in-vivo not only to transport grepafloxacin from blood to intestine but also to limit its intestinal absorption.
Taurocholic acid-induced secretion in normal and cystic fibrosis mouse ileum
Authors: Hardcastle J , Hardcastle P T , Chapman J , Taylor C J 
Published: July 2003

Abstract
Bile acids cause secretion throughout the intestinal tract and this process contributes to maintaining the fluidity of intestinal contents. In cystic fibrosis (CF) defective intestinal secretion can lead to excessive dehydration of the luminal contents and the development of clinical symptoms. This study was designed to investigate bile acid-induced secretion in mouse ileum and to determine whether this process was defective in CF. Taurocholic acid-induced secretion was monitored as a rise in short-circuit current (SCC) in ileal sheets from normal (Swiss MF1) and transgenic CF mice. Taurocholic acid increased the SCC in both intact and stripped ileal sheets from Swiss MF1 mice. This effect was due to a stimulation of electrogenic Cl− secretion as it was inhibited by Cl−-free conditions, serosal furosemide (frusemide), mucosal diphenylamine-2-carboxylic acid (DPC) and increased serosal K+ concentration, without being affected by reduced mucosal Na+ concentration. Taurocholic acid-induced secretion was inhibited by tetrodotoxin, indicating the involvement of a neural pathway, but this did not include capsaicin-sensitive afferent neurons or muscarinic cholinoreceptors. Mucosal mast cells also contributed to the response. Responses in tissues from transgenic wild-type mice were similar to those obtained with Swiss MF1 animals, but ilea from CF mice exhibited a lower basal SCC with significantly reduced secretory responses to acetylcholine and taurocholic acid. We concluded that taurocholic acid induces ileal secretion by a mechanism that entails activation of enteric nerves and degranulation of mucosal mast cells. Impaired bile acid-induced secretion in CF may contribute to luminal dehydration.
Confirmation of the anxiolytic-like effect of dihydrohonokiol following behavioural and biochemical assessments
Authors: Maruyama Yuji , Kuribara Hisashi , Kishi Eiko , Weintraub Susan T , Ito Yoshihisa 
Published: July 2003

Abstract
Previous studies in this laboratory revealed that dihydrohonokiol-B (DHH-B; 3′-(2 propenyl)-5-propyl-(1,1′-biphenyl)-2,4′-diol), a partially reduced derivative of honokiol, was an effective anxiolytic-like agent in mice at an oral dose of 0.04 mg kg−1, and at higher doses, when evaluated by the elevated plus-maze test. The aim of this study was to further confirm the anxiolytic-like effect of DHH-B using an additional behavioural procedure (Vogel's conflict test in mice) and a biochemical assessment (in-vitro determination of muscimol-stimulated 36Cl− uptake into mouse cortical synaptoneurosomes). As in earlier experiments, DHH-B (0.04–1 mg kg−1, p.o.) was shown to prolong the time spent in the open-sided arms of the elevated plus-maze in a dose-dependent manner. Moreover, in the Vogel's conflict test, DHH-B (5 mg kg−1, p.o.) significantly increased punished water intake. In tests with mouse cerebral cortical synaptoneurosomes, 10 and 30 μm of DHH-B significantly increased 36Cl− influx in the absence of muscimol. In the presence of 25 μm muscimol, the addition of 1 μm DHH-B led to significant enhancement of 36Cl− uptake, while 30 μm DHH-B was required to further stimulate the 36Cl− uptake induced by 250 μm muscimol. The results of these studies confirm that DHH-B is a potent anxiolytic-like agent and that GABAA receptor-gated Cl−-channel complex is involved in the anxiolytic-like efficacy of DHH-B.
Comparison of suppressive potency between prednisolone and prednisolone sodium succinate against mitogen-induced blastogenesis of human peripheral blood mononuclear cells in-vitro
Authors: Sugiyama Kentaro , Kawada Tomie , Sato Hiroshi , Hirano Toshihiko 
Published: July 2003

Abstract
Clinically, both prednisolone and prednisolone sodium succinate are widely used as immunosuppressive agents for the treatment of various allergic disorders. However, whether prednisolone sodium succinate itself has immunosuppressive or anti-inflammatory effects is unclear, and prednisolone sodium succinate may exhibit its efficacy only after hydrolytic conversion to prednisolone in-vivo. If this is the case, the impairment of prednisolone sodium succinate conversion to prednisolone in some clinical conditions may attenuate the efficacy of prednisolone sodium succinate. We therefore compared the pharmacological efficacy of prednisolone with that of prednisolone sodium succinate in-vitro using human peripheral blood mononuclear cells (PBMCs). PBMCs were obtained from 5 healthy subjects and 1 patient with pneumonia. The cells were incubated in the presence of concanavalin A and the cell growth was estimated by 3-(4,5-dimethyl thiazo-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Both prednisolone and prednisolone sodium succinate dose-dependently suppressed PBMC blastogenesis. Mean (s.d.) prednisolone and prednisolone sodium succinate IC50 (concentration of drug that gave 50% inhibition of cell growth) values were 580.0 (1037.9) and 3237.1 (4627.3) nm, respectively. The ratio of prednisolone IC50/prednisolone sodium succinate IC50 ranged from 0.005 to 0.230. Thus, prednisolone sodium succinate potency was markedly lower than that of prednisolone. After incubation of PBMCs with 100 μm prednisolone sodium succinate, 22.7–42.9 μm prednisolone was liberated into the culture medium, as determined by HPLC. The ratio of prednisolone liberation from prednisolone sodium succinate was not affected by the presence of fetal bovine serum or PBMC, or both, in the culture medium. These results suggested that the PBMC-suppressive effects of prednisolone sodium succinate might be due, at least partially, to prednisolone liberated from prednisolone sodium succinate into the culture medium. Prednisolone sodium succinate can be converted to prednisolone in the absence of serum or PBMCs, but the ratio of this conversion was very slow (t£frac12; &gt; 4 days). Therefore, impairment of the enzymatic conversion of prednisolone sodium succinate to prednisolone in some pathological conditions such as liver diseases may result in attenuation of the clinical efficacy of prednisolone sodium succinate.