bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drug Metabolism: Intestinal Bacterial Hydrolysis is Required for the Appearance of Compound K in Rat Plasma after Oral Administration of Ginsenoside Rb1 from Panax ginseng
Authors: Akao Teruaki , Kida Hiroaki , Kanaoka Matao , Hattori Masao , Kobashi Kyoichi 
Published: April 2011

Abstract
Ginsenoside Rb1 from Panax ginseng root is transformed into compound K via ginsenosides Rd and F2 by intestinal bacterial flora. Among 31 defined intestinal strains from man, only Eubacterium sp. A-44 transformed ginsenoside Rb1 into compound K via ginsenoside Rd. The ginsenoside Rb1-hydrolysing enzyme isolated from Eubacterium sp. A-44 was identical to a previously purified geniposide-hydrolysing β-D-glucosidase.
When ginsenoside Rb1 (200 mg kg−1) was administered orally to germ-free rats, neither compound K nor any other metabolite was detected in the plasma, intestinal tract or cumulative faeces 7 or 15 h after administration. Most of the ginsenoside Rb1 administered was recovered from the intestinal tract, especially the caeca, and cumulative faeces indicating poor absorption of ginsenoside Rb1. When ginsenoside Rb1 was administered orally to gnotobiote rats mono-associated with Eubacterium sp. A-44, a significant amount of compound K was detected in the plasma and considerable amounts were found in the caecal contents and cumulative faeces 7 and 15 h after administration. A small amount of ginsenoside Rb1 was detected in the caecal contents only 7 h after administration.
These results indicate that orally administered ginsenoside Rb1 is poorly absorbed from the gut but that its metabolite compound K, produced by ginsenoside Rb1-hydrolysing bacteria such as Eubacterium sp. A-44 in the lower part of intestine, is absorbed.
Synergistic Effects of Some Pairs of Antioxidants and Related Agents on Mouse Leukaemia L5 178Y Cell Growth In-vitro
Authors: Suzuki Takahiro , Ezure Toru , Ishida Masaru 
Published: April 2011

Abstract
The effects of simultaneous administration of some dyadic combinations of antioxidants or vitamins and related agents on cellular proliferation of mouse leukaemia L5178Y cells in-vitro have been examined experimentally.
The data were analysed on the basis of the concept of independence for evaluation of interactions between biologically active agents. An approach for evaluation of the synergism or antagonism of the action of two agents is proposed in which the types and extents of interactions are described by response-surface diagrams. The combinations phytol with trans-retinol, abscisic acid with trans-retinol, and menadione with sodium L-ascorbate were synergistic, whereas menadione with trans-retinal, and plumbagin with trans-retinol were antagonistic in the dose-range tested.
These results reveal that the interactions between two agents depend not only on the combinations of agents but also on the dose ranges or the ratios of agents under the experimental domain studied.
Comparative Measurement of of an Antineoplastic Glucan the Molecular Weight from BCG Vaccine
Authors: Farrugia Isabelle V , Dadey Eric J , Ashline Kirk , Groves Michael J 
Published: April 2011

Abstract
Bacillus Calmette-Guérin (BCG) vaccine, developed originally for the prophylaxis of tuberculosis, is a potent immunostimulant used to treat superficial bladder carcinoma in man. The aim of this study was to compare the molecular weight and self-association properties of an antineoplastic glucan (PS1A1) extracted from BCG vaccine as determined by different techniques including diffusion, light-scattering and chromatographic methods.
In the diffusion experiments, a semi-empirical relationship was derived between the effective diffusion coefficients, Dp, and the weight-average molecular weights, Mw, of several dextrans used as standards, according to the equation Dp = 2.233 times 10−6 x Mw−0.66. On the basis of this relationship, the molecular weight of PS1A1 was found to be 57.4 kDa, although, unexpectedly, membrane association was high, most probably because of molecular branching. In the light-scattering experiment it was observed that, unlike dextran, PS1A1 undergoes concentration-dependent multimerization in water. However, the molecular weight of PS1A1 in 0.1 M sodium chloride ranged from 60 to 68 kDa, with a mean of 65 kDa, over the same concentration range. This value was in agreement with the molecular weight determined for PS1A1 by gel-filtration chromatography in previous studies, suggesting that 65 kDa represents the approximate monomeric size of the unassociated molecule.
Thus, it was evident that the aggregation was suppressed by electrolyte. Elemental analysis by X-ray fluorescence showed that PS1A1 contained carbon, oxygen, hydrogen and phosphorus, indicating that hitherto unobserved ionized phosphate groups might promote electrostatic interactions.
The Effect of the Mode of Administration on the Hypolipidaemic Activity of Niacin: Continuous Gastrointestinal Administration of Low-dose Niacin Improves Lipid-lowering Efficacy in Experimentally-induced Hyperlipidaemic Rats
Authors: Lomnicky Yossef , Friedman Michael , Luria Myron H , Raz Itamar , Hoffman Amnon 
Published: April 2011

Abstract
The effect of different routes and modes of administration of niacin (nicotinic acid) on its hypolipidaemic activity has been evaluated. Our working hypothesis was that the major sites of niacin action are located presystemically (i.e. in the gut wall or the liver, or both) which would make niacin a gastrointestinal drug. For such drugs continuous administration to the gastrointestinal tract is expected to augment their efficacy compared with bolus oral administration or parenteral administration.
The hypothesis was examined in two rat models of experimentally induced hyperlipidaemia—Model A, based on a cholesterol-enriched diet, and Model B, in which acute hyperlipidaemia is induced by intraperitoneal administration of triton (225 mg kg−1). Continuous administration of niacin into the duodenum at 1.66 mg h−1 (total dose 40 mg kg−1 day−1) for up to 7 days (Model A) or at 2.22 mg h−1 over 18 h (Model B) had significantly greater lipid-reducing effects both on total cholesterol and on triglyceride levels (15–25%) and elevation of high-density lipoprotein (HDL) cholesterol levels than did bolus oral administration of the same dose. Continuous duodenal infusion of niacin also had an even greater lipid-reducing effect than continuous intravenous infusion of the drug at the same rate and dose.
The results indicate that the site(s) of action are located presystemically and that continuous duodenal administration of a low dose of niacin (40 mg kg−1) has a greater lipid-lowering effect than a higher dose (200 mg kg−1) administered by peroral bolus administration. These conclusions were validated by administration of a specially designed niacin sustained-release matrix tablet formulation that was non-invasively administered to hyperlipidaemic rats. The hypolipidaemic activity of the sustained-release tablet was of similar magnitude to that resulting from continuous duodenal administration, thus providing a pharmacodynamic rationale for this mode of administration.
Pharmacokinetic Differences Between Lansoprazole Enantiomers in Rats
Authors: Arimori Kazuhiko , Yasuda Kazuto , Katsuki Hisakazu , Nakano Masahiro 
Published: April 2011

Abstract
Because limited information is available about potential differences between the pharmacokinetics and pharmacodynamics of the enantiomers of lansoprazole, the enantioselective pharmacokinetics of the compound have been investigated in rats.
There was a noticeable difference between the serum levels of the enantiomers of lansoprazole and of their metabolites, 5-hydroxylansoprazole enantiomers, after oral administration of the racemate (50 mg kg−1) to rats. Cmax (maximum serum concentration) and AUC (area under the serum concentration-time curve) for (+)-lansoprazole were 5–6 times greater than those for (—)-lansoprazole, whereas for (+)-5-hydroxylansoprazole both values were significantly smaller than those for the (—) enantiomer. CLtot/F values (where CLtot is total clearance and F is the fraction of the dose absorbed) for (+)-lansoprazole were significantly smaller than those for the (—) enantiomer. There was no significant difference between the absorption rate constants of the lansoprazole enantiomers in the in-situ absorption study. The in-vitro protein-binding study showed that binding of (+)-lansoprazole to rat serum proteins was significantly greater than for the (—) enantiomer. The in-vitro metabolic study showed that the mean metabolic ratio (45.9%) for (—)-lansoprazole was significantly greater than that (19.8%) for the (+) enantiomer in rat liver microsomes at 5.6 μM lansoprazole.
These results show that the enantioselective disposition of lansoprazole could be a consequence of the enantioselectivity of plasma-protein binding and the hepatic metabolism of the enantiomers.
Pharmacokinetics and Hypotensive Effect of Diltiazem in Rabbits: Comparison of Diltiazem with its Major Metabolites
Authors: Yeung Pollen K F , Feng Joe D Z , Buckley Susan J 
Published: April 2011

Abstract
To assess the contribution of its metabolites to the antihypertensive effects of diltiazem, a previously established rabbit model has been used to compare the pharmacokinetics and haemodynamic effects of the drug with those of its major metabolites deacetyldiltiazem (M1) and deacetyl-N-monodemethyldiltiazem (M2).
Diltiazem, M1 and M2 were administered separately to each animal (n = 5 or 6 per study group) as a single 5 mg kg−1 intravenous dose. Blood samples, systolic and diastolic blood pressure (SBP and DBP) and heart rate were recorded for each rabbit up to 8 h, and urine samples were collected for 48 h post-dose. Plasma concentrations of diltiazem and its major metabolites were determined by HPLC. The results showed that systemic clearance (CL) and volume of distribution at steady state (Vdss) were smaller for diltiazem than for the metabolites. Diltiazem and the metabolites reduced both SBP and DBP, the effects of diltiazem being most potent. Their effects on heart rate were highly variable and not statistically different between treatment groups (P &gt; 0.05).
These results indicate that diltiazem is a more potent hypotensive agent than M1 or M2, possibly because of the higher plasma concentrations secondary to the smaller CL and Vdss of diltiazem compared with the metabolites. The effects of the metabolites might, however, be more sustained.
The Kinetic Profile of Vancomycin in Neonates
Authors: Silva R , Reis E , Bispo M A , Almeida A M , Costa I M , Falcão F , Palminha J M , Falcão A C 
Published: April 2011

Abstract
The pharmacokinetic parameters of vancomycin in a neonatal population have been characterized to enable development of optimum dosage guidelines for neonatal intensive-care units and to examine the relationship between these pharmacokinetic parameters and various demographic, developmental and clinical factors which might be associated with changes in the kinetic profile of vancomycin.
Forty-four infants (twenty-five males and nineteen females) with suspected or proven Gram-positive infection and who received intravenous vancomycin between October 1993 and December 1996 were included in this retrospective analysis. Gestational age ranged from 25 to 40 weeks and postconceptional age at the time of the study ranged from 28 to 45 weeks. Sixty case-studies were obtained from the forty-four patients, with one period of study corresponding to one week or one cycle of therapy. Vancomycin pharmacokinetic parameters were determined by use of a one-compartment model. By regression analysis the current weight (g) was shown to be the stronger covariate, and both vancomycin clearance (L h−1) and volume of distribution (L) had to be normalized. The vancomycin volume of distribution depended on the postconceptional age with a cut-off at 32 weeks, whereas vancomycin clearance depended on the presence or absence of concomitant treatment with indomethacin or of mechanical ventilation, or both.
On the basis of the pharmacokinetic parameters obtained we suggest initial dosage guidelines for vancomycin ranging from 10 mg kg−1 every 8 h to 10 mg kg−1 every 12 h, depending on the demographic and clinical characteristics of the patients. The results obtained enabled application of better a priori and a posteriori dosage schedules to infants in neonatal intensive-care units by use of the Bayesian approach, although further prospective study is recommended before direct extrapolation to patients in other settings.
6-Mercaptopurine Pharmacokinetics After Use of Azathioprine in Renal Transplant Recipients with Intermediate or High Thiopurine Methyl Transferase Activity Phenotype
Authors: Escousse A , Guedon F , Mounie J , Rifle G , Mousson C , D’Athis P 
Published: April 2011

Abstract
Prevention of allograft transplant rejection by the immunosuppressive 6-thiopurine drug azathioprine is limited by haematological toxicity (leucopenia or agranulocytosis). This toxicity is particularly apparent in subjects with low thiopurine methyltransferase activity (TPMTase) phenotype (1% in the Caucasian population). The thiopurine derivative 6-mercaptopurine is the active metabolite of azathioprine, and it would be of interest to measure, after validation of plasma measurements, the mean values of the pharmacokinetic parameters in transplant patients with high or intermediate TPMTase phenotypes (85 and 14% of the Caucasian population, respectively).
We measured erythrocyte TPMTase activity in 103 kidney transplant recipients of high or intermediate phenotype and calculated, after a test dose of azathioprine, the mean values of the pharmacokinetic parameters for 6-mercaptopurine. We also compared these values with the same parameters from one subject with low TPMTase activity phenotype. The mean observed area under the plasma concentration-time curve (AUC) was 190±140 ng mL−1 h and the elimination rate constant (el***) was 1.92±1.
The pharmacokinetic parameters (AUC, Ke1, t.1/2el (the elimination half-life)) of 6-mercaptopurine in transplant patients are normally distributed and suitable for acceptance as a gold standard value for this population of Caucasian transplant patients. It seems useful to calculate these parameters, representative of the systemic exposure of individual patients to the drug, before prescribing these subjects azathioprine immunosuppressive treatment. In subjects with low TPMTase phenotype these pharmacokinetic measurements could also be an index of dose reduction.
Ouabain-induced Increase in Dopamine Release from Mouse Striatal Slices is Antagonized by Riluzole
Authors: Boireau A , Meunier M , Imperato A 
Published: April 2011

Abstract
We have examined the effects of riluzole, a neuroprotective drug which stabilizes voltage-dependent sodium channels in their inactivated state and inhibits the release of glutamate in-vivo and in-vitro, on the release of newly taken up [3H]dopamine induced by ouabain, a potent and selective inhibitor of Na+/K+-ATPase in mouse striatal slices in-vitro.
Riluzole potently (IC50 (concentration resulting in 50% inhibition) = 0.9±0.3 μM) and dose-dependently antagonized ouabain-stimulated [3H]dopamine release, the effect being observed at low concentrations. Tetrodotoxin (1 μM) and nomifensine (10 μM) also abolished ouabain-induced [3H]dopamine release. Blockade of glutamate receptors with dizocilpine (1 μM) and 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione (YM-90K; 10 μM), alone or in combination, was without effect. Incubation of striatal slices with 50 μM La3+, which blocks voltage-dependent calcium channels, did not inhibit [3H]dopamine release induced by ouabain.
The potent effects of riluzole observed in this model are probably related to its ability to block voltage-dependent sodium channels. The consequences of this activity are critically discussed in relation to the protective action of riluzole previously reported in various models of Parkinson’s disease and other neurodegenerative disorders.
Anti-nicotinic Properties of Anticholinergic Antiparkinson Drugs
Authors: Gao Z G , Liu B Y , Cui W Y , Li L J , Fan Q H , Liu C G 
Published: April 2011

Abstract
The nature of the antagonism by anticholinergic compounds of nicotine-induced convulsion in mice has not been defined clearly. Although, because they do not compete effectively for agonist binding to brain tissue in-vitro, these compounds are thought to be non-competitive antagonists in the brain, pharmacological evidence is lacking. This study describes the anti-nicotinic properties of the clinically used anticholinergic antiparkinson drugs, benztropine, biperiden, caramiphen, ethopropazine, procyclidine and trihexyphenidyl.
Nicotine-induced convulsion and arecoline-induced tremor in mice were effectively prevented by these drugs. The concentrations of benztropine, biperiden, caramiphen, ethopropazine, procyclidine and trihexyphenidyl affording 50% prevention of nicotine-induced convulsion (ED50 values) were 7.4, 4.6, 7.8, 4.9, 3.1 and 3.3 mg kg−1, respectively. The classical muscarinic receptor antagonist atropine had potent anti-muscarinic effects but very weak anti-nicotinic activity. The classical nicotinic receptor antagonist mecamylamine had potent anti-nicotinic activity but no anti-muscarinic effects. The pattern of shift of the dose-response curve for nicotine-induced convulsion in mice was determined in the presence of increasing concentrations of the anticholinergic antiparkinson drugs. These drugs were found to increase the ED50 (0.49 mg kg−1) of nicotine-induced convulsion in a dose-related manner. The maximum effect of nicotine and the slope of nicotine dose-response curve were not significantly influenced by either low or high doses of benztropine, procyclidine or trihexylphenidyl, which suggests competitive action. Biperiden, caramiphen and ethopropazine, at low doses which significantly increased the ED50 of nicotine, did not affect the maximum effect of nicotine or the slope of the nicotine dose-response curve; at higher doses, however, they reduced the maximum effect and the slope, which suggests that these drugs have both competitive and non-competitive properties in antagonizing nicotine-induced convulsion in mice.
The experiments demonstrate that the anticholinergic antiparkinson drugs and mecamylamine effectively antagonize nicotine-induced convulsion, but atropine does not; some of these drugs have competitive properties whereas others seem to have both competitive and non-competitive properties in antagonizing nicotine-induced convulsion in mice.
Anti-HIV Activity and Mechanism of Action of Macrocyclic Diamide SRR-SB3
Authors: Mahmood Naheed , Jhaumeer-Lauloo Sabina , Sampson Julia , Houghton Peter J 
Published: April 2011

Abstract
The importance of cyclic compounds as anti-cancer and anti-viral agents has been recognized for some time. We have studied a series of macrocyclic amide derivatives for activity against HIV infection of T lymphocytes in-vitro.
Compounds containing aromatic rings and sulphur atoms were generally active, however the selectivity was greatly enhanced when two benzene rings were bridged by a disulphide linkage to produce 7-methyl-6,7,8,9-tetrahydrodibenzo[c,k][1,2,6,9]-dithiadiazacyclodode-cine-5,10-dione (SRR-SB3). This compound was studied in detail with different cell and virus infections including macrophages and chronically infected H9 cells. It was active with an EC50 (the dose affording 50% inhibition of infection) of 0.05—0.1 μgmL−1 and a TC50 (concentration reducing uninfected cell growth by 50%) of 50μmL−1. The compound did not inhibit protease, but seemed to act by inhibiting maturation of progeny virus, by interfering with precursor protein processing. It was synergistic with AZT (3′-azido-3′-deoxythymidine; zidovudine) when tested in-vitro.
The unusual mode of action and potent anti-HIV activity in T lymphocytes and macrophages makes this compound a potential candidate for clinical trials.
Comparison of the Efficacy of Free and Non-ionic-surfactant Vesicular Formulations of Paromomycin in a Murine Model of Visceral Leishmaniasis
Authors: Williams D , Mullen A B , Baillie A J , Carter K C 
Published: April 2011

Abstract
Non-ionic-surfactant vesicular (NIV) formulations of paromomycin have been tested in-vitro and in-vivo for their activity against Leishmania donovani.
Production of NIV was dependent both on the surfactant used and on the concentration of paromomycin; only two of the surfactants studied formed vesicles at the highest paromomycin concentration (9mg mL−1). At surfactant-lipid concentrations.1.5mM, suspensions of NIV (drug- or glucose-loaded) were cytotoxic to macrophages infected with L. donovani; high levels of nitrite were produced in cell supernatants. At surfactant-lipid concentrations &lt; 1.5 mM, drug-loaded NIV were more effective than the same dose of free drug, in terms of the percentage of cells infected and the number of parasites/cell. At surfactant-lipid concentrations.0.15mM, drug-loaded NIV were ineffective in-vitro. Invivo, treatment with decaethylene glycol mono n-hexadecyl ether paromomycin NIV was more effective than hexaethylene glycol mono n-hexadecyl ether paromomycin NIV, in terms of suppression of liver and spleen parasite burdens. Against liver parasites, both types of paromomycin-loaded NIV were more effective than free drug. Neither the NIV nor free forms of paromomycin caused significant suppression of bone-marrow parasites.
The study shows that entrapment of paromomycin in NIV can be used to increase its antileishmanial activity in-vitro and in-vivo.
Biphasic Insulin-releasing Effect of BTS 67 582 in Rats
Authors: Storey David A , Bailey Clifford J 
Published: April 2011

Abstract
BTS 67 582 (1,1-dimethyl-2(2-morpholinophenyl)guanidine fumarate) is being developed as a short-acting anti-diabetic insulin secretagogue. The effect of BTS 67 582 on the phasic pattern of insulin release was assessed in anaesthetized normal rats by measuring arterial plasma insulin concentrations while arterial glucose concentrations were fixed at 6, 8.5 and 12.5 mM.
Intravenous BTS 67 582 (10mgkg−1) induced an immediate but transient increase in insulin concentrations which declined by 10min (first phase). This was followed by a smaller but sustained increase in insulin concentrations (second phase). The increment from basal to peak insulin release (0–2 min) was independent of glucose, but the first phase was maintained for longer and the second phase was greater at the highest concentration of glucose (12.5 mM). BTS 67 582 also extended the first-phase insulin response to a standard intravenous glucose challenge and enhanced the rate of glucose disappearance by approximately 12%.
Thus BTS 67 582 causes biphasic stimulation of insulin release and augments the insulin-releasing effect of glucose.