bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in Gastric Mucosal Permeability Induced by Haemorrhagic Shock in the Anaesthetized Rat: - Modulation by Acid
Authors: Calatayud Sara , Barrachina M Dolores , García-Zaragoza Eugenia , Mattsson Hillevi , Esplugues Juan Vicente
Published: April 2011

Gastric mucosal damage induced by haemorrhagic shock in the anaesthetized rat has been evaluated by studying changes in capillary-to-lumen clearance of fluorescein isothiocyanate (FITC)-labelled dextran.

Haemorrhagic shock (20 min ischaemia + 20 min reperfusion) induced a significant increase in blood-to-lumen permeability to FITC-dextran of different molecular weight (10 000, 40 000 and 70 000) without modifying the macroscopic integrity of the gastric mucosa. The increase in vascular permeability was dependent on the time of administration of the tracer and was correlated with an elevation of the protein content of the gastric lumen. Intravenous administration of the secretagogue pentagastrin (20 or 50 μg kg−1 h−1) did not significantly modify the vascular permeability to dextran in control animals or in animals subjected to haemorrhagic shock. When the intraluminal pH was reduced by intragastric administration of acidic saline solution, only pH 1, which itself induced the appearance of macroscopic mucosal lesions, significantly increased vascular permeability to dextran, both in control animals and in animals subjected to haemorrhagic shock.

These findings suggest that stress induced by haemorrhagic shock increases vascular gastric permeability to dextran, by an acid-independent mechanism, without affecting the macroscopic integrity of the gastric mucosa.
Neuropharmacology: Effects on Rat Brain K1- and K2-Opioid Receptors after Chronic Treatment with Non-peptide K-Agonists
Authors: McConnaughey Mona M , Zhai Qing Zhu , Ingenito Alphonse J
Published: April 2011

Injection of K-agonist dynorphins and non-peptide K-agonists into the hippocampus induces a reduction in blood pressure. It has been postulated that K-opioid agonists and K-receptors are important in one mechanism of antihypertension and might have clinical potential for the treatment of hypertension. We have investigated whether chronic treatment with U-50488H and U-62066E, two non-peptide K-agonists, effects brain K1- or K2-receptor numbers or affinities in areas that might correlate with changes in blood pressure.

K 1- and K2-Opioid receptor affinities and densities were determined in cortex, hippocampus, hypothalamus, midbrain and pons after 14 days subcutaneous infusion of two non-peptide K-agonists, U-50488H and U-62066E, 9.6 mg kg day−1, by means of osmotic minipumps, to spontaneously hypertensive rats (SHR) and to Wistar-Kyoto (WKY) rats. This infusion significantly reduced blood pressure. Brains were removed within 48 h of the end of drug infusion and K-receptor binding studies were performed on homogenates from each brain area using [3H]U-69593 to assay K1-receptors and [3H]bremazocine to assay K2-receptors. U-62066E treatment seemed to cause a slight decrease in the number of [3H]bremazocine binding sites (K2-receptors) from 98.2 ± 9 to 74.9 ± 8 fmol (mg protein)−1 in the hippocampus when compared with SHR controls. A small decrease in K2-receptor density in the pons of WKY rats was also observed after U-50488H treatment (control, 51.2±5; U-50488H-treated, 24.3±9 fmol (mg protein)−1). Although SHR blood pressure values were consistently reduced by treatment with K-agonists, there was little if any significant change in apparent numbers of K1- or K2-receptors or their affinities in any of the brain regions examined.

These data indicate that although chronic treatment with K-agonists reduces blood pressure in SHR, the treatment does not elicit major changes in brain K-receptors either in SHR or in WKY rats. The potential use of K-agonists for treating hypertension might not cause receptor changes in the brain and might, therefore, result in fewer side effects or negligible rebound hypertension.
Brain Extracellular Levels of the Putative Antipsychotic CI-1007 and Its Effects on Striatal and Nucleus Accumbens Dopamine Overflow in the Awake Rat
Authors: Iyer Raj N , Davis M Duff , Juneau Paul L , Giordani Anne B
Published: April 2011

The compound CI-1007 (R-(+)-1,2,3,6-tetrahydro-4-phenyl-1[(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine maleate) has been identified as a partial dopamine agonist and putative antipsychotic in in-vitro and in-vivo neurochemical, neurophysiological and behavioural tests.

By use of microdialysis in conjunction with high-performance liquid chromatography (HPLC) with electrochemical detection, the effects of the drug on brain dopamine release, previously observed in anaesthetized animals, were shown to occur in awake animals also. Detection of peripherally administered CI-1007 in the brain, i.e. evidence of the drug’s ability to penetrate the blood-brain barrier, was achieved by use of in-vivo brain microdialysis in awake, freely moving rats and capillary HPLC in combination with tandem mass spectrometry (HPLC/MS/MS). Intravenous administration of CI-1007 (40 mg kg−1) significantly inhibits dopamine release in the nucleus accumbens, a region associated with dopamine hyperactivity in schizophrenia, while having a non-significant impact on the striatal dopamine neurotransmission which is critical to regular motor function.

The differential neurochemical profile of the drug indicates its potential usefulness in treating positive disease symptoms and implies that its extrapyramidal side effects are lower than those of typical antipsychotics.
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

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

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

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

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

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

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 > 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

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

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

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

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

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

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 < 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

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.
The Influence of the Neuropeptide Galanin on the Contractility and the Effective RefractoryPeriod of Guinea-pig Heart Papillary Muscle Under Normoxic and Hypoxic Conditions
Authors: Kocic Ivan
Published: April 2011

The aim of this study was to discover the effects of galanin, a neuropeptide comprising 29 amino acids capable of activating inward-rectifier K+ channels (IK1) in cardiomyocytes, on the force of contraction (Fc), velocity of contraction (+dF/dt), velocity of relaxation (—dF/dt) and effective refractory period (ERP) of guinea-pig heart. The influence of galanin on the time-course of hypoxia-induced disturbances in contractility and ERP was also examined. Experiments were performed on the isolated right ventricle papillary muscle of guinea-pig heart.

In the concentration range 0.001–0.01μM, galanin had no significant effect on the measured parameters. At 0.03 and 0.1 μM, galanin exerted a positive inotropic action and prolonged ERP. Further increasing the concentration led to a negative inotropic action and significant shortening of ERP. Although simulated hypoxia induced a significant drop in Fc, +dF/dt and —dF/dt, and a significant shortening of ERP, recovery of all the measured parameters was complete after 10min reperfusion. In the presence of 0.03 and 0.1 μM galanin the effect of hypoxia on the contractility of papillary muscle was more profound and reperfusion did not result in complete recovery. In contrast, addition of 1 μM galanin to the hypoxic solution significantly protected the muscle and recovery of the tissues during reperfusion was rapid and complete (in 5 min).

One can conclude that galanin at lower concentrations induced a positive inotropic action and a prolongation of ERP, but increased the sensitivity of heart muscle to hypoxia. At higher concentrations however, galanin exerted a negative inotropic action but protected the muscle against hypoxia-induced disturbances in contractility.
Gastroprotective Effect of l-Phenyl-3-(4-hydroxy-3,5-di-tert-butylphenyl)prop-2-en- 1 -one in Rats
Authors: Rao P N Praveen , Rao Mahadev , Rao M N A
Published: April 2011

1-Phenyl-3-(4-hydroxy-3,5-di-tert-butylphenyl)prop-2-en-1-one (PHP), an antioxidant, has been studied for gastroprotective activity in-vitro and in-vivo, more specifically for its capacity to inhibit in-vitro iron- and copper-driven oxidant damage at acidic pH values mimicking intragastric conditions in the clinical setting.

Our studies showed significant inhibition of both iron- and copper-driven oxidant damage at pH 3.5 and 5.3. Intragastric and intraperitoneal administration of PHP (250mgkg−1) reduced gastric mucosal haemorrhagic lesions in stress-induced and ethanol-induced rat models. The gastroprotective effect of PHP against ethanol was reversed significantly by prior treatment with a dose of indomethacin that inhibits prostaglandin biosynthesis, indicating a possible role of prostaglandins in its gastroprotective effect. Treatment of PHP replenished reduced levels of gastric mucosal non-protein sulphydryls in ethanol-treated rats, suggesting the mediation of its effect through sulphydryls.

These results indicate that PHP was active at acidic pH. This is an interesting observation because highly acidic pH is known to be important in the development of gastric ulcers. Our study suggests that PHP might protect gastric mucosa by its capacity to scavenge free radicals.
Disposition of 4-Methylbenzoylglycine in Rat Isolated Perfused Kidney and Effects of Hippurates on Renal Mitochondrial Metabolism
Authors: Masereeuw Rosalinde , Moons Miek M , Russel Frans G M
Published: April 2011

Hippurates tend to accumulate within proximal tubule cells during renal secretion. High intracellular concentrations can alter proximal tubular function or lead to tubular toxicity. In this study we examined the renal disposition of the hippurate 4-methylbenzoylglycine, a compound known for its high renal intrinsic clearance in-vivo. The effect of intracellular accumulation on mitochondrial respiration was also measured in-vitro and compared with that of the 2-methyl and 4-amino analogues.

Experiments were performed with either 2.5% pluronic or a combination of 2.2% pluronic and 2% bovine serum albumin (BSA) as oncotic agents. Within the concentration range studied (1–200 μg mL−1) tubular secretion seemed to be a function of the amount of unbound drug in the perfusate. Renal excretion data were best fitted by a model in which a Michaelis-Menten term was used to describe active secretion. Parameters obtained after the analysis of renal excretion data were the maximum transport velocity (TM = 55 ± 2 μg min−1) and the Michaelis-Menten constant for tubular transport (KT = 4.2 ± 0.8 μg mL−1). The compound accumulated extensively in kidney tissue, ratios up to 600 times the perfusate concentration were reached. Accumulation could be explained by active tubular uptake and data were analysed best by a model similar to the model used to describe renal excretion. Calculated parameters were theoretical maximum capacity (RM = 300 ± 210 μg g−1) and affinity constant for renal accumulation (KA = 5.0 ± 4.4 μg mL−1). The high intracellular concentrations of 4-methylbenzoylglycine had no effect on kidney function and mitochondrial oxygen consumption. The 2-methyl analogue reduced mitochondrial respiration slightly, but 4-aminobenzoylglycine (p-amino-hippurate) caused a significant reduction.

In conclusion, this study shows that renal accumulation of a hippurate is determined by the efficiency of its tubular secretion. Whether the high intracellular concentrations affect tubular cell functioning depends on the analogue involved.
Ultrastructural Localization of Nicorandil in the Heart of Rats
Authors: Kitajima Shunichi , Tsuchiya Yoko , Sakai Kazushige
Published: April 2011

To examine the intracellular localization of nicorandil in the heart, [14C]nicorandil and [3H]nicorandil (3 mg kg−1) were given orally to rats.

The maximum concentration (Cmax) of nicorandil in the myocardium was reached 15 min after the oral dosing. At this time subcellular localization of nicorandil was examined. Nicorandil and its denitrated metabolite, SG-86 were found in mitochondrial fractions and in cytosolic and microsomal fractions of the heart. Electron-microscopic autoradiograms recorded 15 min after oral dosing of 3 mg kg−1 [3H]nicorandil to rats also showed the presence of silver grains generated by the radioactive nicorandil or its metabolites in the mitochondria of the heart.

We conclude that nicorandil given orally to rats is distributed in mitochondria of the heart.
Hydroxylated Metabolites of Thalidomide: Formation In-vitro and In-vivo in Man
Authors: Eriksson Tommy , Björkman Sven , Roth Bodil , Björk Henrik , Höglund Peter
Published: April 2011

There is renewed interest in the clinical use of thalidomide, because of its unique immunomodulating action. Because data on the metabolism of thalidomide in man are very sparse, the aim of this study was to develop HPLC assays for the 5-hydroxy, 5,6-dihydroxy, 4,5-dihydroxy and 5′-hydroxy metabolites of thalidomide and to investigate their possible formation in man—in-vitro in liver homogenates and in-vivo in healthy volunteers.

Reversed-phase HPLC assays with UV detection were developed for quantification of the metabolites in the low ng mL−1 range in plasma and incubate samples. The stability of the metabolites was investigated and degradation was avoided by rapid chilling and acidification of the samples. After incubation of thalidomide with fraction S9 from human liver, formation of the 5-hydroxy and 5′-hydroxy metabolites could be demonstrated. The 5′-hydroxy metabolite was found, in low concentrations, in plasma samples from eight healthy male volunteers who had received thalidomide orally. The other three metabolites could not be found by HPLC with detection limits of 1–2 ng mL−1.

Thus the formation of two hydroxylated metabolites of thalidomide in the liver in man was demonstrated, but only one of these could be detected in the circulation.
Antinociceptive Effect in Mice of a Hydroalcoholic Extract of Neurolaena lobata (L.) R. Br. and its Organic Fractions
Authors: Gracioso Juliano S , Paulo Marçal Q , Lima Clélia A Hiruma , Brito Alba R M Souza
Published: April 2011

An infusion of the aerial parts of Neurolaena lobata (L.) R. Br. (Compositae-Asteraceae) is used in Caribbean folk medicine to treat several kinds of pain. In this investigation we studied the acute oral toxicity of the hydroalcoholic extract of the plant and the antinociceptive effect of the extract and of its hexane- and chloroform-partitioned fractions, given orally, in nociception and inflammatory models in mice.

No signs of toxicity were observed for oral doses up to 5000 mg kg−1 in mice. Morphine hydrochloride (10 mg kg−1), dipyrone sodium (200 mg kg−1), the hydroalcoholic extract (1000 mg kg−1), and its chloroform- and hexane-partitioned fractions (100 mg kg−1) significantly inhibited acetic acid-induced abdominal constriction in mice (100, 95, 47, 62 and 60% inhibition, respectively when compared with the negative control). In the hot-plate test in mice, morphine hydrochloride, the chloroform- and hexane-partitioned fractions, but not the hydroalcoholic extract, resulted in a significant latency increase in all observation times. In the acetic acid-induced abdominal constriction in mice, pretreatment of the animals with naloxone significantly reversed the analgesic effect of morphine, but not that of the hydroalcoholic extract or of its hexane- and chloroform-partitioned fractions. Finally, administration of the hexane- and chloroform-partitioned fractions (100 mg kg−1) had a significant anti-oedematogenic effect on carrageenan-induced oedema in mice.

These data show that the hydroalcoholic extract of N. lobata and, in particular, its partitioned fractions have significant analgesic properties when assessed through these pain models. Their antinociceptive effect might be the result of interference with the inflammatory process.
Optimization of Sustained-release Diltiazem Formulations in Man by use of an In-vitro/In-vivo Correlation
Authors: Yu K , Gebert M , Altaf S A , Wong D , Friend D R
Published: April 2011

In-vitro/in-vivo correlations (IVIVC) are useful for predicting in-vivo results from in-vitro data. An IVIVC has been used to optimize a hydrocolloidal-based matrix tablet designed to be bioequivalent to an existing once-daily diltiazem HCl*** product (Dilacor XR 240 mg; Rhone-Poulenc Rorer).

Data from a preliminary formulation dosed to fasted and fed subjects were used to establish the IVIVC. The correlation was then used during reformulation of the dosage forms to predict changes in the maximum plasma concentration (Cmax) and the area under the plasma-concentration-time curve (AUC) for fasted and fed subjects using in-vitro dissolution data.

The IVIVC adequately predicted plasma profiles of two optimized formulations in studies with fasted and fed subjects.
Prediction of Serum Vancomycin Concentrations using One-, Two- and Three-compartment Models with Implemented Population Pharmacokinetic Parameters and with the Bayesian Method
Authors: Wu Guang , Furlanut Mario
Published: April 2011

Although previous studies have shown that vancomycin has a complicated pharmacokinetic profile requiring description using a two- or, better, three-compartment model, until recently predictions of serum vancomycin concentrations have been mainly based on one- or two-compartment models using computer software packages. In this study, we have predicted serum vancomycin concentrations in 59 patients using one-, two- and three-compartment models with implemented population pharmacokinetic parameters in the Abbott PKS program and by use of the Bayesian method.

The percentage errors of predictions made using the one-compartment model were smaller when either the Bayesian method or implemented population pharmacokinetic parameters were used (medians of −8·61% and −9·49%, respectively). Predictions using the one-compartment model with the Bayesian method were less biased (median of −1·52 μgmL−1). The best predictions were those made using the three-compartment model with the Bayesian method—they were most accurate (median of 3·40 μg mL−1) and highly precise (median of 11·53 μg2mL−1).

The results suggest that predictions made using the one-compartment model with implemented population pharmacokinetic parameters are preferable if no samples are available, otherwise predictions made using the three-compartment model with the Bayesian method are preferable. The results also supported our previous argument that the greater the number of compartments involved in individualization, the better the predictions obtained using the Bayesian method.
Effects of Tetramethylpyrazine on Portal Hypertensive Rats
Authors: Chang Fang-Chi , Chen Ke-Ji , Lin Jaung-Geng , Hong Chuang-Ye , Huang Yi-Tsau
Published: April 2011

The effects of tetramethylpyrazine, an alkaloid isolated from a Chinese herb Ligusticum wallichii Franch have been assessed in portal hypertensive rats.

Portal hypertension was induced by partial portal vein ligation in Sprague-Dawley rats. Two weeks after ligation, when the hyperdynamic state had stabilized, rats were anaesthetized after an overnight fast and cannulated for measurement of mean arterial pressure, portal venous pressure, cardiac index and heart rate. Tetramethylpyrazine (3·0, 9·9 and 30mgkg−1) induced dose-dependent reductions of portal venous pressure and mean arterial pressure after intravenous infusion. The maximum percentage reduction of portal venous pressure after tetramethylpyrazine was 6·0±0·8, 9·3±1·6 and 20±2% of baseline for doses of 3·0, 9·9 and 30·0mgkg−1, respectively. Also, total peripheral resistance was significantly reduced by tetramethylpyrazine and cardiac index was slightly increased.

Our results showed that tetramethylpyrazine induced portal pressure reduction in portal hypertensive rats.
Prejunctional Control of pH 6-Induced Bronchoconstriction by NK1, NK2, μ-Opioid, β2-Adrenoceptor and Glucocorticoid Receptors in Guinea-pig Isolated Perfused Lung
Authors: Auberson Serge , Lacroix Jean S , Kordestani Rouzbeh K , Lundberg Jan M
Published: April 2011

This study investigated the release of calcitonin-gene related peptide-like (CGRP) immunoreactivity and bronchoconstriction induced by pH 6 buffer in guinea-pig isolated perfused lung.

Both pH 6-induced CGRP-like immunoreactivity and bronchoconstriction were completely abolished after systemic pretreatment with capsaicin. Pretreatment with the NK2 receptor antagonist SR 48968 (5 times 10−7M) completely inhibited bronchoconstriction and significantly reduced the immunoreactivity induced by the pH 6 buffer. The NK1 antagonist SR 140333 (5 times 10−7M) and, to a lesser extent the NK1 antagonist CP 96345, morphine (5 times 10−6M), the α2-adrenoceptor agonist UK 14304 (10−7M) and betamethasone (10−6M) significantly reduced both pH 6-induced bronchial response and CGRP-like immunoreactivity overflow. The effects of morphine and UK14304 were partially reversed by naloxone (5 times 10−5M) and idazoxan (5 times 10−5M).

Therefore, NK1, NK2, μ-opioid, α2-adrenoceptor and glucocorticoid receptors seemed to have a prejunctional action on pH 6 buffer-induced CGRP-like immunoreactivity and bronchoconstriction.
Use of Protease Inhibitors to Improve Calcitonin Absorption from the Small and Large Intestine in Rats
Authors: Tozaki Hideyuki , Odoriba Tomokazu , Iseki Tomoya , Taniguchi Toshio , Fujita Takuya , Murakami Masahiro , Muranishi Shozo , Yamamoto Akira
Published: April 2011

The objective of this study was to examine the effects of protease inhibitors on the absorption of calcitonin from different regions of the intestine in rats. The absorption experiments were investigated by in-situ use of closed intestinal loops in rats and stability of calcitonin was examined in mucosal homogenates and intestinal fluids. The intestinal absorption of calcitonin was evaluated by measurement of its hypocalcaemic effect.

No substantial hypocalcaemic response was observed when calcitonin was administered into the jejunum or colon. A slight hypocalcaemic effect was observed after administration of calcitonin into the ileum. Of the co-administered protease inhibitors, bacitracin (20 mM) strongly promoted calcitonin absorption from the jejunum, ileum and colon. A significant hypocalcaemic effect was also obtained after intestinal administration of calcitonin with soybean trypsin inhibitor (10mgmL−1), camostat mesylate (20mM) or aprotinin (2mgmL−1). In the stability experiment, bacitracin reduced the degradation of calcitonin in the different intestinal homogenates. Soybean trypsin inhibitor significantly reduced the degradation of calcitonin in the fluids of the small intestine. We also examined the different endopeptidases in gut luminal fluids and the different exopeptidases in gut mucosal homogenates of rats. The ranking order for the total endopeptidase activity of the intestinal fluids was jejunum > ileum > colon. That for total exopeptidase activity of the intestinal mucosa was jejunum > ileum > colon.

These results suggest that endo- and exopeptidases might be responsible for the hydrolysis of calcitonin and that protease inhibitors might usefully improve absorption of calcitonin to the systemic circulation from the large intestine.
Delayed Healing of Chronic Gastric Ulcer after Helicobacter pylori Infection in Mice
Authors: Makino Mitsuko , Koga Tetsufumi , Ito Keiichi , Kawada Harumi , Tabata Keiichi
Published: April 2011

It has been suggested that there is a close relationship between Helicobacter pylori and the onset or recurrence of gastroduodenal disease. The aim of this study was to examine the effect of H. pylori on the healing of chronic gastric ulcers induced in mice.

H. pylori administered to nude mice delayed the healing of experimental acetic acid-induced gastric ulcers. Histological examination showed the occurrence of high densities of H. pylori on the surface of epithelial cells and in the ulcerated area. Repeated administration of amoxicillin (10 mg kg −1 daily for 5 days) eradicated H. pylori and increased the rate of healing of gastric ulcers in H. pylori-infected mice, but metronidazole, which also eradicated the organisms, did not significantly affect the rate of healing.

In conclusion, H. pylori-infection delayed the healing of gastric ulcers induced by the serosal application of acetic acid in mice, possibly by aggravation or prolongation of the mucosal inflammation. Amoxicillin eradicated H. pylori and promoted gastric ulcer healing in mice infected with H. pylori.
A Comparative Study of the Effects of Sparteine, Lupanine and Lupin Extract on the Central Nervous System of the Mouse
Authors: Pothier J , Cheav S-L , Galand N , Dormeau C , Viel C
Published: April 2011

Lupin is toxic because of its alkaloid content, sparteine and lupanine in particular. Although the pharmacological properties of sparteine are well known those of lupanine have not been much studied. This paper reports procedures for extraction, purification and crystallization of lupanine, and methods for the preparation of an extract for injection of Lupinus mutabilis Sweet, and for the determination of the acute toxicity and maximum non-lethal dose (DL0) of lupanine, sparteine and lupin extract in the mouse.

The three substances were tested on the central nervous system (CNS) for locomotor activity, for interaction with specific drugs used for treatment of the CNS (the stimulant drugs amphetamine and pentetrazol and the depressant drugs pentobarbital and chlorpromazine) and for analgesic activity.

The results indicate that lupanine and lupin extract are less toxic than sparteine and that at the doses studied the three products have a weak sedative effect on the CNS.