bluuebunny/crossref_metadata_2025 huggingface dataset:
Sympathomimetic Actions of Methylenedioxymethamphetamine in Rat and Rabbit Isolated Cardiovascular Tissues
Authors: Fitzgerald J L , Reid J J
Published: April 2011

The aim of this study was to investigate the actions of methylenedioxymethamphetamine (MDMA) in several isolated cardiovascular tissues. In spontaneously beating rat atria, concentration-dependent positive chronotropic responses to MDMA and amphetamine were blocked by the neuronaluptake inhibitor desipramine (1 μm) and the β-adrenoceptor antagonist propranolol (1 μm). In atria incubated with [3H]noradrenaline to label transmitter stores, 10 μm MDMA and 1 μm amphetamine increased the resting outflow of radioactivity, while 1 μm desipramine had no effect on resting outflow. The MDMA- and amphetamine-induced release of radioactivity were blocked by 1 μm desipramine. MDMA, amphetamine and desipramine each enhanced the electrical stimulation-induced (2 Hz, 30-s train) release of radioactivity; the enhancing effects of MDMA and amphetamine were blocked by 1 μm desipramine. In rat isolated perfused hearts, MDMA (1 and 10 μm) increased heart rate by a similar amount to the increase caused by noradrenaline (10 and 50 Nm). MDMA also induced dysrhythmias in 7 out of 11 rat isolated perfused heart preparations. In rabbit isolated perfused and superfused ear arteries preloaded with [3H]noradrenaline, MDMA increased the resting release of radioactivity by 230 ± 18% (n = 6) of control resting release; the increase was accompanied by a rise in perfusion pressure of 17 ± 7 mmHg (n = 6). MDMA also facilitated the vasoconstrictor responses to noradrenaline (3–9 ng) and perivascular nerve stimulation (1–5 Hz, 10-s train). MDMA-induced vasoconstriction and the facilitation of vasoconstrictor responses to noradrenaline and electrical stimulation were blocked by 1 μm desipramine. These results suggest that MDMA has similar sympathomimetic activity to amphetamine on cardiovascular tissues. The sympathomimetic actions of MDMA could account for the cardiovascular side-effects associated with its use.
Determination of Protein Binding of a Highly Lipophilic Drug, Isocarbacyclin Methyl Ester (TEI-9090), Using a Polydimethylsiloxane-coated Glass Beads Assay
Authors: Minagawa Toshiya , Kohno Yoshiro , Suwa Toshio , Tsuji Akira
Published: April 2011

An adsorption technique with polydimethylsiloxane-coated glass beads (PDMS-GB) was developed to determine the protein binding of a highly lipophilic and hydrophobic drug. The present assay method is based on the quantitative adsorption of unbound drug to the PDMS-GB. This method of batch separation in a glass assay tube has an advantage of simplicity and rapidity. To evaluate the reliability of PDMS-GB assay, we compared the protein binding of diazepam in serum in-vitro measured by ultrafiltration and PDMS-GB assay. There was no significant difference between the extent of binding measured by each method. Using PDMS-GB assay, we determined the protein binding of the prostaglandin I2 (PGI2) analogue isocarbacyclin methyl ester (TEI-9090), whose binding cannot be measured by commonly employed techniques (equilibrium dialysis, ultrafiltration, gel filtration or ultracentrifugation) because of a high degree of adsorption to membranes, resins or tubes. The percentage of TEI-9090 bound in human serum, 4% human serum albumin (HSA, fatty acid-free) and dog serum were ∼98, ∼87 and ∼95%, respectively, and these values were independent of TEI-9090 concentration up to 10 ng mL−1. The binding of isocarbacyclin (TEI-7165) to serum protein in man, dogs, rabbits and rats, determined by ultrafiltration, was also high (>90%). While the displacement of TEI-9090 and TEI-7165 binding to HSA by aspirin, salicylic acid and indomethacin was not observed, clofibric acid and free fatty acids significantly inhibited the protein binding of both compounds. These results indicate that the binding site of TEI-9090 and TEI-7165 on HSA could be identical with the possible binding site of PGI2.
Factors Influencing Gel-strengthening at the Mucoadhesive-mucus Interface
Authors: Mortazavi S Alireza , Smart John D
Published: April 2011

Mechanical spectroscopy was used to examine some of the factors that may affect mucus gel strengthening: the effect of adding various concentrations of sodium chloride; mucoadhesive polymer molecular weight and its concentration; and the introduction of anionic, cationic and neutral polymers. A reduction in the storage modulus of the mucus/mucoadhesive mixture was observed with the introduction of sodium chloride. A poly(acrylic acid) with a molecular weight of 750 kDa gave the optimum mucus gel strengthening effect relative to other molecular weights. An anionic polymer was found to strengthen the mucus gel much more than a neutral or cationic polymer. It was proposed that the gel strengthening effect could be due to the formation of hydrogen bonded intermolecular complexes between the mucoadhesive and the mucus molecules. Furthermore, the complex formed is influenced by the ionic strength of the environment, and the molecular weight, nature and concentration of the mucoadhesive. In all cases the changes in the rheological properties of the mixes could be correlated directly to the strength of mucoadhesion reported in previous studies.
Depletion of Pulmonary Glutathione Using Diethylmaleic Acid Accelerates the Development of Oxygen-induced Lung Injury in Term and Preterm Guinea-pig Neonates
Authors: Langley Simon C , Kelly Frank J
Published: April 2011

Dietary or chemical depletion of pulmonary glutathione in adult rats and mice, has been demonstrated to exacerbate the toxic effects of high oxygen concentrations. The present paper has examined this phenomenon in a guinea-pig model of prematurity, using the electrophilic agent diethylmaleic acid (DEM) to provide a transient (up to 12 h) pulmonary glutathione depletion. Full-term and 3-days preterm guinea-pig pups were studied to assess the possible role for glutathione deficiency as a mechanism mediating the increased susceptibility of the immature lung to oxygen free-radical damage. The administration of DEM to guinea-pig neonates depleted lung glutathione by 90% (term) or 68% (preterm) over 2 h. On exposure of pups to 95% oxygen for 48 h, DEM increased the incidence of oxygen-related death to 31 % in term pups and 100% in preterm pups. Term pups exposed to hyperoxia and treated with DEM showed evidence of pulmonary injury, indicated by an influx of neutrophils into the lung airspaces, and elevated microvascular permeability. Control pups exposed to 95% oxygen were found to have uninjured lungs after 48 h. We conclude that glutathione is an essential component of the pulmonary antioxidant array in neonates. Glutathione may be of particular importance in the early phase of oxygen exposure. The deficiency of lung glutathione observed in preterm animals may account for their increased susceptibility to oxygen-induced pulmonary injury.
N
G-Nitro-l-arginine methyl ester inhibits the effect of an H3-histaminergic receptor agonist on NANC contraction in guinea-pig perfused bronchioles
Authors: Burgaud J L , Oudart N
Published: April 2011

A role for nitric oxide in the H3-histaminergic agonist-induced inhibition of the non-adrenergic, non-cholinergic (NANC) contraction has been studied in guinea-pig perfused bronchioles. (R)-α-Methylhistamine ((R)-α-MeHA), an agonist for H3 receptors, inhibited the NANC contraction induced by electrical field stimulation. NG-Nitro-l-arginine methyl ester (l-NAME) (50 μm), an inhibitor of nitric oxide synthesis, blocked the effect of (R)-α-MeHA. The effect of l-NAME was reversed by l-arginine (50 μm). l-NAME, l-arginine or (R)-α-MeHA were without effect on exogenous substance P- or neurokinin A-induced contractile responses of the perfused bronchioles. These results show that an H3-agonist inhibited the release of neurotransmitters in NANC nerve endings of guinea-pig perfused bronchioles presumably by production of nitric oxide.
Pharmaceutical Evaluation of Carbamazepine Modifications: Comparative Study for Photostability of Carbamazepine Polymorphs by using Fourier-transformed Reflection-absorption Infrared Spectroscopy and Colorimetric Measurement
Authors: Matsuda Yoshihisa , Akazawa Rieko , Teraoka Reiko , Otsuka Makoto
Published: April 2011

The tablet surface was evaluated without physical damage by means of Fourier-transform infrared reflection-absorption spectroscopy (FT-IR-RAS) and colorimetric measurement (colour difference, AE) of the carbamazepine polymorphs I, II and III, after photodegradation at two irradiation intensities (30 and 120 J cm−2  s−1) under a near-UV fluorescent lamp. The surface of sample pellets of all crystalline forms turned gradually from white to yellow-orange upon exposure to light, and the discoloration rate of form II was faster than that of forms I and III, indicating that form II was the most unstable of the three. The major photoproducts were identified by HPLC, NMR and MS analyses. The carbamazepine content on the surface of the tablet was determined based on the absorption at 1685 cm−1 atributable to C = O stretch vibration in the FT-IR-RAS spectra before and after irradiation by a near-UV fluorescent lamp. The semilogarithmic plots of the photodegradation profiles of the various polymorphs were straight lines, including the induction period, indicating that degradation of the drug on the surface followed first-order kinetics. The induction periods of all forms were not significantly different. However, the degradation rate constant of form II at 12.0 Jcm−2  s−1 was 5·1 and 1·5 times larger than those of forms I and III, respectively.
Study of the Compaction Mechanisms of Lactose-based Direct Compression Excipients using Indentation Hardness and Heckel Plots
Authors: Monedero Perales Maria Del Carmen , Muñoz-Ruiz Angel , Antequera Maria Victoria Velasco , Ballesteros Maria Rosa Jiménez-Castellanos
Published: April 2011

Indentation hardness of tablet surfaces has been used to determine the consolidation mechanisms of the lactose-based excipients Fast Flo Lactose, Ludipress, Cellactose and Tablettose. The Leuenberger equation has been modified to obtain values of compressibility and compactability by using a value of compactability obtained from a tablet at maximum applied force and by substituting deformation resistance by relative deformation resistance. Also, parameters obtained from plots of the Heckel tablet-indie and ejected-tablet methods were calculated in order to establish the comparative consolidation mechanisms in the lactose-based excipients under study. The possibility of using the absolute value of the difference between upper and lower surface hardnesses of the tablets made on an eccentric press is suggested as an alternative method to determine the comparative consolidation mechanisms of different substances.
Effect of Hydroxypropyl-β-cyclodextrin on the Antimicrobial Action of Preservatives
Authors: Lehner S J , Müller B W , Seydel J K
Published: April 2011

The interaction between hydroxypropyl-β-cyclodextrin (HP-β-CyD) and several preservatives with different chemical structures was investigated in aqueous solution. Complex stability constants of the 1:1 complexes were calculated from differential spectra. Using the serial dilution test the antimicrobial activities of the preservatives and their complexes against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Candida albicans were tested and MIC values determined. For highly water-soluble substances like thimerosal and bronopol, low or no inactivation was found; the more lipophilic substances, such as the phenolic compounds, showed strong inactivation when used in combination with HP-β-CyD. The loss in activity by complex formation correlated with the bound fraction, thus suggesting that the appropriate antimicrobial substance for the preservation of cyclodextrin solutions can be selected according to the results of this study.
Protective Effects of Arginine-vasopressin on Aspirin-induced Gastric Mucosal Damage in Anaesthetized Dogs
Authors: Hung Chen-Road , Wang Jiahn-Jyh , Chang Wen-Chang , Shen Ching-Liang
Published: April 2011

The protective effects of graded doses of arginine-vasopressin (AVP) on acidified acetylsalicylic acid (ASA) solution-induced changes in gastric prostaglandin E2 (PGE2) secretion, mucus production, acid back-diffusion and mucosal damage were studied in the bilateral truncal vagotomized stomach of anaesthetized dogs. After 1–4 h intragastric irrigation of the stomach with AVP (1–100 ng kg−1) plus 20 min acidified ASA solution, a significant (P < 0·05) inhibition in gastric mucosal lesions and acid back-diffusion produced by acidified ASA solution was observed. The reduction in the gastric PGE2 secretion and in mucus production provoked by the same dose of acidified ASA solution was also diminished. Furthermore, a correlation (r = 0·883; P < 0·01) between AVP-induced inhibition in ASA-provoked reduction in gastric PGE2 secretion and in mucus production was found. During the experiment, the heart rate, the peripheral arterial blood pressure and the gastric arterial blood pressure were not altered by AVP (1–100 ng kg−1). Thus, intragastric AVP protects gastric mucosa against ASA-induced damage without producing cardiovascular side effects. The inhibitory effects of AVP (100 ng kg−1) on acidified ASA-induced reduction in PGE2 and mucus secretion, as well as on ASA-induced enhancement in acid back-diffusion and erosion production were dose-dependently reversed by a specific V1 antagonist, 1-(β-mercapto-β,β-cyclopentamethylene-propionic acid), 2-(o-methyl)tyrosine-Arg8-vasopressin. From the above results, it is suggested that the protective effects of intragastric AVP on gastric mucosa against acidified ASA-induced damage is at least partly due to stimulation of the biosynthesis of gastric PGE2, which may contribute to the increase in the gastric mucus secretion and to the decrease in acid back-diffusion. Furthermore, the endogenous PGE2 stimulated by AVP may be mediated by V1-receptor activation.
Anti-inflammatory Activity of Polygonum bistorta, Guaiacum officinale and Hamamelis virginiana in Rats
Authors: Duwiejua M , Zeitlin I J , Waterman P G , Gray A I
Published: April 2011

The aqueous ethanolic extracts of Polygonum bistorta L. Polygonaceae, Guaiacum officinale L. Zygophyllaceae and Hamamelis virginiana L. Hamamelidaceae were screened for anti-inflammatory activity. Administered (100 and 200 mg kg−1, p.o.) before the induction of carrageenan rat paw oedema, extracts of P. bistorta significantly suppressed both the maximal oedema response and the total oedema response (monitored as area under the time course curve). H. virginiana was inactive and G. officinale was only active at 200 mg kg−1. At 200 mg kg−1 administered before the induction of adjuvant arthritis, P. bistorta significantly inhibited both the acute and chronic phases of the adjuvant-induced rat paw swelling, while G. officinale and H. virginiana were only active against the chronic phase. Further studies on P. bistorta (100–800 mg kg−1) revealed a dose-dependent inhibition of the carrageenan-induced rat paw oedema over the dose range 100–400 mg kg−1, the E50 value being approximately 158·5 mg kg−1. The extract (200 mg kg−1), administered after the onset of the inflammatory responses reversed the course of both the carrageenan- and adjuvant- induced rat paw swelling. The results confirm that the extracts of P. bistorta, G. officinale and H. virginiana contain anti-inflammatory substances.
Effect of Three Lipophilic Methotrexate Derivatives Upon Mediator Release by Lipopolysaccharide-stimulated Rat Peritoneal Macrophages
Authors: Williams A S , Topley N , Amos N , Williams B D
Published: April 2011

The ability of methotrexate and three lipophilic derivatives (methotrexate-γ-dimyristoylphos-phatidylethanolamine (MγD), methotrexate-α-dimyristoylphosphatidylethanolamine (MαD) and metho-trexate-α-γ-di-dimyristoylphosphatidylethanolamine (MαγD) to modulate mediator release by lipopolysaccharide-stimulated rat peritoneal macrophages was investigated. At nontoxic concentrations, approximately 10 nmol/105 cells, MαD and MγD produced 11·06±1·0 and 75·6 ± 5·2%, respectively, inhibition of tumour necrosis factor (TNF) release (mean ± s.e.m., n = 4). At this same dose MαγD resulted in 68·8 ± 2·1 % inhibition of TNF but cellular ATP levels were reduced by 80%. The inhibitory activity of all three derivatives was dose-dependent. Non-derivatized methotrexate at a concentration of 25 nmol/105 cells had no inhibitory effect upon TNF release (14·7 ±0·8%, n = 3). Determination of prostaglandin E2 (PGE2) levels in the same samples demonstrated that all three conjugates were powerful inhibitors of prostaglandin release. At a quarter of the conjugate concentrations described above the monoamides MαD (31 nmol/105 cells) and MγD (2·5 nmol/105 cells) maintained their effects on PGE2 production with 73±2·3 and 71±2·0% (n=4) inhibition, respectively. At this lower concentration, however, the diamide MαγD (3·1 nmol/105 cells) was less effective in reducing the amount of PGE2 released from the macrophages (29 ± 18%, n = 4). Maximal PGE2 inhibition by each of the conjugates was attained at approximately 5 nmol/105 cells. Unconjugated methotrexate (range of 2·5–20 nmol/105 cells) did not inhibit the release of PGE2 from lipopolysaccharide-stimulated macrophages.
Inhibitory Effects of Daunorubicin on Endothelium-dependent Vasorelaxing Response to Acetylcholine of Rat Aorta
Authors: Wakabayashi Ichiro , Hatake Katsuhiko , Yoshimoto Sachiko , Sakamoto Kunihiro
Published: April 2011

The effect of daunorubicin on the endothelium-dependent vasorelaxing response to acetylcholine was investigated using rat isolated aorta and compared with the effect of aclarubicin. Treatment of aortic strips with daunorubicin (20 μM) significantly attenuated the relaxing response to acetylcholine in the absence of tetraethylammonium, but not in its presence. Pretreatment with daunorubicin at a higher concentration (50 μM) or with aclarubicin (20 μM) strongly attenuated the relaxing response to acetylcholine; this attenuation was unaffected by the presence of tetraethylammonium. The increase in aortic cGMP in response to acetylcholine was also significantly suppressed by pretreatment with 50 μM daunorubicin or 20 μM aclarubicin, but not by treatment with 20 μM daunorubicin. The inhibitory effect of 20 μM aclarubicin on the acetylcholine-induced responses was stronger than that of 50 μM daunorubicin. Even in strips pretreated with both 50 μM daunorubicin and 20 μM aclarubicin, relaxation induced by 0·1 μM sodium nitroprusside was retained. These results suggest that daunorubicin at 20 μM inhibits the endothelium-dependent vasorelaxing response to acetylcholine via a mechanism other than the nitric oxide-mediated pathway, whilst at 50 μM, it inhibits the nitric oxide-mediated vasorelaxation.
Binding Sites of Fluorescent Probes on Human Serum Albumin
Authors: Muller N , Lapicque F , Drelon E , Netter P
Published: April 2011

Human serum albumin is known to have two major and selective drug binding sites, termed sites I and II. The fluorescent probes, dansylamide and dansylsarcosine selectively interact with sites I and II, respectively. However, the binding site of the fluorescent probe dansylglycine on human serum albumin is not clear from the literature. This study investigated whether dansylglycine interacts tightly with site I or II. Spectrofluorimetric titrations (quenching and complex) and circular dichroism measurements were performed to determine the binding characteristics of dansylglycine to human serum albumin. Modification in probe fluorescence was described by fluorescence titrations to be a result of competitive displacement by ligands. The pattern of displacement of this probe by several ligands whose primary binding sites are exactly known, enabled the identification of its specific binding site. The fluorescence of dansylglycine is only extensively changed when ligands of site II are added, suggesting that it strongly interacts with the benzodiazepine/indole binding site on human serum albumin.
Decreased cerebral 5-HT1A receptors during ageing: reversal by Ginkgo biloba extract (EGb 761)
Authors: Huguet François , Drieu Kathy , Piriou Alain
Published: April 2011

Investigation of [3H]8-hydroxy-2(di-n-propylamino)tetralin binding to 5-HT1A receptors in cerebral cortex membranes of Wistar rats showed that the maximal number of binding sites (Bmax) was reduced significantly (22%) in aged (24-month-old) as compared with young (4-month-old) animals. Chronic treatment with Ginkgo biloba extract did not alter binding in young rats but increased binding density significantly (33%) in aged rats. These results confirm previously described age-related 5-hydroxytryptaminergic alterations. Together with data in the literature, they also suggest a restorative effect in aged rats, associated with decreased receptor density resulting from the protective action of Ginkgo biloba extract treatment on neuronal membrane.
Selectivity of LG50643 for Postjunctional Muscarinic-receptor Subtype in the Guinea-pig Trachea
Authors: D’Agostino G , Renzetti A R , Zonta F , Subissi A
Published: April 2011

The effects of (±)-LG50643, a new N-quaternary tropinic ester of phenylcyclohexene carboxylic acid, endowed with a potent antimuscarinic activity, have been investigated on muscarinic receptor-mediated responses of the guinea-pig trachea to electrical field stimulation. An isolated preparation which allows the simultaneous measurement of tritiated acetylcholine release (prejunctional effect) and smooth muscle contraction (postjunctional effect) was used. The guinea-pig epithelium-deprived trachea was stimulated with 500 pulses (20 Hz, 1 ms, 9 V for 5 s, 30 s apart) in the presence of indomethacin (1 μm). Three successive pre- and postjunctional responses were observed. The potencies (– logEC50) of (±)-LG50643 for pre- and postjunctional muscarinic receptors were determined and compared with those of selective muscarinic antagonists. In addition, the affinity values of (±)-LG50643 for muscarinic-receptor subtypes were determined in radioligand binding experiments in cerebral cortex, heart and salivary glands of rat as target tissues for M1, M2 and M3 receptors, respectively. The results obtained in both functional and binding assays indicate (±)-LG50643 is a potent and selective antagonist for the M3-receptor subtype.
The effect of (—)-4-(2-hydroxy-3(N-isopropylamino)-propoxyimino)-cis-carane on basal and forskolin-stimulated accumulation of cyclic AMP in the cerebral cortical slices of the rat
Authors: Librowski Tadeusz , Nalepa Irena , Czarnecki Ryszard , Vetulani Jerzy
Published: April 2011

(–)-4-(2-Hydroxy-3(N-isopropylamino)-propoxyimino)-cis-carane, a local anaesthetic and platelet aggregation inhibitor which is much more potent than lignocaine, facilitated forskolin-induced cyclic (c) AMP accumulation in cerebral cortical slices of the rat. Lignocaine was ineffective in this respect. It is hypothesized that a cAMP-related mechanism may be involved in increased efficacy of the compound.
Selective effects of pentamidine on cytosolic and granule-associated enzyme release from zymosan-activated human neutrophilic granulocytes
Authors: Arnott M A , Bennett N D , Cairns D , Hay J
Published: April 2011

Therapeutic concentrations (0·3–1·5 mg L−1) of pentamidine isethionate, normally obtainable in-vivo after parenteral administration of the drug, did not affect the in-vitro activity of the enzymes lysozyme, β-glucuronidase or myeloperoxidase released from zymosan-activated human neutrophilic granulocytes. At concentrations of 0·7, 1·1 and 1·5 mg L−1, activity of cytosolic enzymes lactate dehydrogenase and glucose-6-phosphate dehydrogenase were reduced relative to untreated cells (P< 0·001 and P < 0·01, respectively), but not in a dose-dependent fashion. Cell viability, as determined by dye-exclusion remained unaffected.
The Influence of Surface Properties on Uptake of Oil into Complex Coacervate Microcapsules
Authors: Rabiskova M , Song J , Opawale F O , BURGESS D J
Published: April 2011

A range of surfactants with different hydrophile-lipophile balance (HLB) values was selected to investigate the influence of interfacial properties on the uptake of oil droplets into complex coacervate microcapsules. The well characterized gelatin/acacia complex coacervate system was used in this study and the encapsulation of squalane, and oleic acid was investigated. The surfactants investigated were Span 85, Span 80, Span 40, egg yolk lecithin, and Tween 80. Combinations of surfactants were utilized to obtain intermediate HLB values. The percentage oil encapsulated was determined gravimetrically, based on the initial concentration and the amount extracted from the microcapsules. The aqueous interfacial tension values of the oils and oil/surfactant systems were measured using the Wilhelmy plate method. The interfacial properties were correlated to the percentage oil uptake by the coacervate phase. The relative hydrophobicity/lipophilicity of the oil influenced its uptake by complex coacervate droplets. The presence of surfactant affected oil uptake, depending on the HLB value of the surfactant or surfactant mixture. Uptake of squalane by the gelatin/acacia coacervates was found to be optimized by the addition of surfactants with HLB values in the range 2·5–6. The percentage uptake of oil decreased rapidly for systems prepared containing surfactants with HLB values outside this range. No correlation was observed between oil uptake by the coacervate phase and the interfacial tension of the oil and oil/surfactant systems with double-distilled deionized water.
Investigating the Surface Properties and Bioadhesion of Buccal Patches
Authors: Guo Jian-Hwa
Published: April 2011

By using a two-roll milling method, a new bioadhesive polymer patch formulation for drug controlled delivery and consisting of Carbopol 934P (CP), polyisobutylene (PIB), and polyisoprene (PIP) was prepared. The effects of different ratios of CP:PIB:PIP on the surface properties, adhesion, and swelling of buccal patches were investigated. It was found that the surface properties of buccal patches were not only dependent on the CP content but also dependent on the PIB:PIP ratio. The strongest peeling strength was found on the buccal patches with a CP:PIB:PIP ratio of 50: 43·75: 6·25. The maximum bioadhesion of patches was found following 2- to 8-h contact with the test medium, and this observation could be explained by the interpenetration of macromolecular chains at the polymer-polymer interface (based on the diffusion theory of polymer adhesion).
Pharmacokinetic Characteristics of 5-Fluorouracil and Mitomycin C in Intraperitoneal Chemotherapy
Authors: Kuzuya Takafumi , Yamauchi Masaji , Ito Akihiro , Hasegawa Masaya , Hasegawa Takaaki , Nabeshima Toshitaka
Published: April 2011

Eight patients with malignancies confined to the peritoneal space participated in this study. Five hundred milligrams 5-fluorouracil or 10 mg mitomycin C was diluted in 1 L saline. The mixed solution was injected intraperitoneally through the semi-permanent peritoneal catheter. Blood and peritoneal fluid were collected after injection. 5-Fluorouracil concentrations in the peritoneal fluid were 1000 times those in serum, while mitomycin C concentrations were 100 times those in serum. Areas under the concentration vs time curve (AUC) were calculated by the trapezoidal method with extrapolation to infinity. The ratio of peritoneal fluid AUC to serum AUC was about 1400 for 5-fluorouracil and 80 for mitomycin C. Patterns for the absorption and elimination from systemic circulation were similar for both compounds. Drug concentrations in the peritoneal fluid and serum were analysed according to the compartment model. The half-life in the peritoneal fluid (t½p) and the rate constant from the peritoneal fluid to the systemic circulation (ka) were nearly equal for both 5-fluorouracil and mitomycin C (t½p, 1·0 h for 5-fluorouracil and 1·3 h for mitomycin C; ka 0·71 h−1 for 5-fluorouracil and 0·68 h−1 for mitomycin C), although the apparent volume of distribution (Vds/F) and clearance in the peritoneal cavity (CLp) for mitomycin C (78 Lm−2 and 1.8 L h−1 m−2) were about twice the values for 5-fluorouracil (149 L m−2 and 0·8 L h−1 m−2).
Separation and Quantification of Murein and Precursors from Enterobacter cloacae after Treatment with Trimethoprim and Sulphadiazine
Authors: Richards R Michael E , Xing Dorothy K L
Published: April 2011

The intracellular concentrations of the soluble murein precursors UDP-Mur-NAc-pentapeptide in the cytoplasm, the membrane-bound lipid precursor disaccharide pentapeptide and the muropeptides of Enterobacter cloacae cultures treated with trimethoprim (12·5μg mL−1) and sulphadiazine (250 μg mL−1) were determined by using capillary zone electrophoresis analysis. In the presence of trimethoprim, UDP-Mur-NAc-pentapeptide as well as disaccharide pentapeptide accumulated. In the case of sulphadiazine-treated cells, the concentration of UDP-Mur-NAc-pentapeptide roughly paralleled the control cells but sulphadiazine caused a slow incremental accumulation of disaccharide pentapeptide. The muropeptide composition of the murein indicated that the differences between the peptidoglycans produced by the control cells and the cells grown in the presence of either trimethoprim or sulphadiazine alone or in combination were quite marked. The results suggest that the enhanced activity of trimethoprim plus sulphadiazine against E. cloacae is caused by an additional effect on the inhibition of the bacterial peptidoglycan biosynthesis and that this additional effect is a fundamental part of the antibacterial action of the antimetabolites. This effect leads to changes of cell morphology and resultant changes in bacterial cell permeability.
Use of the Walden Product to Evaluate the Effect of Amino Acids on Water Structure
Authors: Lutz Olivier , Vrachopoulou Maria , Groves Michael J
Published: April 2011

The Walden Product, the product of viscosity (η0) and conductivity at infinite dilution of a solution (Λ0), provides a measurement of the water-structuring activity of the solute. Measuring the effect of concentration on viscosity of solutions of amino acids, together with the conductivity of solutions of sodium chloride containing increasing concentrations of the amino acids, enabled Walden Products to be determined. The classical form of the Walden Product (Λ0η0) was used, together with a modified form, Λ0ηc, in which ηc was the slope of the concentration/viscosity curve. Most amino acids demonstrated modest water-structure-breaking activity but l-lysine, l-glutamic acid and l-aspartic acid, and their respective salts, all showed relatively higher activity. Dextrose behaved as a classical water-structure maker and, when added progressively, reversed the breaking activity of l-lysine. It is speculated that effects seen in bulk water may also occur at emulsion droplet surfaces, thereby inducing structural changes associated with the occasional rapid instability experienced when making admixtures of phospholipid-stabilized emulsions and additives such as amino acids and dextrose.
A Study of Modified Betaines as Cryoprotective Additives
Authors: Lloyd Andrew W , Olliff Cedric J , Rutt Ken J
Published: April 2011

Glycinebetaine and N-modified betaines have been previously shown to be effective at reducing leakage from liposomes on freeze-thaw procedures. This study involved the preparation of a series of other modified betaines and the comparison of their abilities to reduce leakage from frozen multilamellar liposomes. All the compounds investigated, with the exception of the octyl ester of betaine, reduced the degree of leakage on freezing and thawing with additive concentrations up to 0·6 m. The betaine esters were less effective than betaine as cryoprotective additives and caused an increase in the leakage from unfrozen liposomes. Taurinebetaine, a sulphobetaine, was also less effective at reducing leakage on freezing than betaine and again increased leakage from unfrozen liposomes. Increasing the number of methylene groups between the carboxylate group and the nitrogen improved the ability to reduce leakage, particularly at lower additive concentrations.
Peracylated β-Cyclodextrins as Novel Sustained-release Carriers for a Water-soluble Drug, Molsidomine
Authors: Uekama Kaneto , Horikawa Takashi , Yamanaka Masayuki , Hirayama Fumitoshi
Published: April 2011

Peracylated β-cyclodextrins with different alkyl chains (acetyl-octanoyl) were prepared by acylating all hydroxyl groups of β-cyclodextrin (β-CyD), and their physical properties were evaluated. These hydrophobic β-CyDs decreased the release rate of molsidomine, a peripheral vasodilator, in proportion to the lengthening of alkyl chain and suppressed a peak plasma level of molsidomine following oral administration of peracylated β-CyD complexes to dogs. Among the peracylated β-CyDs tested, perbutanoyl-β-CyD maintained sufficient plasma drug levels for a long period of time, while other peracylated β-CyDs having shorter or longer chains were inappropriate to control the in-vivo release behaviour of molsidomine. The prominent retarding effect of perbutanoyl-β-CyD was ascribable to the appropriate mucoadhesive property and hydrophobicity, compared with other peracylated β-CyDs. The present results suggest that perbutanoyl-β-CyD is particularly useful in modifying the release rate of water-soluble drugs as a novel slow-release carrier.
Human Calcitonin Delivery in Rats by Iontophoresis
Authors: Thysman Sophie , Hanchard Cecile , Préat Veronique
Published: April 2011

In-vitro iontophoresis (0·33 mA cm−2) of calcitonin (50 μg mL−1, pH 4) was performed with the hairless rat skin model. Direct current was as potent as pulse current (2·5 kHz on/off 1/1) iontophoresis in promoting transdermal permeation of calcitonin. Increase in duration of current application from 20 min to 1 h did not increase calcitonin flux. Results suggest that calcitonin can be blocked in the skin pores through which it travels or can accumulate in the skin and be progressively released from the depot. Invivo experiments showed that transdermal iontophoretic administration of calcitonin induced a hypocalcaemic effect in rats.
Effects of ZCR-2060 on Allergic Airway Inflammation and Cell Activation in Guinea-pigs
Authors: Abe Tooru , Yoshida Kenji , Omata Takeshi , Segawa Yoshihide , Matsuda Kazuo , Nagai Hiroichi
Published: April 2011

The effects of 2-(2-(4-(diphenylmethyl)-1-piperadinyl) ethoxy) benzoic acid malate (ZCR-2060) on allergic airway inflammation and inflammatory cell activation in guinea-pigs were studied. Allergic airway inflammation was induced by inhalation of antigen into actively-sensitized animals and the increase in inflammatory cells into bronchoalveolar lavage fluid (BALF) was measured. Aeroantigen-induced infiltration of inflammatory cells, especially eosinophils and neutrophils, in BALF gradually increased, and reached a peak at 6 or 9 h after the challenge. ZCR-2060 (1 mg kg−1 p.o.) clearly inhibited the increase of eosinophil numbers in BALF. Moreover, the effect of ZCR-2060 on inflammatory cell activation in terms of chemotaxis and superoxide generation in-vitro was studied. ZCR-2060 (10−6-10−4  m) inhibited the platelet-activating factor (PAF)-induced chemotaxis of eosinophils and neutrophils, but did not inhibit the leukotriene B4-induced chemotaxis of eosinophils and the formyl-Met-Leu-Phe-induced chemotaxis of neutrophils. PAF-induced superoxide anion generation by eosinophils, neutrophils and alveolar macrophages was inhibited by ZCR-2060 (10−6-10−4  m). However, ZCR-2060 did not affect phorbol myristate acetate-induced superoxide anion generation by eosinophils, neutrophils and alveolar macrophages. These results indicate that ZCR-2060 inhibits allergic airway inflammation, and PAF-induced inflammatory cell activation in guinea-pigs. ZCR-2060 may prove useful for the treatment of allergic airway inflammation or allergic disorders, especially inflammatory cell infiltration and activation.
Flavanones with Potent Antibacterial Activity against Methicillin-resistant Staphylococcus aureus
Authors: Iinuma Munekazu , Tsuchiya Hironori , Sato Masaru , Yokoyama Junji , Ohyama Masayoshi , Ohkawa Yasutoshi , Tanaka Toshiyuki , Fujiwara Syuu , Fujii Teruhisa
Published: April 2011

With the therapeutic concept of using the defensive ability of plants against microbial infections, phytoalexin, an antimicrobial phytochemical was studied for its ability to inhibit the growth of methicillin-resistant Staphylococcus aureus (MRSA). Extracts from Sophora exigua (Leguminosae) were fractionated by serial chromatography and the anti-MRSA activity of each fraction was determined by the agar-plate method. Among the active isolates, 5,7,2′,6′-tetrahydroxy-6-isoprenyl-8-lavandulyl-4′-methoxyflavanone (exiguaflavanone D) completely inhibited the growth of all the MRSA strains examined at the concentration of 1·56–6·25 μg mL−1, and 5, 2′,6′-trihydroxy-8-lavandulyl-7-methoxy-flavanone (exiguaflavanone B) inhibited at a concentration of 50 μg mL−1. This former compound is expected to be a phytotherapeutic agent for MRSA infections as an alternative to conventional antibiotics with unwanted side-effects or the appearance of antibiotic-resistant bacteria.
Does α1-Acid Glycoprotein Act as a Non-functional Receptor for α1-Adrenergic Antagonists?
Authors: Qin Mingsheng , Øie Svein
Published: April 2011

The ability of a variety of α1-acid glycoproteins (AAG) to affect the intrinsic activity of the α1, -adrenergic antagonist prazosin was studied in rabbit aortic strip preparations. From these studies, the activity of AAG appears to be linked to their ability to bind the antagonist. However, a capability to bind prazosin was not the only requirement for this effect. The removal of sialic acid and partial removal of the galactose and mannose residues by periodate oxidation of human AAG all but eliminated the ability of AAG to affect the intrinsic pharmacologic activity of prazosin, although the binding of prazosin was not significantly affected. The presence of bovine AAG, a protein that has a low ability to bind prazosin, reduced the effect of human AAG on prazosin activity. Based upon these results, we propose that AAG is able to bind in the vicinity of the α1-adrenoceptors, therefore extending the binding region for antagonists in such a way as to decrease the ability of the antagonist to interact with the receptor. The carbohydrate side-chains are important for the binding of AAG in the region of the adrenoceptor.
Characterization of the Prejunctional Adenosine Receptors in the Rat Anococcygeus Muscle
Authors: Coates Jill , Green Mark A , Sheehan Michael J , Strong Peter
Published: April 2011

Adenosine receptor agonists inhibited electrically-evoked contractions of the rat isolated anococcygeus muscle. The compounds tested were: N6-cyclopentyladenosine (CPA), N((S, trans)-2-hydroxycyclopentyl)adenosine (GR79236), the R- and S-isomers of phenylisopropyladenosine (PIA), 5′-N-ethylcarboxamidoadenosine (NECA), ((2-(4-(2-carboxyethyl)phenyl)ethyl)amino)-N-ethylcarbox-amidoadenosine (CGS 21680) and N-((2-methylphenyl)methyl)adenosine (metrifudil). The rank order of agonist potency was: CPA = R-PIA = GR79236 = NECA » S-PIA > metrifudil > CGS 21680, which is consistent with an effect mediated by adenosine A1 receptors. A similar rank order of potency was obtained for inhibition of electrically-evoked contractions of the guinea-pig ileum. However, there may be a lower receptor reserve in rat anococcygeus compared with the guinea-pig ileum, since higher concentrations of agonists were necessary to produce effects in the anococcygeus than in the guinea-pig ileum and S-PIA behaved as a partial agonist. The effect of NECA was antagonized in rat anococcygeus and guinea-pig ileum by the mixed A1/A2 receptor antagonist, 8-phenyltheophylline (pA2 values of 6·8 and 6·9, respectively). The selective A1-receptor antagonist, 8-cyclopentyl-l,3-dipropylxanthine (DPCPX), also blocked the inhibitory response to NECA in both tissues. Here, however, the pA2 values (9·6 and 8·6, respectively) were slightly but significantly different. These values confirm that the prejunctional adenosine receptors of the rat anococcygeus are of the A1 type, and suggest that they are similar but not necessarily identical to those of the guinea-pig ileum. The differing potencies of DPCPX as an antagonist of NECA between the preparations may reflect a tissue-dependent variation in sensitivity to this antagonist.
Studies on the Synthesis of Some Xanthonoid Derivatives Possessing Antiplatelet Effects
Authors: Lin Chun-Nan , Fang Song-Chwan , Lin Hsien-Cheng , Ko Feng-Nien , Shieh Bor-Jinn , Liu Hong-Wen , Teng Che-Ming
Published: April 2011

2,3- and 3,4-Dihydroxyxanthone react with ethyl 2,3-dibromopropanoate to form the new, substituted 1,4-benzodioxanes 3 and 4, respectively. The regioisomers 3a and 3b; 4a and 4b were separated by column chromatography and characterized for evaluation of the antiplatelet effects in rabbit washed platelets and human platelet-rich plasma. The ethoxycarbonyl derivatives 3a (20 μm) and 3b (20 μm) strongly inhibited the aggregation of rabbit washed platelets induced by arachidonic acid and collagen. The compound 4b showed the most potent inhibition of rabbit washed-platelet aggregation induced by arachidonic acid (IC50 = 8·3 μm). Of the compounds tested in human platelet-rich plasma, compound 4b exhibited the most potent inhibition of primary and secondary aggregation induced by adrenaline (IC50 = 8·6 μm). We conclude that the antiplatelet effects of these four ethoxycarbonyl derivatives are mainly due to an inhibitory effect on thromboxane formation and interference in the adrenaline-receptor interaction.
Anti-complement activity of oleanolic acid: an inhibitor of C3-convertase of the classical complement pathway
Authors: Kapil Aruna , Sharma Shalini
Published: April 2011

Oleanolic acid is a naturally occurring compound, isolated from Luffa cylindrica, which inhibits the in-vitro immuno-haemolysis of antibody-coated sheep erythrocytes by guinea-pig serum. In further experiments this reduced immunohaemolysis was found to be due to inhibition of the C3-convertase of the classical complement pathway. The threshold concentration for inhibition of C3-convertase was 100 μg mL−1. However, higher concentrations of oleanolic acid showed constant inhibitory effects on immunohaemolysis. Oleanolic acid also exhibited weak inhibitory effects on individual components of the complement system.
Buspirone and 1-(2-pyrimidinyl)-piperazine attenuate xylazine-induced antinociception in the mouse
Authors: Cao Bo-Jin , Li Wei-Ping
Published: April 2011

The effects of subcutaneous pretreatment with buspirone and its major metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) on the antinociceptive effect of xylazine were examined using the mouse acetic acid assay. Both buspirone and 1-PP dose-dependently attenuated the antinociceptive action of subcutaneously administered xylazine (0·8 mg kg−1), with ED50 values of 7·3 mg kg−l for buspirone and 3·4 mg kg−1 for 1-PP. Pretreatment with either buspirone (8 mg kg−1) or 1-PP (4 mg kg−1) increased the antinociceptive ED50 of xylazine 3–4-fold. These data support the involvement of α2-adrenoceptor and 1-PP in the pharmacological activity of buspirone.
Improvement of Transdermal Delivery of Tetragastrin by Lipophilic Modification with Fatty Acids
Authors: Setoh Kazunari , Murakami Masahiro , Araki Naoko , Fujita Takuya , Yamamoto Akira , Muranishi Shozo
Published: April 2011

The in-vitro permeability of chemically modified tetragastrin with fatty acids through the rat skin was studied. The permeability of these compounds through intact skin and stripped skin of rat was determined with a Franz-type diffusion cell. The permeation of tetragastrin across the intact skin was improved by chemical modification with acetic acid and butyric acid. However, tetragastrin and caproyl-tetragastrin did not permeate across the intact skin up to the end of experiment. The permeation of tetragastrin across the stripped skin was improved by chemical modification, the skin flux of these acyl derivatives being in the order: acetyl > butyroyl > caproyl. The stability of tetragastrin in skin homogenate was also significantly improved by chemical modification with fatty acids.

These results suggest that chemical modification of tetragastrin with fatty acids increases its lipophilicity, which makes it permeable across the stratum corneum. Moreover, the chemical modification reduced the degradation of tetragastrin in the viable skin, resulting an increase in permeation of tetragastrin across the skin.
Permeability of NS-3, a Thyrotropin-releasing Hormone Analogue, into the Brain After Its Systemic Administration in Rats: A Microdialysis Study
Authors: Itoh Yoshinori , Sugimoto Taketoshi , Ukai Yojiro , Morino Akira , Kimura Kiyoshi
Published: April 2011

The concentration of NS-3 (montirelin hydrate, CG 3703), a thyrotropin-releasing hormone (TRH) analogue, in the cerebral cortex of urethane-anaesthetized rats was measured after its systemic administration (1 mgkg−1, i.v.), using in-vivo microdialysis coupled with a radioimmunoassay.

The concentration in microdialysates was highest (24nM) during the first 20 min after injection, and it fell below the detection limit (3.5 nM) 100 min after treatment. The maximal interstitial concentration was estimated to be 0.51 μM.

From these results, it is suggested that NS-3 can readily penetrate into the brain.
Tableting Characteristics of Micro-aggregated Egg Albumin Particles Containing Paracetamol
Authors: Torrado-DurÁn Juan J , Torrado Santiago , CadÓrniga Rafael , Augsburger Larry L
Published: April 2011

The tableting characteristics of micro-aggregated egg albumin particles containing paracetamol were evaluated and compared with non-micro-encapsulated paracetamol and coagulated egg albumin particles.

Mean yield pressure values of micro-aggregated egg albumin particles containing paracetamol and coagulated egg albumin particles were 30·5 and 49·3 MPa, respectively, which were lower than the mean yield pressure obtained for paracetamol (97-5 MPa). Paracetamol tablets obtained with micro-aggregated egg albumin particles did not show the capping characteristic of conventional paracetamol tablets. Crushing strength of paracetamol tablets obtained with egg micro-aggregated particles was similar to that obtained using paracetamol granulated with povidone and gelatin as binders at 3 and 6% (w/w) concentrations. Drug release from the paracetamol tablets depends on the choice of excipients. Crospovidone showed good protective characteristics for the tableting of micro-aggregated particles.

Crushing strength of paracetamol tablets formed from egg albumin-coated particles could be increased using crospovidone or microcrystalline cellulose as fillers and was decreased by the use of magnesium stearate. Nevertheless, magnesium stearate was useful to decrease the ejection force.
In-vivo and In-vitro Correlation for Delayed-release Behaviour of a Molsidomine/O-carboxymethyl-O-ethyl-β-cyclodextrin Complex in Gastric Acidity-controlled Dogs
Authors: Horikawa Takashi , Hirayama Fumitoshi , Uekama Kaneto
Published: April 2011

The in-vivo absorption behaviour of molsidomine from the delayed-release tablets of an O-carboxy-methyl-O-ethyl-β-cyclodextrin complex was investigated using gastric acidity-controlled dogs under fasted and non-fasted conditions.

The in-vitro release profiles were generated by changing the pH of the dissolution medium at different rotation paddle speeds. The absorptivity of molsidomine in the high acidity dog was correlated with the pH-changed release profile (pH 1·2 to 7·0 after 2 h), whereas that in the low acidity dog was correlated with the release profile at a constant pH of 7·0. The absorption in fasted dogs was well correlated with the in-vitro release at the low-rotation paddle speed (< 5 rev min−1), whereas that in the non-fasted dogs was correlated with that of high rotation (100 rev min−1).

The present results suggested that the in-vivo delayed-release behaviour of the complex is predictable from the in-vitro release profiles generated using pH-variable dissolution testing apparatus at different rotation speeds of the paddle.