bluuebunny/crossref_metadata_2025 huggingface dataset:
Extract of Juglandaceae regia Inhibits Growth, In-vitro Adherence, Acid Production and Aggregation of Streptococcus mutans
Authors: Jagtap A G , Karkera S G
Published: October 2002

Aqueous and alcoholic extracts from Juglandaceae regia, used as chewing sticks to maintain oral hygiene, were tested for their ability to inhibit the growth and some physiological functions of Streptococcus mutans.

Both the aqueous and the alcoholic extract strongly inhibited the growth, in-vitro adherence, acid production and glucan-induced aggregation of S. mutans. At a concentration of 8% w/v, the aqueous extract produced a 95% inhibition (P < 0.05) of adherence of S. mutans to glass and a 40% inhibition (P < 0.05) of adherence to tooth surface. The alcoholic extract at a concentration of 10% w/v produced a 95% inhibition (P < 0.05) of adherence of S. mutans to glass and a 56% inhibition (P < 0.05) of adherence to tooth surface. At concentrations of 2% w/v the aqueous and alcoholic extracts significantly inhibited (P < 0.05) glucan-induced aggregation of S. mutans and the in-vitro salivary glycolytic reaction for up to 5 h. Bactericidal effects on S. mutans were also evident. At a concentration of 10% w/v, the zone of inhibition observed with the aqueous extract was 12 ± 0.01 mm and that observed with the alcoholic extract was 12.6 ± 0.02 mm. As the in-vitro studies had shown that both the aqueous and the alcoholic extract of J. regia, at concentrations of 10% w/v, could inhibit the growth as well as the acid-producing ability of S. mutans, they were tested at the same concentration for their activity in-vivo. Three subjects were employed. Parameters monitored were salivary bacterial count and salivary glycolysis. Mouth-rinsing with the aqueous but not the alcoholic extract significantly reduced total streptococcal counts in the salivary samples obtained up to, and including, 3 h after rinsing, compared with the counts obtained pre-rinsing or after placebo rinsing. Mouth-rinsing with the aqueous extract produced a 65%, 27% and 78% reduction (P < 0.05) in the streptococcal count in the salivary samples obtained 10 min, 1 h and 3 h after rinsing, respectively. Both the aqueous and the alcoholic extract also inhibited the glycolytic reaction by the salivary bacteria for up to 90 min post-rinsing.

This study provides evidence to justify the use of J. regia sticks as an aid to maintain oral hygiene.
Stimulatory Effect of Procaine on the Growth of Several Microalgae and Cyanobacteria
Authors: Suzuki Takahiro , Ezure Toru , Yamaguchi Toyoshi , Domen Hirotaka , Ishida Masaru , Schmidt Walter
Published: October 2002

Procaine has been used to stimulate plant growth and it has been noted that it also promotes growth of microorganisms. The effect of procaine hydrochloride concentration on the growth rates of several species of microalgae and cyanobacteria was studied under both photoautotropic and heterotrophic growth conditions. Procaine hydrochloride was added to cultures at concentrations over the range 0.01–1000 mg L−1.

A stimulating effect of procaine hydrochloride on photoautotrophic growth was observed for the cyanobacteria Anabaena cylindrica and Anabaena variabilis, and for the salt-tolerant green algae Dunaliella primolecta and Dunaliella parva. During active growth in batch culture an increase in growth rate (compared with control culture without procaine hydrochloride) of about 25% was observed at 0.1 mg L−1 of procaine hydrochloride for A. cylindrica. However, procaine hydrochloride was toxic at concentrations of > 10 mg L−1. Simultaneous administration of hydrolysis products of procaine, p-amino-benzoic acid and diethyl aminoethanol, in lieu of procaine hydrochloride, was as effective as procaine in stimulating growth of A. cylindrica. Heterotrophic growth of Chlorella ellipsoidea and Prototheca zopfii was not stimulated by procaine hydrochloride over the concentration range studied (0.1–10 mg L−1).

The combined effects of procaine hydrochloride concentration and four other environmental factors (temperature, light intensity, CO2 concentration in the flushing gas and NaCl concentration) on growth rate of D. primolecta was modelled using both a neural network approach and a response surface method. These results indicate that procaine hydrochloride exerts different effects on the growth of microalgal and cyanobacterial cells as functions of dosage, species and culture conditions.
Brittle-Ductile Transitions in Sucrose and the Influence of Lateral Stresses During Compaction
Authors: Roberts R J , Rowe R C
Published: October 2002

Sucrose, in a range of particle sizes, has been compacted to investigate both the effect of brittle-ductile transition and the effect of lateral stresses on the deformation stress as measured using Heckel plots.

All particles with a diameter greater than 30 μm exhibited cracking in line with both theoretical predictions and literature data from hammer and ball milling. In addition, crack lengths in compressed particles examined microscopically were very similar to those predicted from the deformation stress, confirming the applicability of the model.
Development and Validation of a Recirculatory Physiological Model of the Myocardial Concentrations of Lignocaine after Intravenous Administration in Sheep
Authors: Upton Richard N , Zheng D A , Grant Cliff , Martinez Allison M
Published: October 2002

A recirculatory physiological model of the determinants of the myocardial concentrations of lignocaine after intravenous administration was developed in sheep and validated with the intention of analysing and predicting the outcome of altered dose regimens and various pathophysiological states on the initial myocardial concentrations of lignocaine.

The structure and parameters of the model were determined by hybrid modelling of the time-courses of the pulmonary artery, arterial and coronary sinus concentrations of lignocaine after the intravenous administration of 100 mg of lignocaine over 5 min to 5 chronically instrumented sheep. The model accounted for the determinants of the myocardial concentrations via compartments for venous mixing, the lung (a single-compartment model with a first-order loss) and the heart (a single flow-limited compartment). Recirculation and the remainder of the body were represented as a single tissue pool with a clearance term. The distribution volume of the heart was 0.42 ± 0.009 L, which gave a half-time of myocardium: blood equilibration of 2.37 min. The distribution volume of the lungs was 5.40 ± 0.23 L, with an apparent first-order loss of 1.02 L min−1 representing deep distribution or metabolism. The validity of the model was tested by comparing the predictions of the model with the equivalent data collected in 6 sheep when lignocaine (89 mg) was administered via a complex dose regimen with a faster initial rate of infusion (39.1 mg min−1), declining exponentially to basal infusion rate (7.02 mg min−1) over 8 min. The predictions of the model were in general agreement with these data.

It is concluded that the model was sufficient to account for the effect of altered dose regimens of lignocaine on the time-course of its myocardial concentrations.
Stereoselective Metabolism of the Monoterpene Carvone by Rat and Human Liver Microsomes
Authors: Jäger Walter , Mayer Marion , Platzer Peter , Reznicek Gottfried , Dietrich Hermann , Buchbauer Gerhard
Published: October 2002

The large amounts of carvone enantiomers consumed as food additives and in dental formulations justifies the evaluation of their biotransformation pathway. The in-vitro metabolism of R-(—)- and S-(+)-carvone was studied in rat and human liver microsomes using chiral gas chromatography.

Stereoselective biotransformation was observed when each enantiomer was incubated separately with liver microsomes. 4R, 6S-(—)-Carveol was NADPH-dependently formed from R-(—)-carvone, whereas 4S, 6S-(+)-carveol was produced from S-(+)-carvone. Metabolite formation followed Michaelis-Menten kinetics exhibiting a significant lower apparent Km (Michaelis-Menten Constant) for 4R, 6S-(—)-carveol compared with 4S, 6S-(+)-carveol in rat and human liver microsomes (28.4 ± 10.6 μM and 69.4 ± 10.3 μM vs 33.6 ± 8.5 μM and 98.3 ± 22.4 μM). The maximal formation rate (Vmax) determined in the same microsomal preparations yielded 30.2 ± 5.0 and 32.3 ± 3.9 pmol (mg protein)−1 min−1 in rat liver and 55.3 ± 5.7 and 65.2 ± 4.3 pmol (mg protein)−1 min−1 in human liver microsomes. Phase II conjugation of the carveol isomers by rat and human liver microsomes in the presence of UDPGA (uridine S'-diphosphogluaronic acid) only revealed glucuronidation of 4R, 6S-(—)-carveol. Vmax for glucuronide formation was more than 4-fold higher in the rat liver compared with human liver preparations (185.9 ± 34.5 and 42.6 ± 7.1 pmol (mg protein)−1 min−1, respectively). Km values, however, showed no species-related difference (13.9 ± 4.1 μM and 10.2 ± 2.2 μM).

This study demonstrated stereoselectivity in phase-I and phase-II metabolism for R-(—)- and S-(+)-carvone and might be predictive for carvone biotransformation in man.
Effects of Pegylated Recombinant Human Megakaryocyte Growth and Development Factor on 5-Fluorouracil-induced Thrombocytopenia in Balloon-injured Rats
Authors: Harada Katsuhiko , Tazunoki Yoshiko , Ide Youichi , Takeuchi Akihiko , Kawahara Jun-Ichi , Suzuki Takamoto
Published: October 2002

We examined whether pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) affected 5-fluorouracil-induced thrombocytopenia without inducing more severe intimal thickening after injury to rat carotid arteries. Rat carotid arteries were injured using a balloon catheter on day 0. 5-Fluorouracil (100 mg kg−1) or vehicle was intravenously administered on day 1 in balloon-injured rats. PEG-rHuMGDF (100 μg kg−1) or vehicle was intravenously administered once a day on days 1–5 to balloon-injured rats given 5-fluorouracil or vehicle.

5-Fluorouracil (100 mg kg−1, i.v.) caused a significant decrease in the platelet count from day 3 and peaked on days 7–9 in balloon-injured rats. PEG-rHuMGDF (100 μg kg−1, i.v.) reduced this decrease on days 9 and 11. The administration of PEG-rHuMGDF did not accelerate the intimal thickening of balloon-injured arteries in rats treated with 5-fluorouracil compared with control balloon-injured rats. PEG-rHuMGDF did not increase plasma tumour growth factor-β (TGF-β1) from days 0–9 in balloon-injured rats compared with control balloon-injured rats.

These results suggest that PEG-rHuMGDF ameliorated 5-fluorouracil-induced thrombocytopenia without accelerating the intimal thickening of balloon-injured arteries.
Histamine Release Induced by Antimicrobial Agents and Effects of Antimicrobial Agents on Vancomycin-induced Histamine Release from Rat Peritoneal Mast Cells
Authors: Toyoguchi Teiko , Ebihara Mitsutaka , Ojima Fumiyoshi , Hosoya Jun , Shoji Tohru , Nakagawa Yoshito
Published: October 2002

Vancomycin and certain fungicides may cause anaphylactoid reactions. We investigated the effects of vancomycin, miconazole and fluconazole on histamine release in rat peritoneal mast cells. Vancomycin and miconazole provoked histamine release in a dose-dependent manner. In contrast, fluconazole did not provoke histamine release at concentrations of 3 times 10−6 - 3 times 10 −3  m.

Vancomycin is efficacious in the treatment of Gram-positive bacterial infections; patients presenting themselves with mixed infections require concomitant therapy with a second antimicrobial agent. We investigated the effect of fosfomycin sodium, cilastatin sodium or fluconazole on vancomycin-induced histamine release. Fosfomycin sodium inhibited vancomycin-induced histamine release but neither cilastatin sodium nor fluconazole inhibited it in the mole ratios of daily doses used in humans.

These results suggest that vancomycin and miconazole provoke histamine release in rat mast cells, but that fluconazole probably does not, while fosfomycin sodium may inhibit vancomycin-induced histamine release.
Protection of Rat Hepatocytes Exposed to CCl4 In-vitro by Cynandione A, a Biacetophenone from Cynanchum wilfordii
Authors: Lee Mi Kyeong , Yeo Hosup , Kim Jinwoong , Kim YOUNG CHOONG
Published: October 2002

To identify hepatoprotective agents from plant sources we use primary cultures of rat hepatocytes injured by CCl4. The hepatoprotective agents are the compounds that mitigate the injury caused by CCl4. Using this system we have investigated the biochemical mechanisms involved in the hepatoprotective activity of cynandione A, a biacetopherone, isolated from the roots of Cynanchum wilfordii Hemsley (Asclepiadaceae). Cynandione A (50 μm) significantly reduced (approximately 50%) the release into the culture medium of glutamic pyruvic transaminase and sorbitol dehydrogenase from the primary cultures of rat hepatocytes exposed to CCl4. Glutathione, superoxide dismutase, catalase and glutathione reductase play important roles in the cellular defence against oxidative stress. Cynandione A appeared to protect primary cultured rat hepatocytes exposed to CCl4 from significant drops in the levels of each of these four specific markers. Cynandione A also ameliorated lipid peroxidation by up to 50% as demonstrated by a reduction in the production of malondialdehyde.

These results suggest that cynandione A protected the hepatocytes from CCl4-injury by maintaining the level of glutathione and by inhibiting the production of malondialdehyde, due to its radical scavenging properties.
Chemical Characterization and Biological Activity of Macfadyena unguis-cati (Bignoniaceae)
Authors: Duarte D S , Dolabela M F , Salas C E , Raslan D S , Oliveiras A B , Nenninger A , Wiedemann B , Wagner H , Lombardi J , Lopes M T P
Published: October 2002

Macfadyena unguis-cati (L.) has been widely used in folk medicine as an anti-inflammatory, antimalarial and antivenereal. The purpose of this study was to chemically characterize the main plant components, and to evaluate the biological properties of some of the fractions derived from leaves (MACb) and liana (MACa) of this plant.

Chemical characterization allowed the identification of the compounds corymboside, vicenin-2, quercitrin, chlorogenic acid, isochlorogenic acid, lupeol, β-sitosterol, β-sitosterylglucoside, allantoin and lapachol.

The biological screening of fractions and/or purified substances derived from fractions revealed antitumoral and antitrypanosomal activities in fractions MACa/lapachol and MACb/MACb21, respectively. The anti-lipoxygenase and anti-cyclooxygenase effect seen in fractions MACa and MACb showed a partial correlation with the anti-inflammatory property attributed to this plant.
Membrane Permeation by Multidrug-resistance-modulators and Non-modulators: Effects of Hydrophobicity and Electric Charge
Authors: Castaing Madeleine , Brouant Pierre , Loiseau Alain , Santelli-Rouvier Christiane , Santelli Maurice , Alibert-Franco Sandrine , Mahamoud Abdallah , Barbe Jacques
Published: October 2002

This study was designed to test the hypothesis that lipophilic cationic drugs with only roughly similar structures mediate the reversal of multidrug-resistance (MDR) by interacting with membrane phospholipids. The permeation properties of MDR-modulators and non-modulators were studied by quantifying their ability to induce the leakage of Sulphan blue through the membrane of negatively charged unilamellar liposomes.

Of the 22 compounds under investigation, only those bearing a net positive electric charge per molecule (z) ≥0.2 induced dye leakage. All these efficient drugs are well-known MDR-modulators: calcium-channel blockers (propranolol, verapamil, diltiazem and dipyridamole), calmodulin antagonists (clomipramine and thioridazine) and antiparasitic agents (mepacrine, thioacridine derivatives and quinine). The non-modulators tested, including antineoplasic agents and steroids, did not induce any membrane permeation. The permeation process was a co-operative one (1.1 < Hill coefficient < 4.1) and the permeation doses inducing 50% dye leakage (PD50) were 1.9–11.2 mm. The permeation ability of the MDR-modulators (log(1/PD50)) increased significantly with octanol-buffer distributions per unit net electric charge ((logD)/z).

The results provide evidence that a complex interplay occurs between the electric charge and the lipophilicity of the MDR-modulators when a dye leakage is induced through model membranes, and probably also when the MDR is reversed in leukaemic cells.
Effect of P450 Isozyme-selective Inhibitors on In-vitro Metabolism of Retinoic Acid by Rat Hepatic Microsomes
Authors: Ahmad Mobashar , Nicholls Paul J , Smith H John , Ahmadi Masoud
Published: October 2002

Cytochrome P450-mediated 4-hydroxylation of retinoic acid is an important pathway in the termination of its biological action and the activity of certain P450 isozymes has been studied in non-induced male rat hepatic microsomes using isozyme-selective inhibitors.

The importance of the activity of the isozyme to retinoic acid metabolism was, 2A6 (diethyl dithiocarbamate as selective inhibitor) > 1A1/1A2 (7,8-benzoflavone) >> 1A1 (ellipticine) > 3A4 (naringenin, ketoconazole) as shown by the respective apparent IC50 values of 0.12, 0.34, 2.7, 9.25 and 13.5 μm with 2C8–10, 2D6 and 2E1 having little effect on metabolism.

It is concluded that although the P450 3A family normally constitutes half the total rat hepatic P450 activity, other hepatic isozymes (1A1, 1A2 and 2A6) are also involved in retinoic acid metabolism. This suggests that the horizons for the design of potential anticancer agents acting through inhibition of retinoic acid metabolism may be widened to include structures which do not resemble the established hetereocyclic base P450 3A4 inhibitors.
Protective Effect of N-Acetylcysteine on Rat Liver Cell Membrane During Methanol Intoxication
Authors: Dobrzyñska I , Skrzydlewska E , Kasacka I , Figaszewski Z
Published: October 2002

Methanol is oxidized in-vivo to formaldehyde and then to formate, and these processes are accompanied by the generation of free radicals. We have studied the effect of N-acetylcysteine on liver cell membrane from rats intoxicated with methanol (3.0 g kg−1).

Evaluation of the effect was achieved by several methods. Lipid peroxidation and surface charge density were measured. An ultrastructural study of the liver cells was undertaken. The concentration of marker enzymes of liver damage (alanine aminotransferase and aspartate aminotransferase) in blood serum was measured.

Methanol administration caused an increase in lipid peroxidation products (approximately 30%) as well as in surface charge density (approximately 60%). This might have resulted in the membrane liver cell damage visible under electron microscopy and a leak of alanine aminotransferase and aspartate aminotransferase into the blood (increase of approximately 70 and 50%, respectively). Ingestion of N-acetylcysteine with methanol partially prevented these methanol-induced changes. Compared with the control group, lipid peroxidation was increased by approximately 3% and surface charge density by approximately 30%. Alanine aminotransferase and aspartate aminotransferase activity increased by 9 and 8%, respectively, compared with the control group.

The results suggested that N-acetylcysteine was an effective antioxidant in methanol intoxication. It may have efficacy in protecting free radical damage to liver cells following methanol intoxication.
Sedum telephium L. Polysaccharide Content Affects MRC5 Cell Adhesion to Laminin and Fibronectin
Authors: Raimondi L , Banchelli G , Dalmazzi D , Mulinacci N , Romani A , Vincieri F F , Pirisino R
Published: October 2002

In traditional medicine the fresh leaves and juice of Sedum telephium L. are used as wound-healing promoters. Cell adhesion represents a primary event in wound repair and in tissue homeostasis, and therefore we have investigated the effect of Sedum juice and its main fractions, polysaccharides and flavonols, on human fibroblast (MRC5) adhesion to fibronectin and laminin.

Our findings revealed that total Sedum juice strongly inhibited cell adhesion to laminin and fibronectin (EC50 1.03 ± 0.12 mg mL−1). This anti-adhesive feature was concentrated mainly in the two polysaccharide fractions (EC50 values comprised between 0.09 and 0.44 mg mL−1). The flavonol fractions did not seem to contribute to this effect.

A first attempt to elucidate the polysaccharide-related anti-adhesive feature of Sedum juice was also performed.

The results confirmed that natural polysaccharides, with chemical structures different from heparin, were able to interfere with integrin-mediated cell behaviour and they contributed to the outstanding effects of Sedum juice and to the role of polysaccharides in cell-matrix interaction.
Review Nimesulide: Some Pharmaceutical and Pharmacological Aspects—An Update
Authors: Singla Anil K , Chawla M , Singh A
Published: October 2002

Nimesulide, a non-steroidal anti-inflammatory drug (NSAID), is administered orally or rectally twice daily for a variety of inflammation and pain states. This is a unique NSAID, not only because of its chemical structure but also because of its specific affinity to inhibit cyclooxygenase-2 (COX-2), thus exerting milder effects on the gastrointestinal mucosa. Current data on selective COX-2 inhibitors suggest that they may have an efficacy similar to that of standard NSAIDs. Initial general clinical experience with selective COX-2 inhibitors appears to show that they are particularly promising in individuals at risk because of renal diseases, hypertension or congestive heart failure.

Various experimental models and clinical studies have demonstrated the anti-inflammatory efficacy of nimesulide. Nimesulide is superior, or at least comparable in efficacy, to other NSAIDs, but is better tolerated and has less potential for adverse reactions. Thus, selective COX-2 inhibitors should have anti-inflammatory effects devoid of side effects on the kidney and stomach. They may also demonstrate new important therapeutic benefits as anticancer agents as well as help prevention of premature labour and even retard the progression of Alzheimer's disease. No clinically significant drug interactions have been reported for nimesulide.

Not much has been reported about the pharmaceutical aspects of nimesulide. Its poor aqueous solubility poses bioavailability problems in-vivo. This could be overcome by the formation of inclusion complexes with β-cyclodextrin, as has been reported by various researchers. However, absence of any in-vivo data regarding the relative absorption of nimesulide from β-cyclodextrin complex compared with that from conventional formulations of the drug makes the use of such fast-releasing complexes rather questionable. Only a limited number of assay procedures (HPLC, spectrophotometric, spectrofluorimetric) for the determination of nimesulide and its metabolite in plasma/urine samples or in dosage forms have been reported in the literature.

The purpose of this review is to provide a concise overview of the pharmacological and pharmaceutical profile of nimesulide. Various investigations carried out recently are reported, although older references to research performed on nimesulide have also been included, where appropriate.
Uptake of Ibuprofen, Indomethacin and Ketoprofen into Isolated Rabbit Parietal Cells
Authors: Deninger Michael J , Schoenwald Ronald D
Published: October 2002

In the United States and other countries, non-steroidal anti-inflammatory drugs (NSAIDs) can be purchased without a prescription. Due to their widespread use, the drugs' most common side effect, gastric toxicity, becomes a more serious concern. Gastric toxicity can occur directly by contact with mucous membranes or indirectly by the inhibition of prostaglandin production in the gastric mucosa. We have studied the uptake of NSAIDs in gastric tissue, specifically parietal cells removed from the rabbit stomach.

New Zealand White rabbits were killed and then used to harvest parietal cells. The purified cells were used to study the uptake of ibuprofen, indomethacin and ketoprofen (NSAIDs) over time and under different experimental conditions.

The effects of concentration were investigated for all three NSAIDs. In addition, indomethacin and ibuprofen were used to investigate the mechanism of uptake. Studies were determined for the effects of varied extracellular pH from pH 6 to 8, and inhibitory conditions from depressed temperature (5°C), metabolic inhibitors (sodium azide and 2,4-dinitro-phenol), an ionophore (nigericin) and a sodium free support medium. The interaction of NSAIDs with lysed parietal cells was investigated also.

Initial rate data indicated that Michaelis-Menten kinetics were apparent; however, poor solubility of all three NSAIDs prevented complete characterization of the inclusion of a passive transport mechanism. Uptake showed a statistically significant increase (P = 0.01 to 0.05) as pH decreased, also suggesting contribution from a passive mechanism. Studies with inhibitors showed minimal effects. However, uptake at equilibrium for the ionophore, nigericin, showed a 10-fold increase over the control for ibuprofen (P = 0.005) and a 1.4-fold increase for indomethacin (P = 0.04). Depressed temperature (5°C) increased the initial rate and uptake at equilibrium 2.1- and 2.2-fold, respectively, for ibuprofen (P < 0.01). For indomethacin depressed temperature increased the initial rate and uptake at equilibrium 2.7- and 5.2-fold, respectively (P < 0.01). The increases at 5°C suggests that adsorption may be an important uptake component. Experiments with lysed parietal cells showed a non-specific uptake phenomenon, suggesting an adsorption component was occurring also.
Effect of Loperamide on Na+/d-Glucose Cotransporter Activity in Mouse Small Intestine
Authors: Klaren P H M , Giesberts A N , Chapman J , White S J , Taylor C J , Hardcastle P T , Hardcastle J
Published: October 2002

The μ-opioid agonist loperamide is an antidiarrhoeal drug which inhibits intestinal motility and secretion. Its anti-absorptive effects are less well investigated, but may be mediated through calmodulin. We have investigated further the effect of loperamide on the intestinal Na+-dependent d-glucose transporter (SGLT1). Brush-border membrane vesicles were prepared from mouse small intestine, and uptake of [3H]glucose was measured.

Na+-dependent glucose uptake displayed the typical overshoot at 34 s; the peak value was 1.6 nmol mg−1. The overshoot disappeared in the presence of phlorizin or when Na+ was replaced by K+. Extravesicular loperamide dose-dependently inhibited SGLT1 activity with an IC50 value of 450 μmol L−1. Loperamide displayed a mixed inhibition type: the apparent Vmax decreased from 0.9 to 0.5 nmol mg−1/15 s, the apparent Km increased from 0.23 to 1.13 mmol L−1 glucose. Na+ kinetics were more complex, but loperamide inhibited net glucose uptake by 90% at 100 mmol L−1 Na+. Glucose uptake was unchanged by agents affecting calmodulin activity. Loperamide inhibited intestinal Na+, K+-ATPase activity, whilst sucrase activity was unaffected.

SGLT1 activity was inhibited by loperamide, but this effect was not mediated through calmodulin. As this action is only evident at high concentrations of loperamide a non-specific mechanism may be involved.
The Effects of Streptozotocin-induced Diabetes and Aldose Reductase Inhibition with Sorbinil, on Left and Right Atrial Function in the Rat
Authors: Sellers Donna J , Chess-Williams Russell
Published: October 2002

Diabetes mellitus is frequently associated with the complications of cardiovascular disease. Activation of the aldose reductase (or polyol) pathway has long been implicated as an underlying factor for the development of many diabetic complications and indeed, treatment with aldose reductase inhibitors has been shown to prevent or reverse many of these diabetic complications. This study examines the effects of 14-day streptozotocin-induced diabetes on α1 and β-adrenoceptor-mediated responses in rat isolated left and right atria. The effects of treatment with the aldose reductase inhibitor (ARI) sorbinil were also studied. A positive inotropic response was observed to both isoprenaline and phenylephrine in left atria. Diabetes of 14 days duration resulted in a supersensitivity of these tissues to the β-adrenoceptor agonist in comparison with controls, while responses to the α1-adrenoceptor agonist were unaltered. Spontaneously beating right atria from diabetic rats was found to have a depressed resting rate compared with control tissues, although positive chronotropic β-adrenoceptor-mediated responses were not affected by diabetes. Phenylephrine produced α1-adrenoceptor-mediated chronotropic responses in right atrial tissues, and these were found to be enhanced in rats with diabetes. Treatment of diabetic rats with the ARI sorbinil was successful in preventing only one of the observed diabetes-induced changes in atrial function, namely the supersensitivity of left atria to isoprenaline. Sorbinil treatment did, however, alter responses of control left and right atria in a manner similar to diabetes.

In conclusion, streptozotocin-induced diabetes of 14 days duration was found to cause a number of alterations in the functioning of both left and right atria. ARI treatment with sorbinil failed to prevent all but one of these changes, and in addition altered responses of atria from control rats, having a similar effect to that produced by diabetes. These data suggest that sorbinil may have effects in addition to, and independent of, aldose reductase inhibition in the cardiovascular system.
Liquid Chromatography-Atmospheric Pressure Chemical Ionization Mass Spectrometry as a Tool for the Characterization of Anthraquinone Derivatives from Chinese Herbal Medicine
Authors: Li Wenkui , Chan Chi-Leung , Lueng Hei-Wun
Published: October 2002

We have examined the anthraquinone derivatives of a Chinese herb medicine ‘Rhubarb’ by using HPLC/MS/MS, equipped with an atmospheric pressure chemical ionization source.

The simultaneous determination of five ingredients in the sample extracts by HPLC/MS/MS was demonstrated. Product ion spectra of these components in the extracts were obtained and matched against known standards. Concentrations of these active ingredients were estimated by multiple reaction monitoring in the negative ion mode using a single HPLC run.
Aerosol Delivery of Amphotericin B Desoxycholate (Fungizone) and Liposomal Amphotericin B (AmBisome): Aerosol Characteristics and In-vivo Amphotericin B Deposition in Rats
Authors: Ruijgrok E J , Vulto A G , Van Etten E W M
Published: October 2002

In the treatment or prophylaxis of invasive pulmonary aspergillosis, it may be attractive to administer the antifungal agent amphotericin directly to the pulmonary route via aerosol inhalation. In this study, we describe the aerosol characteristics of aerosolized non-liposomal amphotericin B (Fungizone) and liposomal amphotericin B (AmBisome), and the in-vivo aerosol deposition.

Aerosols were generated with a Collison nebulizer. Aerosol amphotericin concentrations and mass median diameters were measured. In-vivo pulmonary deposition was evaluated by measuring amphotericin concentrations in lungs of treated rats. Whole body aerosol deposition was determined by measuring radioactivity in tissues of rats after treatment with radiolabelled liposomes. For Fungizone and AmBisome, aerosol amphotericin concentrations were 24.5 ± 4.9 and 23.8 ± 3.0 μg L−1, respectively. The values for the median mass diameter were 1.38 and 2.26 μm for Fungizone and 2.43 and 1.97 μm for AmBisome. Amphotericin concentrations in lungs after 60-min nebulization of Fungizone or AmBisome were 24.2 ± 6.4 and 21.7 ± 2.6 μg g−1, respectively. After nebulization of radiolabelled liposomes, no radioactivity was retrieved from tissues other than the lungs or the gastrointestinal tract. Nebulization of either Fungizone or AmBisome leads to respirable aerosols and results in a substantial lung tissue concentration of amphotericin and low systemic exposure of amphotericin B. Aerosol administration of either Fungizone or AmBisome may be an attractive approach to prevent or treat pulmonary aspergillosis.
Anthraquinone-Oligodeoxynucleotide Conjugates as Inhibitors of Gene Transcription
Authors: Gibson V , Anderson R J , Hartley J A , McAdam S R , Cairns D
Published: October 2002

Several anthraquinone-oligodeoxynucleotide conjugates have been synthesized and their inhibition of transcription of the bla gene in E. coli has been determined.

All conjugates at 10 μm inhibited transcription and three conjugates inhibited mRNA production by 40 to 50% for periods of up to 60 min.
The Use of Atomic Charges and Orbital Energies as Hydrogen-bonding-donor Parameters for QSAR Studies: Comparison of MNDO, AM1 and PM3 Methods
Authors: Ghafourian Taravat , Dearden John C
Published: October 2002

Hydrogen-bonding, important in drug-receptor interactions, also determines the solubility and partitioning of drugs between phases. It is, therefore, important to incorporate the effects of hydrogen-bonding in studies of quantitative structure-activity relationships (QSAR).

In this study the atomic charge on the most positively charged hydrogen atom in a molecule and the energy of the lowest unoccupied molecular orbital (LUMO) have been used as a measure of hydrogen-bond-donor capacity. For several hydrogen-bonding acids the Mulliken atomic charges and the energy of the LUMO produced by use of three semi-empirical methods, AM1, PM3 and MNDO, and MNDO electrostatic-potential-derived atomic charges, have been compared in correlations with solvatochromic hydrogen-bonding acidity (σα2H).

Atomic charges and LUMO energies, particularly those calculated by use of the AM1 and MNDO methods, were found to correlate well with σα2H. They were also found to be good models of hydrogen-bonding in QSAR correlations.
Inert Gas Sparge Leads to Alternate Reaction Pathway
Authors: Franchini Miriam K , Carstensen Jens T
Published: October 2002

The effect of sparging with an inert gas (argon) was evaluated during the investigation of the solution kinetics of an oxidation-prone amphiphilic drug containing a sulphide moiety.

Samples stored with an air headspace in pH 7 and 8 phosphate buffers at elevated temperatures and in the absence of light degraded to two main products, a sulphoxide and a cinnamic acid analogue. Initially, this appeared to be a sequential mechanism which could be blocked by removing oxygen. Instead, argon-sparge forced the direct degradation to the cinnamate, which was evidenced by the formation of a strong odour of sulphide. In addition, argon-sparged samples remained colourless, while those sparged with oxygen or stored with an air headspace turned yellow and had negligible odour. The half-lives for samples stored in pH 8 buffers at 93°C at an initial drug concentration of 25 mg mL−1 were 128 days (argon sparged), 86 days (air headspace), and 65 days (oxygen sparged).

The results indicated that for the drug under study, sparging with an inert gas affected the mechanism as well as the rate of the reaction at elevated temperatures.
Distribution of α1L-Adrenoceptors in Canine Prostate: Characterization by Quantitative Autoradiography
Authors: Suzuki Yasunori , Moriyama Nobuo , Okaya Yuki , Kanada Atsunori , Nishimatsu Hiroaki , Kawabe Kazuki , Aisaka Kazuo
Published: October 2002

Our aim was to determine the distribution of α1L-adrenoceptors in canine prostate by an autoradiographic technique using [3H]JTH-601 (an α1L-adrenoceptor antagonist) and [3H]JTH-601-G1 (an active metabolite of JTH-601).

Prostates were removed from three male beagle dogs. Several slices of the specimens were incubated with 5 nm of [3H]JTH-601, [3H]JTH-601-G1 and [3H]tamsulosin (an α1A-adrenoceptor antagonist). For macroscopic autoradiography, visualization was performed using an imaging plate and image-analyser. To examine microscopic localization of binding sites, preparations were exposed, developed and fixed.

Specific binding of [3H]JTH-601 and [3H]JTH-601-G1 was observed diffusely throughout the entire interstitium on macroscopic autoradiography. Specific binding of [3H]tamsulosin was also recognized although the binding was weaker than that of [3H]JTH-601. On microscopic autoradiograms, the grains of each ligand were mainly distributed on smooth muscle.

These results indicate morphologically that specific binding sites of JTH-601 and JTH-601-G1 exist in canine prostate, suggesting the distribution of α1L-adrenoceptors in this tissue, in addition to α1A-adrenoceptors.
Anti-hypercholesterolaemia, Antioxidant Activity and Free Radical Scavenger Effects of Traditional Chinese Medicine Prescriptions Used for Stroke
Authors: Lin Chun-Ching , Yen Feng-Lin , Hsu Feng-Fang , Lin Jer-Min
Published: October 2002

The generation of oxygen radicals and lipid peroxidation may be factors in the cerebral damage secondary to ischaemia of the cerebrovascular disease, as in stroke. Five traditional Chinese medicinal prescriptions were investigated for their antioxidant activity: Shiee Fuu Jwu Iu Tang (TCMP1), Oh Yaw Shuen Chin Saan (TCMP2), Buu Yang Hwan Wim Tang (TCMP3), Sheau Shiuh Ming Tang (TCMP4), and Chir Hwu Jia Long Guu Mini Lih Tang (TCMP5).

Anti-lipid peroxidation, anti-superoxide formation and free radical scavenger activity were determined by the FeCl2—ascorbic acid-induced lipid peroxidation effects on lipids in-vitro, xanthine oxidase inhibition, cytochrome C system and an electron spin resonance spectrometer, respectively. The results showed that TCMP5 had greater anti-lipid peroxidation and anti-superoxide formation activity than the other prescriptions. TCMP4 had the greatest free radical scavenging effect, TCMP5 showed the greatest superoxide radical scavenger activity and TCMP3 showed the greatest hydroxyl radical scavenger activity. Tests were also performed to evaluate the effects of the five prescriptions on blood lipid in-vivo. The test showed that the prescriptions decreased the level of total cholesterol and LDL-cholesterol in serum in high cholesterol-fed rats.

From these results, it seems probable that these prescriptions may be effective in the prevention and therapy of stroke and ischaemia.
Endothelium-independent Vasorelaxant Effect of Dioclein, a New Flavonoid Isolated from Dioclea grandiflora, in the Rat Aorta
Authors: Trigueiro F , Côrtes S F , Almeida R N , Lemos V S
Published: October 2002

We have investigated the endothelium-independent vasorelaxant effect of the new Flavonoid dioclein (5,2′,5′-trihydroxy-6–7-dimethoxyflavanone) in the rat aorta.

In endothelium-denuded vessels, dioclein induced a concentration-dependent relaxation of aortic rings precontracted with noradrenaline (IC50 = 3.5 ± 0.89 times 10−4 M and KCl (IC50 = 5.2 ± 1.2 times 10−4 M). In the absence of extracellular calcium, dioclein reduced the contraction induced by noradrenaline (maximal reduction approximately 33%) but not that induced by caffeine. Dioclein also produced a concentration-dependent inhibition of the sustained contractions induced by the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate in normal (IC50 = 4.0 ± 0.2 times 10−4 M) and Ca2+ -free solution (IC50 = 4.0 ± 0.3 times 10−4 M).

The results indicate that the endothelium-independent vasorelaxant effect of dioclein may be explained by inhibition of contractions dependent on activation of protein kinase C, voltage-dependent Ca2+ influx and on the release of intracellular Ca2+ stores sensitive to noradrenaline.
The Effect of Different Dosing Schedules of UCN-01 on its Pharmacokinetics and Cardiohaemodynamics in Dogs
Authors: Kurata N , Imabeppu S , Nitoh M , Kobayashi H , Kuwabara T , Kobayashi S
Published: October 2002

7-Hydroxy-staurosporine (UCN-01) is now under development as a novel anticancer drug. In clinical studies, different infusion schedules are being investigated in the USA and Japan. To examine the effect of different infusion schedules on the pharmacokinetics and cardiohaemodynamics of UCN-01, dogs were treated with UCN-01 as either a 3-h or a 24-h constant intravenous infusion. Blood pressure and heart rate, together with UCN-01 concentrations during and after infusion, were monitored. To analyse the relationship between the pharmacokinetics and cardiohaemodynamics of UCN-01, the plasma concentration of UCN-01 at the end of infusion (Cend), the area under the plasma concentration versus time curves (AUC0-∞) and the mean residence time (MRT) were used. As indices of cardiohaemodynamic changes, the area under decreasing systolic blood pressure and increasing heart rate versus time curves (dAUCpressure and AUCheart rate) were calculated by the trapezoidal method.

For the 3-h (0.22 and 0.65 mgkg−1) and 24-h infusion (0.81 to 6.48 mgkg−1), systolic and diastolic blood pressures fell after or during infusions, accompanied by a dose-dependent increase in heart rate for both infusions. During both infusion schedules, the plasma concentrations of UCN-01 gradually increased and Cend showed a dose-proportional increase. After that, UCN-01 was eliminated bi-exponentially with an elimination half-life of 5.14 ± 1.12 to 8.32 ± 1.80 h. The total clearance (CLtotal) ranged from 0.383 to 0.666 ± 0.149L h−1kg−1. There was no significant difference in these parameters among the doses in each infusion schedule, indicating that UCN-01 has a linear pharmacokinetic profile over the dose range examined for each infusion, and there were also no significant differences between the 3-h and 24-h infusion except for MRT. The pharmacokinetic parameters of Cend, AUC0-∞ and slope0-3h exhibited a degree of correlation with the AUCheart rate in the 3-h infusion and correlated significantly with the dAUCpressure in the 24-h infusion. The MRT did not correlate with cardiohaemodynamic changes during either infusion.

In conclusion, the pharmacokinetic profile of UCN-01 after the shorter infusion is similar to that after the longer one. However, a longer dosing period of UCN-01 increased the residence time in comparison with the shorter infusion. This may be due to the effect on the circulatory function in dogs.
Recombinant Human Lactoferrin is Effective in the Treatment of Helicobacter felis-infected Mice
Authors: Dial E J , Romero J J , Headon D R , Lichtenberger L M
Published: October 2002

Recombinant human lactoferrin possesses in-vitro antibiotic and anti-inflammatory activity similar to the native form. It was tested for in-vivo activity in mice infected with the gastritis-inducing bacterium Helicobacter felis.

A two-week course of treatment with lactoferrin was sufficient to partially reverse both infection-induced gastritis and the infection rate, and fully reverse gastric surface hydro-phobicity changes. A comparison of lactoferrin with amoxicillin and standard triple therapy revealed no differences in infection rate.

These results show that recombinant human lactoferrin is effective in a mouse model of Helicobacter infection, and support further testing of this promising agent for this application.
Effects ofUncaria tomentosaTotal Alkaloid and its Components on Experimental Amnesia in Mice: Elucidation Using the Passive Avoidance Test
Authors: Abdel-Fattah Mohamed A-F , Matsumoto Kinzo , Tabata Keiichi , Takayama Hiromitsu , Kitajima Mariko , Aimi Norio , Watanabe Hiroshi
Published: October 2002

The effects of Uncaria tomentosa total alkaloid and its oxindole alkaloid components, uncarine E, uncarine C, mitraphylline, rhynchophylline and isorhynchophylline, on the impairment of retention performance caused by amnesic drugs were investigated using a step-down-type passive avoidance test in mice. In this test, the retention performance of animals treated with the amnesic and test drugs before training was assessed 24 h after training.

Uncaria tomentosa total alkaloid (10–20 mgkg−1, i.p.) and the alkaloid components (10–40 mg kg−1, i.p.), as well as the muscarinic receptor agonist oxotremorine (0.01 mgkg−1, i.p.), significantly attenuated the deficit in retention performance induced by the muscarinic receptor antagonist scopolamine (3mgkg−1, i.p.). The effective doses of uncarine C and mitraphylline were larger than those of other alkaloid components. Uncarine E (20mgkg−1, i.p.) also blocked the impairment of passive avoidance performance caused by the nicotinic receptor antagonist mecamylamine (15 mgkg−1, i.p.) and the N-methyl-D-aspartate (NMDA) receptor antagonist (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP; 7.5 mgkg−1, i.p.), but it failed to affect the deficit caused by the benzodiazepine receptor agonist diazepam (2 mgkg−1, i.p.). Rhynchophylline significantly reduced the mecamylamine-induced deficit in passive avoidance behaviour, but it failed to attenuate the effects of CPP and diazepam.

These results suggest that Uncaria tomentosa total alkaloids exert a beneficial effect on memory impairment induced by the dysfunction of cholinergic systems in the brain and that the effect of the total alkaloids is partly attributed to the oxindole alkaloids tested. Moreover, these findings raised the possibility that the glutamatergic systems are implicated in the anti-amnesic effect of uncarine E.
Sustained Release of 5-Fluorouracil from Polymeric Nanoparticles
Authors: McCarron Paul A , Woolfson A David , Keating Siobhán M
Published: October 2002

The use of biodegradable nanoparticles loaded with 5-fluorouracil was investigated as a potential means to sustain the release of this drug. Nanoparticles prepared from four biodegradable polymers were loaded with 5-fluorouracil using three loading concentrations of drug and three different concentrations of added polymer.

Washing particles using a centrifugation/re-suspension with ultrasound protocol was found to dislodge the majority of drug, resulting in an over-estimation of incorporation efficiency and low levels of strongly entrapped drug. Increasing the initial 5-fluorouracil concentration before polymer/monomer addition increased the drug loading in both washed and unwashed particles. Increasing the amount of polymer used to make nanoparticles did not increase loadings, but did produce increased amounts of unusable polymer waste. Drug release from nanoparticles was evaluated using a Franz cell diffusion apparatus, which showed an initial burst effect followed by a slower release phase over 24 h. Indeed, nanoparticles prepared from poly(lactide-co-glycolide) released 66% of their 5-fluorouracil payload over this period.

It was concluded that 5-fluorouracil-loaded nanoparticles could be readily included into a hydrogel-based delivery system to provide sustained drug release for trans-epithelial drug-delivery applications.
Enhancement of Anti-metastatic Activity of Pentoxifylline by Encapsulation in Conventional Liposomes and Sterically Stabilized Liposomes in Murine Experimental B16F10 Melanoma Model
Authors: Sant V P , Nagarsenker M S , Rao S G A , Gude R P
Published: October 2002

Pentoxifylline has been shown to exhibit anti-metastatic activity by inhibiting homing of B16F10 melanoma cells in the murine experimental metastasis model. In this study, the effect of encapsulation of pentoxifylline in conventional and sterically stabilized liposomes on its anti-metastatic activity in the murine experimental metastasis model was investigated.

After a single intravenous dose (10, 20 or 40 mg kg−1), pentoxifylline solution, as well as conventional pentoxifylline liposomes, significantly reduced the number of pulmonary nodules compared with the untreated control group. Conventional pentoxifylline liposomes showed significantly higher inhibition (69%) of pulmonary tumour nodule formation at a dose of 20 mg kg−1 as compared with pentoxifylline solution (49%) at the same dose. Encapsulation of pentoxifylline in sterically stabilized liposomes prepared by incorporation of monomethoxypolyethyleneglycol (5000)-cholesteryl ester further enhanced the inhibition of pulmonary nodule formation (77%) at a dose of 20 mg kg−1 as compared with conventional pentoxifylline liposomes.

Overall, the results suggest that encapsulation of pentoxifylline in conventional liposomes enhanced its anti-metastatic activity. Steric stabilization of pentoxifylline liposomes also resulted in a two-fold increase in anti-metastatic activity (at dose of 10 mg kg−1) as compared with conventional liposomes.