bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition by the Bioflavonoid Ternatin of Aflatoxin B1-induced Lipid Peroxidation in Rat Liver
Authors: Souza M F , Tomé A R , Rao V S N 
Published: July 2003

Abstract
Aflatoxin B1, a metabolite of Aspergillus flavus is a potent hepatotoxic and hepatocarcinogenic mycotoxin. Lipid peroxidation and oxidative DNA damage are the principal manifestations of aflatoxin B1-induced toxicity which could be mitigated by antioxidants. Many plant constituents, e.g. flavonoids, lignans and spice principles (capsaicin, curcumin, eugenol, etc.) have been reported to prevent liver damage associated with lipid peroxidation. In this study we investigated ternatin, a tetramethoxyflavone isolated from Egletes viscosa, for possible protection against liver injury induced by aflatoxin B1 in rats.
Seventy two hours after a single intraperitoneal dose of aflatoxin B1 (1 mg kg−1), the concentration of malondialdehyde, the product of lipid peroxidation in liver homogenates, and serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly elevated (P &lt; 0.01). Subcutaneous ternatin (25 mg kg−1) pretreatment greatly reduced aflatoxin B1-induced increases in the levels of serum enzymes (ALT from 5071 ± 763 to 293 ± 66 international unitsL−1 and AST from 4241 ± 471 to 449 ± 108 international units L−1) and elevated malondialdehyde levels (from 11.37 ± 1.27 to 0.79 ± 0.22 nmol (mg wet tissue)−1) in a manner similar to oral vitamin E (300 mg kg−1), a standard antioxidant. Further, histological changes induced by aflatoxin B1 such as hepatocellular necrosis and bile-duct proliferation were markedly inhibited in animals pretreated with ternatin or vitamin E.
These data provide evidence that ternatin inhibits lipid peroxidation and affords protection against liver damage induced by aflatoxin B1. Ternatin might, therefore, be a suitable candidate for the chemoprevention of aflatoxicosis associated liver cancer.
Cellular Uptake and Release of Two Contrasting Iron Chelators
Authors: Cable Hazel , Lloyd John B 
Published: July 2003

Abstract
Desferrioxamine and CP94 (1,2-diethyl-3-hydroxypyridin-4-one) are metal chelators used or proposed for use in the clinical treatment of iron overload. Recent data on their capacity to deplete intracellular iron led to the conjecture that the differences observed arose from the different membrane-penetration properties of the two compounds.
The time-course of accumulation and subsequent release of [14C]CP94 by the rat visceral yolk sac in-vitro was compared with that of [14C]desferrioxamine and for 125I-labelled poly(vinylpyrrolidone), a marker for fluid-phase endocytosis. The results indicate that [14C]CP94 crosses the plasma and lysosome membranes rapidly whereas [14C]desferrioxamine and 125I-labelled poly(vinylpyrrolidone) are effectively incapable of crossing these membranes, entering cells only by endocytosis.
It is concluded that although CP94 readily enters and leaves cells, desferrioxamine has the potential to accumulate to high concentration in the lysosomes and complex with intralysosomal iron. The results support and extend the proposed correlation between pharmacological activity and capacity for membrane penetration.
Inhibition by 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) of Responses to Nitric Oxide-donors in Rat Pulmonary Artery: Influence of the Mechanism of Nitric Oxide Generation
Authors: Homer Kerry L , Fiore Steven A , Wanstall Janet C 
Published: July 2003

Abstract
ODQ, (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase) inhibits vasorelaxant responses to nitric oxide (NO)-donor drugs, but the extent of the inhibition varies depending on the NO donor studied. The purpose of this study was to test the hypothesis that these variations in the effects of ODQ reflect differences in the mechanisms whereby each NO donor generates NO.
On pulmonary artery preparations pre-contracted submaximally with phenylephrine, ODQ (3 μM) almost abolished the relaxant responses to glyceryl trinitrate, isosorbide dinitrate and nitroprusside; each of these drugs requires activation in the tissue (by enzymes or reducing agents) to generate NO. In contrast, ODQ (3 μM) caused a parallel shift in the concentration-relaxation curves to linsidomine (SIN-1), FK409, MAHMA NONOate and spermine NONOate (1.63 to 2.54 log units) with no depression in maximum response; each of these NO donors generates NO in the physiological bathing solution without requiring tissue activation. For the four drugs in this group, the effects of 10 μM ODQ were not significantly greater than the effects of 3 μM ODQ; thus there was an ODQ-resistant component to the response suggesting that part of the response involved a mechanism that was independent of soluble guanylate cyclase.
NO donors that require tissue activation probably generate NO within the smooth-muscle cell, whereas those that do not require tissue activation generate NO outside the cell. Hence it is concluded that the site of NO generation (intra- or extracellular) might determine whether or not there is an ODQ-resistant component in the relaxation response.
Alginate-Pectin-Poly-L-lysine Particulate as a Potential Controlled Release Formulation
Authors: Liu Ping , Krishnan T R 
Published: July 2003

Abstract
Drug delivery particulates were prepared using alginate, polylysine and pectin. Theophylline, chlorothiazide and indomethacin were used as the model drugs for in-vitro assessments, and mannitol was the model for assessing paracellular drug absorption across Caco-2 cell monolayers. Alginate and pectin served as the core polymers and polylysine helped to strengthen the particulates. Use of pectin specially helped in forming a more robust particulate that was more resistant in acidic pH and modulated the release profiles of the encapsulated model drugs in the alkaline pH. Alginate and pectin were also found to enhance the paracellular absorption of mannitol across Caco-2 cell monolayers by about three times. The release rate could be described as a first-order or square-root time process depending on the drug load.
Use of alginate-polylysine-pectin particulates is expected to combine the advantages of bioadhesion, absorption enhancement, and sustained release. This particulate system may have potential use as a carrier for drugs that are poorly absorbed after oral administration.
Formulation and Biological Activity of Antineoplastic Proteoglycans Derived from Mycobacterium vaccae in Chitosan Nanoparticles
Authors: Tian Xin-Xin , Groves Michael J 
Published: July 2003

Abstract
Although heat-killed suspensions of Mycobacterium vaccae have been tested clinically against tuberculosis and cancer, from a pharmaceutical perspective it would be advantageous to utilize isolated active components rather than the heat-degraded bacterial materials. In our laboratory we have isolated from M. vaccae a number of high-molecular-weight proteoglycans with considerable immunological and antineoplastic activity.
The structure of one of these, PS4A, obtained by extraction with boiling water, seems to consist of a basic unit with a 20-kDa protein core to which are attached glucans and O-methylated 4-kDa polysaccharides. The molecular weight is (approx.) 50 kDa, but because of self-association, that of the recovered high-molecular-weight fraction is greater than 150 kDa. A similar, but even larger, molecule (PS4α, MW ∼20 MDa) is obtained by cold extraction with 8 M urea. Both are active in-vivo against an S-180 murine sarcoma model but have no activity in-vitro, suggesting an antitumour effect involving activated macrophages. For this reason gelatin nanoparticles are unsuitable as a vehicle but chitosan seemed to be a promising alternative. In this report we describe the production of stable 600–700-nm diameter nanoparticles of chitosan without organic solvents. Adsorption and release of bovine serum albumin seemed to be affected by the charge of the two reactants and at high doses not all adsorbate was released. PS4A, because of structural and compositional differences, had to be loaded on to the chitosan by freeze drying a suspension of the nanoparticles in a solution of the drug. After a rapid (burst) release phase, the rate of release into water was steady for the next 4h, but not all the drug was released. In-vivo it was evident that PS4A and PS4α were equally active in solution or when formulated in the chitosan nanoparticles.
These results show that chitosan nanoparticles, readily prepared without the use of organic solvents, are a suitable vehicle for the delivery of these immunostimulants from M. vaccae; the formulations might find application as antitumour agents.
Improving the Oral Bioavailability of Albendazole in Rabbits by the Solid Dispersion Technique
Authors: Kohri Naonori , Yamayoshi Yasuko , Xin He , Iseki Ken , Sato Naoki , Todo Satoru , Miyazaki Katsumi 
Published: July 2003

Abstract
We have investigated the oral bioavailability of granules of albendazole, a drug used for treating echinococcosis in man, prepared by the solid dispersion technique.
Rapid dissolution and supersaturation were observed when hydroxypropylmethylcellulose and hydroxypropylmethylcellulose phthalate were used as carriers in the solid dispersion. They inhibited the crystallization of albendazole from the supersaturated solution and maintained an amorphous state for 8h. Gastric acidity-controlled rabbits were used to evaluate the variation in absorption after oral administration of the albendazole solid dispersion. For rabbits with low gastric acidity the bioavailability of orally administered albendazole in the granular form prepared by solid dispersion was more than three times that of albendazole in physical mixtures.
These results suggest that the bioavailability of albendazole in solid dispersions might be high even if there is a great variation in the gastric pH of patients.
Whole-body Autoradiography and Quantitative Organ-level Distribution Study of Deramciclane in Rats
Authors: Hazai István , Pátfalusi Márta , Klebovich Imre , ürmös Iván 
Published: July 2003

Abstract
The distribution of 3H-labelled deramciclane (EGIS-3886), a new 5-HT2 antagonist with anxiolytic activity, has been investigated by whole-body autoradiography and quantitative organ-level determination after intravenous and oral administration to male and female rats at a dose of 3 mg kg−1. Pregnant dams were also studied, but by autoradiography only. In the autoradiographic study 32 organs were investigated, while in the quantitative organ-level study the radioactivity in 15 organs were determined.
There are no sex differences in the distribution of deramciclane, absorption is rapid, elimination is comparatively fast, no specific organ is targeted, and the accumulation of the compound is very unlikely. Penetration of the blood-brain barrier was complete and extremely fast, a very important feature of a potential anxiolytic drug. There is no penetration of the foetus in pregnant dams.
The study demonstrated that deramciclane has advantageous pharmacokinetic properties in rats.
Insulin Lispro: In-vivo Potency Determination by Intravenous Administration in Conscious Rabbits
Authors: Lin Senshang , Wang Shun-Yung , Chen Eung-Cheng , Chien Yie W 
Published: July 2003

Abstract
Insulin lispro is a monomeric analogue of human insulin, produced by genetic engineering, and has been reported to have a more rapid absorption following subcutaneous injection than insulin. Since it has been shown to have a similar hypoglycaemic action to insulin in clinical studies and comparable properties in radioimmunoassay, the feasibility of using a bioassay which was designed originally for insulin, to measure insulin lispro potency was evaluated in this investigation.
A random-dose bioassay protocol, in which insulin lispro and two insulin standards were administered intravenously in a random sequence, was used and validated in nine conscious healthy rabbits. The decline in blood-glucose levels, following the intravenous injection of a dose of insulin or its lispro analogue, was monitored by a continuous glucose monitoring system. A glucose response curve was generated, from which various pharmacodynamic parameters were determined. Compared with the insulin standards, the potencies of insulin lispro determined from nadir, basal glucose normalized nadir, glycaemic reduction and ABGC (area of the blood-glucose response curve under baseline) were observed to have mean (95% confidence limits) values of 97.0 (69.5–124.6)%, 106-3 (72.4–140-2)%, 94.9 (51.8–138-0)% and 102.4 (76.3–128.5)%, respectively. In addition, the coefficients of variation for correspondent parameters were 36.9, 41.5, 59.1 and 33.2%, respectively.
The results indicated that the hypoglycaemic potency calculated from the ABGC values was the most accurate (102.4%) with the least coefficient of variation (33.2%). In conclusion, the potency of insulin lispro can be determined accurately from the ABGC values measured by the random-dose bioassay used.
Assessment of the Adrenergic Effects of Orphenadrine in Rat Vas Deferens
Authors: Pubill D , Canudas A M , Pallàs M , Sureda F X , Escubedo E , Camins A , Camarasa J 
Published: July 2003

Abstract
The peripheral adrenergic effects of orphenadrine, an antiparkinsonian drug, have been evaluated in the rat vas deferens to investigate whether these properties are the same as those of other phencyclidine ligands.
In the low micromolar range, orphenadrine enhanced electrically-evoked and exogenous noradrenaline contractile responses in the epididymal portion of rat vas deferens. It also induced spontaneous activity that was inhibited by prazosin (1 μM) but not by atropine (20 nM). It inhibited accumulation of [3H]noradrenaline in rat vas deferens (IC50 = 14.2 ± 2.3 μM). Orphenadrine competitively inhibited [3H]nisoxetine binding in rat vas deferens membranes (Ki = 1.05 ± 0.20 μM).
It can be concluded that orphenadrine, at low micromolar concentrations, interacts with the noradrenaline reuptake system inhibiting its functionality and thus potentiating the effect of noradrenaline.
Neuropsychopharmacological Profile of the Methanolic Fraction of Bryophyllum pinnatum Leaf Extract
Authors: Pal Siddhartha , Sen T , Chaudhuri A K Nag 
Published: July 2003

Abstract
Neuropharmacological studies were conducted in experimental animals (rats and mice) with the methanolic fraction of Bryophyllum pinnatum leaf extract.
The fraction produced alteration of behaviour pattern, caused dose-dependent potentiation of pentobarbitone sleeping time and had significant analgesic activity. Significant reduction of exploratory behaviour and loss of residual curiosity were among the effects observed with the fraction. The observations suggest that the methanolic fraction of Bryophyllum pinnatum possesses a potent CNS depressant action.
Simple O-Acylated Derivatives of Lysergol and Dihydrolysergol-I: Synthesis and Interaction with 5-HT2A, 5-HT2C and 5-HT1B Receptors, and α1 Adrenergic Receptors
Authors: Pertz Heinz H , Brown Anthony M , Gager Tracey L , Kaumann Alberto J 
Published: July 2003

Abstract
A series of simple O-acylated derivatives of the naturally occurring clavine alkaloids lysergol and dihydrolysergol-I were synthesized and tested in-vitro for their ability to interact with 5-HT2A receptors in rat tail artery, 5-HT2C receptors in piglet choroid plexus, 5-HT1B receptors in guinea-pig iliac artery and α1-adrenergic receptors in rat aorta.
In contrast to the classical ergoline 5-HT2A receptor antagonists methysergide and LY53857, the compounds produced competitive antagonism of the 5-HT response in rat tail artery. Affinities of ergolines 3–14 were higher (pA2 values of 7.33-8.40) than those of the parent alcohols lysergol (1) and dihydrolysergol-I (2), respectively. The introduction of an isopropyl substituent at the N(1) position of the compounds failed to enhance 5-HT2A receptor affinity. Compounds 3–14 exhibited lower affinities for α1-adrenergic receptors than for 5-HT2A receptors. In particular, those lysergol derivatives that had an isopropyl substituent at the N(1) position were highly specific 5-HT2A receptor antagonists (ratio 5-HT2A/α1 = 302–3548).
Selected derivatives of lysergol (3–5, 9–11) which were assayed for radioligand binding at 5-HT2C receptors in piglet choroid plexus had affinities that were similar to those found in rat tail artery. Additionally, lysergol and its N(1)-unsubstituted derivatives were found to be partial agonists (α of 0.2-0.4) for 5-HT2C receptor-mediated inositol phosphate accumulation in piglet choroid plexus. On the other hand, analogues with an isopropyl substituent at N(1) showed no measurable agonist activity. The observation that N(1)-unsubstituted derivatives of lysergol possessed agonist properties at 5-HT2C receptors whereas their agonist activity at 5-HT2A receptors was marginal (α of 0.05 for compound 3 at 1 μM) or not measurable, suggests that these compounds have different abilities to cause conformational change at the two receptor types. Selected derivatives of lysergol (3–5, 9.11) which were examined as ligands for 5-HT1B receptors in guinea-pig iliac artery caused insurmountable blockade of the contractile effect of 5-HT. N(1)-isopropyl derivatives had 30–50-fold lower affinities for 5-HT1B receptors of this tissue than their N(1)-unsubstituted analogues.
It is concluded that O-acylated derivatives of the clavine alkaloids lysergol and dihydrolysergol-I mimic therapeutically relevant ergolines due to the complexity of their pharmacological profile as partial agonists and antagonists at 5-HT2A, 5-HT2C and 5-HT1B receptors, and at α1-adrenergic receptors.
Inhibition by Leukotriene Inhibitors, and Calcium and Platelet-activating Factor Antagonists, of Acute Gastric and Intestinal Damage in Arthritic Rats and in Cholinomimetic-treated Mice
Authors: Rainsford K D 
Published: July 2003

Abstract
The leukotrienes, platelet activating factor and intracellular calcium have been implicated in the development of gastro-intestinal lesions induced by non-steroidal anti-inflammatory drugs (NSAIDs) but the relative significance of these inflammatory mediators in lesion formation has not been established in sensitive and specific models of gastro-intestinal ulceration. In the present study the effects of drugs affecting 5-lipoxygenase activity, the actions of platelet activating factor and intracellular calcium on the development of gastric and intestinal ulceration induced by NSAIDs were investigated in highly sensitive models of ulcerogenicity induced by treatment with either the cholinomimetic, acetyl-β-methyl choline chloride, in mice (gastric mucosal lesions) or adjuvant-induced polyarthritis in rats (gastric and intestinal mucosal lesions) as well as in normal mice (intestinal mucosal lesions).
The 5-lipoxygenase inhibitors, such as MK-886 (-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid), given at doses shown to reduce the indomethacin-induced increase in mucosal leukotriene B4 concentrations were found to partially prevent the development of gastric and intestinal lesion induced by indomethacin and gastric lesions from aspirin, but the same doses of MK-886 did not affect gastric lesions from diclofenac. Pretreatment with these inhibitors at both 3–5 h and 0-0.25 h was required to achieve protection against gastric mucosal damage from indomethacin. Immediate prior administration of platelet activating factor antagonists (e.g. WEB-2086) with the 5-lipoxygenase inhibitors did not affect gastric or intestinal lesions induced by indomethacin. The calcium antagonist, verapamil, was slightly protective against gastric and intestinal lesions induced by indomethacin. Gastric lesions were further prevented by combinations of a single dose of verapamil with a platelet activating factor antagonist but not combined with a 5-lipoxygenase inhibitor; other combinations of verapamil with lipoxygenase inhibitors or platelet-activating factor antagonists being without inhibitory effects on gastric or intestinal lesions compared with the drugs alone.
These results show that 5-lipoxygenase products and intracellular calcium play a major role in acute gastric and intestinal damage by the NSAIDs, but platelet-activating factor has little or no appreciable involvement.
Effects of an Essential Oil from the Bark of Croton cajucara Benth. on Experimental Gastric Ulcer Models in Rats and Mice
Authors: Hiruma-Lima C A , Gracioso J S , Nunes D S , Brito Arm Souza 
Published: July 2003

Abstract
Croton cajucara Benth. (Euphorbiaceae) is widely used in Amazonian folk medicine for the treatment of a wide range of gastrointestinal symptoms. The essential oil from its bark was investigated for acute toxicity in mice and for its ability to prevent the formation of ulceration of the gastric mucosa in different models of experimentally induced gastric ulcer in mice and rats.
When previously administered orally at a dose of 100mg kg-1, the essential oil significantly reduced (P &lt; 0.01) the gastric injury induced by hypothermic restraint stress (48%), indomethacin (47%), ethanol (86%) and pylorus ligature models (87%) in rats. In the HCl/ethanol-induced gastric ulcer model in mice, at oral doses of 100 and 200mg kg-1 the essential oil from C. cajucara significantly reduced (P &lt; 0.01) the formation of gastric lesions by 52% and 67%, respectively, when compared with the control group. In rats submitted to pylorus ligature, the essential oil given orally increased the volume of gastric juice when compared with the control group (P &lt; 0.01). When the essential oil (100mg kg-1) was administered intraduodenally to mice, significant modifications were found in gastric parameters such as pH and total acid content after oil treatment. We observed significant changes (P &lt; 0.01) in gastric juice parameters such as an increase in volume and a decrease in gastric acidity (pH and total acid content). The acute toxicologic effects of the essential oil from C. cajucara were assessed in mice. The LD50 values were 9.3g kg-1 by the oral route and 680mg kg-1 by the intraperitoneal route.
The good yield of essential oil obtained from dried C. cajucara bark (1%) as well as its anti-ulcerogenic activity and low toxicity suggest that pharmacological studies of this substance as a potential new anti-ulcerogenic drug are warranted.