bluuebunny/crossref_metadata_2025_split huggingface dataset:
Granisetron and Ondansetron: Effects on the Ileal Brake Mechanism in the Rat
Authors: Brown N J , Horton A , Rumsey R D E , Read N W 
Published: April 2011

Abstract
Studies were carried out on 20 male adult rats to investigate how the action of the selective 5-HT3-receptor antagonists, granisetron and ondansetron, influence gastrointestinal transit under control conditions and when stomach-to-caecum transit was delayed by ileal infusion of lipid. Stomach-to-caecum transit time (SCTT) was measured using environmental hydrogen analysis. Subcutaneous administration of granisetron (BRL 43694,40, 80 or 150 μg kg−1) significantly delayed the passage of the head of the baked bean meal through the stomach and the small intestine under control conditions (P &lt; 0·05). Similarly, subcutaneous administration of ondansetron (GR 38032F, 80 or 150 μg kg−1) delayed control SCTT of the head of the meal but this did not reach statistical significance. In contrast, granisetron significantly reversed the delay in SCTT induced by ileal infusion of lipid at 40 (P &lt; 0·001), 80 (P &lt; 0·01) and 150 μg kg−1 (P &lt; 0·05). Ondansetron also reversed the lipid-induced delay at 40 (P &lt; 0·01), 80 (P &lt; 0·001) and 150 μg kg−1 (P &lt; 0·001). These apparently conflicting results may be rationalized by postulating the presence of 5-HT3 receptors on afferent nerves which, when inhibited by the specific antagonists, initiate reflexes that both accelerate and delay transit.
Inhibitory Effect of NZ-105, a 1,4-Dihydropyridine Derivative, on Cyclic Nucloeotide Phosphodiesterase Activity
Authors: Yamashita Toru , Masuda Yukinori , Sakai Toshinori , Tanaka Sakuya , Kasuya Yutaka 
Published: April 2011

Abstract
The effects of NZ-105, a 1,4-dihydropyridine calcium antagonist, on the intracellular cyclic nucleotide system were investigated in-vitro. In rabbit isolated aorta, both NZ-105 (1 and 10 μm) and nicardipine significantly and in a concentration-dependent manner increased intracellular cyclic AMP and cyclic GMP content. NZ-105 inhibited bovine cardiac phosphodiesterase activity (Ki 30 μm) by competitive antagonism. The concentration ranges for inhibition were consistent with the range of increases in cyclic nucleotides.
Effect of Nifedipine on Calcium Status and Chemiluminescence Response of Phagocytes During Plasmodium berghei Infection in Mice
Authors: Kalra A , Dubey M L , Ganguly N K , Mahajan R C 
Published: April 2011

Abstract
The macrophages and neutrophils from nifedipine-treated mice, both Plasmodium berghei-infected and uninfected, showed suppressed capacity to generate oxygen free radicals as compared with untreated controls. Nifedipine treatment did not affect resting state free calcium levels in these cells. But the rise in intracellular calcium levels of macrophages and neutrophils following P. berghei infection was significantly less (P &lt; 0·05) in nifedipine-treated mice as compared with untreated groups at various parasitaemia levels. Probably this reflects a more potent effect of nifedipine on these cells in the depolarized state. Similarly, the rise in intracellular calcium levels of these cells following formyl-Met-Leu-Phe (fMLP) stimulation was also significantly less in nifedipine-treated groups than in untreated controls at different parasitaemia levels. A positive correlation between this fMLP-stimulated rise in calcium levels and the chemiluminescence response of macrophages and neutrophils was observed in nifedipine-treated and untreated groups at various parasitaemia levels. Thus the respiratory-burst responses of these cells during P. berghei infection depend on the calcium homeostasis in the cells. The disturbances of the calcium-regulating mechanisms by nifedipine treatment resulted in subnormal phagocytic cell responses which lead to more severe and rapidly fatal P. berghei infection in these animals.
Conversion of flosequinan to the sulphone metabolite in subcellular fractions of human liver, in-vitro
Authors: Kamali F , Edwards C 
Published: April 2011

Abstract
Flosequinan was metabolized in a NADPH-dependent reaction, by S-oxidation to its principal metabolite, the sulphone. Most of the sulphone metabolite was formed within 20 min and reached a plateau by 60 min, following incubations of flosequinan (31, 61 or 122 μm) with the microsomal fraction. Flosequinan was metabolized mainly by the microsomal fraction. The S-oxidation of flosequinan in incubations containing mitochondrial and cytosolic fractions was 13 and 5%, respectively, of that detected in the microsomal fraction. The route of metabolism of flosequinan in-vitro correlates closely with that previously observed in-vivo. This model could be useful for studying the potential effects of other drugs on flosequinan metabolism in-vitro.
Intragastric Distribution of Ion-exchange Resins: a Drug Delivery System for the Topical Treatment of the Gastric Mucosa
Authors: Burton S , Washington N , Steele R J C , Musson R , Feely L 
Published: April 2011

Abstract
Previous studies by this group on freeze-dried oral dosage forms containing finely-divided ion-exchange resins revealed prolonged gastric residence and uniform distribution within the stomach. The present study was carried out to ascertain whether this was due to freeze-drying, properties of the radiolabeled ionic exchange resin, or the small dosing volume used. 99mTc-labelled cholestyramine resin was administered in two dosage forms, a freeze-dried tablet which dissolved in the oral cavity (orally dissolving tablet; ODT) and a 1.5 mL aqueous suspension. Two resin particle sizes (20–40 and 90–125 μm) were studied. Oesophageal transit and intragastric distribution and residence were followed by gamma scintigraphy. In a second study, in six subjects, gastric emptying of the water-soluble fraction of the ODT and 1.5 mL of water, was measured using 99mTc diethylenetriaminepentaacetic acid.
Oesophageal transit of a water-soluble marker and resin in suspension was rapid, but the transit of the resin in the ODTs was significantly prolonged. Regardless of particle size or dosage form, the resin was evenly distributed throughout the stomach with 20–25% remaining for 5.5 h. In contrast, the water-soluble marker cleared from the stomach rapidly from both dosage forms.
We suggest that oral dose forms containing finely-divided ion-exchange resins may form a useful system for topical treatment of the gastric mucosa, for example in targeting to Helicobacter pylori infection.
Aggravating Process Induced by Indomethacin on Chronic Gastric Lesion in Rat. Role of Polymorphonuclear Leucocytes
Authors: Martin Maria José , Motilva Virginia , Luque Maria Isabel , De La Lastra Catalina Alarcon 
Published: April 2011

Abstract
The present study examines the indomethacin-provoked aggravation of chronic ulceration induced by acetic acid in rats. The drug was administered in a single dose, 7 and 14 days after provocation of ulceration. The changes induced by indomethacin in other groups of animals that had been treated for 7 and 14 days with hydroxyurea (which provokes a marked leucopenia) were also studied.
The results obtained demonstrate that indomethacin does not significantly modify the macroscopic index of ulceration nor vascular permeability in the majority of the groups tested. Only in the group that received hydroxyurea for 14 days was there an increase in both parameters. Myeloperoxidase activity was assayed and used as an index of leucocyte infiltration in an attempt to relate the increase in this activity with a gastrolesive effect. Application of acetic acid produced a significant increase in this activity 7 days after induction of chronic injury. Administration of hydroxyurea intraperitoneally was associated with a decrease in the severity of chronic ulceration and neutrophil infiltration into the gastric mucosa. This effect was detectable enzymatically and microscopically. The groups that received indomethacin showed an increase in myeloperoxidase activity, although this increase was only significant in the animals treated with hydroxyurea for 7 and 14 days.
The results suggest that the aggravation provoked by indomethacin is greater when the ulcer curing process is more advanced.
Effect of Selective Inhibition of Potassium Channels on Vasorelaxing Response to Cromakalim, Nitroglycerin and Nitric Oxide of Canine Coronary Arteries
Authors: Pataricza Janos , Toth Gabor K , Penke Botond , Hohn Jozsef , Papp Julius Gy 
Published: April 2011

Abstract
A comparative study was performed on the sensitivity of in-vitro vasorelaxation by nitroglycerin and cromakalim to block glibenclamide, a blocker of ATP-sensitive potassium channels, and iberiotoxin, a selective inhibitor of large-conductance calcium-activated potassium channels.
In isolated canine coronary arteries preconstricted with 25 μM prostaglandin F2α, nitroglycerin (0.005–1.8 μM) and cromakalim (0.15–9.6 μM) produced dose-dependent vasodilations. Glibenclamide (30 μM) had no significant effect on relaxation of the dose-response curve to nitroglycerin and almost completely abolished the relaxation by cromakalim, a known opener of ATP-sensitive potassium channels. Iberiotoxin (90 nM) decreased the maximal response to nitroglycerin and had no effect on the vasodilation induced by cromakalim. The effect of iberiotoxin on the vasorelaxing action of nitric oxide, the active metabolite of nitroglycerin, was also examined. In a low potassium chloride (14.4–20.4 mM) medium, as a contractile stimulus, iberiotoxin inhibited relaxations by exogenous nitric oxide (100–200 nM). Enhancement of potassium concentrations to 35.4–40.4 mM significantly decreased relaxation by nitric oxide and under these conditions the inhibitory action of iberiotoxin disappeared.
The present study demonstrated that in canine coronary arteries, the functional role of two potassium channels can be separated by pharmacological means. Nitroglycerin-induced vasorelaxation may be mediated, at least in part, by its enzymatic breakdown product, nitric oxide that activates large-conductance calcium-activated potassium channels.
Terpene Penetration Enhancers in Propylene Glycol/water Co-solvent Systems: Effectiveness and Mechanism of Action
Authors: Yamane M A , Williams A C , Barry B W 
Published: April 2011

Abstract
The effects of propylene glycol/water co-solvent systems and terpene penetration enhancers (1,8-cineole, menthone, (+)-limonene and nerolidol) on the absorption rate of the model hydrophilic permeant, 5-fluorouracil, were investigated using excised human skin.
Similar fluxes for 5-fluorouracil were obtained from saturated enhancer-free co-solvent systems. Coapplication of each terpene with the drug, both at saturation, in propylene glycol co-solvent systems increased drug flux significantly. Terpene activity depended on the propylene glycol content in the vehicles. Maximum fluxes were obtained from formulations containing the terpenes in 80% propylene glycol systems (highest concentration used), which when normalized to the flux from the pure vehicles yielded enhancement ratios of about 24, 21, 4 and 18, with 1,8-cineole, menthone, (+)-limonene and nerolidol, respectively. Combining the permeation studies with differential scanning calorimetry (DSC) and partitioning experiments revealed that increased lipid disruption is probably an important mechanism involved in the enhancing ability of formulations containing 1,8-cineole, menthone and nerolidol. This was clearly demonstrated by applying thermodynamic principles to interpret DSC results.
This approach has indicated that these terpenes are probably able to disrupt stratum corneum lipids at physiological temperature as manifested by reductions in the entropy changes associated with the lipid-related transitions, particularly T2, the first major lipid transition. Additionally, increased drug partitioning contributed to the effect of the high propylene glycol content formulations. (+)-Limonene, as interpreted from DSC results, produced a freezing point-depression effect on stratum corneum lipids, suggesting little interaction with lipids at skin temperature; its small enhancement effect may involve phase separation of the oil in stratum corneum lipids.
Terpenes in co-solvent systems such as propylene glycol/water at appropriate propylene glycol content might thus be useful vehicles for the delivery of drugs from topical formulations.
Simultaneous Comparison of Nicotinic Receptor Antagonists on Three Nicotinic Acetylcholine Receptors
Authors: Kerr K P , Stevenson J E , Mitchelson F 
Published: April 2011

Abstract
The relative potencies of several nicotinic cholinoceptor antagonists in producing tetanic fade and reduction of striated muscle contraction were investigated in the isolated guinea-pig oesophagus as well as the guinea-pig and rat phrenic nerve-diaphragm preparations. Contractile smooth muscle responses to vagal stimulation, which involves ganglionic activation, were also measured simultaneously with striated muscle responses in the oesophagus.
The relative potency for inhibiting the response of oesophageal smooth muscle to vagal stimulation (20 Hz) was trimetaphan &gt; mecamylamine &gt; hexamethonium &gt; tubocurarine &gt; pancuronium. For oesophageal striated muscle, production of tetanic fade at 100 Hz and reduction in peak tetanic tension at 20 or 100 Hz showed a similar relative potency; pancuronium &gt; tubocurarine &gt; mecamylamine &gt; trimetaphan &gt; hexamethonium and similar results were obtained in the guinea-pig diaphragm for the antagonists investigated (pancuronium, tubocurarine and mecamylamine). In the rat phrenic nerve-diaphragm preparation, production of tetanic fade at 50 Hz and reduction in twitch or tetanic tension all showed the relative potency; tubocurarine &gt; pancuronium &gt; mecamylamine &gt; trimetaphan &gt; hexamethonium.
These findings indicate differences in the nicotinic cholinoceptor subtypes involved in vagal ganglionic responses and those in tetanic fade.
The Effects of Hepatic Microsomal Enzyme Inducers on the Pharmacokinetics of Ouabain after Portal and Systemic Administration to Rats
Authors: Thompson Thomas N , Klaassen Curtis D 
Published: April 2011

Abstract
The microsomal enzyme inducers 3-methylcholanthrene, phenobarbitone and pregnenolone-16α-carbonitrile (PCN) are known to affect other aspects of hepato-biliary disposition in addition to metabolism. This study was designed to determine if presystemic elimination of the non-metabolized xenobiotic ouabain could be altered by these inducers.
Male Sprague-Dawley rats were pretreated with inducers or saline for four days. A day later, ouabain (0.5 mg kg−1) was administered into either the ileocolic vein (portal administration) or the femoral vein (systemic administration). Blood and bile samples were collected for up to 90 min after ouabain administration. Biliary excretion rate and cumulative biliary excretion of ouabain were increased by pretreatment with PCN (75 mg kg−1 day−1) relative to controls. Phenobarbitone pretreatment (75 mg kg−1 day−1) also increased these parameters, but to a lesser extent than PCN. In contrast, 3-methylcholanthrene pretreatment (20 mg kg−1 day−1) had no effect on biliary excretion. Plasma concentrations of ouabain were much lower after PCN pretreatment relative to controls, whereas neither phenobarbitone nor 3-methylcholanthrene had any effect. Similarly, clearance (both biliary and total) and volume of distribution were increased by PCN, but not by phenobarbitone or 3-methylcholanthrene pretreatment. Interestingly, the magnitude of biliary and plasma effects induced by PCN appeared to be comparable whether ouabain was administered portally or systemically.
Pretreatment of rats with PCN, but not phenobarbitone or 3-methylcholanthrene was shown to increase total clearance of ouabain, mainly via an increase in biliary clearance. Furthermore, because the enhanced clearance occurs after systemic as well as after portal administration of ouabain, a significant change in hepatic presystemic elimination was not detected.
Penetration of β-Blockers through Ocular Membranes in A1bino Rabbits
Authors: Sasaki Hitoshi , Igarashi Yoshiaki , Nagano Toshiaki , Yamamura Kenzo , Nishida Koyo , Nakamura Junzo 
Published: April 2011

Abstract
The purpose of this study was to investigate the barrier properties of ocular membranes for controlling the extent and pathway of ocular absorption of instilled β-blockers.
The penetration of β-blockers was measured across the isolated corneal, conjunctival and scleral membranes of the albino rabbit using a two-chamber glass diffusion cell. β-Blockers tested were atenolol, carteolol, tilisolol, timolol and befunolol.
Corneal penetration of befunolol was much higher than that of atenolol. Scraping the epithelium increased corneal penetration of β-blockers. Conjunctival membranes showed higher permeability than corneal and scleral membranes. The penetration parameters were estimated according to Fick's equation. The corneal permeability coefficient showed an apparent linear relationship with penetrant lipophilicity. The lipophilic character of the corneal barrier was determined by the partition coefficient of drug to corneal surface, not by the diffusion coefficient. Conjunctival and scleral permeability coefficients were not determined by the lipophilicity of β-blockers.
These results indicate that the conjunctiva, sclera and cornea of the rabbit eye are sufficiently different in permeation character to control the extent and pathway for ocular absorption.
Absorption of Isosorbide Dinitrate after Administration as Spray, Ointment and Microemulsion Patch. An In-vitro Study Using the Isolated Perfused Bovine Udder
Authors: Kietzmann M , Wenzel B , Löscher W , Lubach D , Müller B W , Blume H 
Published: April 2011

Abstract
The isolated perfused bovine udder is an in-vitro model, which maintains bovine udder skin with an isolated vasculature in a viable state. Using this in-vitro model, the percutaneous absorption and metabolism of isosorbide dinitrate (ISDN) was studied.
The organ was perfused with gassed Tyrode solution for up to 6 h. A region of udder skin was treated topically with 60 mg ISDN as a spray, 60 mg ISDN as an ointment and with 120mg ISDN as a microemulsion patch of 30 cm2. Spray and ointment were applied onto a skin region of 400 cm2. The concentrations of ISDN and its metabolites isosorbide-2-mononitrate and isosorbide-5-mononitrate were measured in perfusate fractions by capillary column gas-liquid chromatography with electron capture detection.
Following topical administration of the different formulations, ISDN as well as its metabolites were detected in the perfusate fractions, thus demonstrating that ISDN is metabolized by the udder skin in-vitro. A maximum amount of ISDN was absorbed after administration as a spray followed by ointment and microemulsion (5, 2·5 and 1·8 μmol total organic nitrate, respectively). In contrast, the ISDN flux per cm2 skin was significantly higher after administration of the microemulsion (64·4 pmol cm−2 min−1 for the microemulsion compared with 21·9 and 10·2 pmol cm−2 min−1 for spray and ointment).
Sapintoxin A and Phorbol 12, 13-Dibutyrate: Two Phorbol Derivatives with Contrasting Effects on Rat Blood Vessel Permeability In-vitro
Authors: Northover A M , Northover B J , Ryves W J , Evans F J 
Published: April 2011

Abstract
Rat isolated small intestine and mesentery were perfused with a gelatin-containing physiological salt solution, and microvascular permeability in the villi was assessed using colloidal carbon as a marker to assess the effect of sapintoxin A in this experimental situation, and to compare it with phorbol 12, 13-dibutyrate.
Sapintoxin A (1, 0·25, 0·1 μm) had no effect on colloidal carbon leakage compared with control values, but significantly increased perfusion pressure. Phorbol 12, 13-dibutyrate (1 μm) significantly increased both colloidal carbon leakage and perfusion pressure. Pretreatment with the protein kinase C inhibitor Ro 31–8220 (1 μm) significantly increased colloidal carbon leakage in the presence of sapintoxin A, but significantly decreased the phorbol 12, 13-dibutyrate-induced leakage of colloidal carbon.
Pretreatment with indomethacin (1 μm) significantly increased colloidal carbon leakage in response to sapintoxin A, but did not affect the response to phorbol 12, 13-dibutyrate. Increases in perfusion pressure caused by sapintoxin A (0·25 μm) and phorbol 12, 13-dibutyrate (1 μm) were reduced by Ro 31–8220, but neither pressor response was affected by indomethacin. Lower concentrations of phorbol 12, 13-dibutyrate (0·25, 0·1 μm) had no effect on colloidal carbon leakage. However, there was a significant increase in perfusion pressure in response to 0·25 μm but not to 0·1 μm phorbol 12, 13-dibutyrate.
When rat mesentery alone was perfused using gelatin-free physiological salt solution, sapintoxin A (1 μm) had no effect on perfusion pressure, whereas phorbol 12, 13-dibutyrate (1 μm) caused a significant increase over a 15-min period, which was completely abolished by pretreatment with Ro 31–8220.
It may be concluded that the permeability-increasing effects of phorbol 12, 13-dibutyrate are dependent on protein kinase C activation.
Further Studies on the Antinociceptive Action of the Hydroalcoholic Extracts from Plants of the Genus, Phyllanthus
Authors: Santos Adair R S , Filho Valdir C , Yunes Rosendo A , Calixto João B 
Published: April 2011

Abstract
The analgesic effects of the hydroalcoholic extracts (HEs) of Phyllanthus urinaria, P. tenellus, P. niruri and P. sellowianus have been investigated in several models of nociception in mice.
The HE of four species of Phyllanthus (1–90 mg kg−1, i.p.) caused a dose-related inhibition of acetic acid-induced abdominal constriction in mice with ID50 values of 5·4, 8·5, 18·2 and 53·0 mg kg−1 and maximal inhibition (%) of 80 ± 2, 67 ± 8, 63 ± 8 and 50 ± 4 for P. urinaria, P. niruri, P. tenellus and P. sellowianus, respectively. In the formalin test, the HE of all Phyllanthus species (0·3–60 mg kg−1, i.p.) caused graded inhibition of both phases of formalin-induced pain, but they were, however, more potent in relation to the second phase of the pain. The ID50 values (mg kg−1) for the first phase were 20·0, 23·0, &gt; 60, and &gt; 60 for the P. urinaria, P. tenellus, P. niruri and P. sellowianus, respectively, and percentages of maximal inhibition were 63 ± 2, 70 ± 2,41 ± 3 and 46 ± 4, respectively. The ID50 values (mg kg−1) for the second phase were 0·71, 4·87, 7·7, 33·0, with maximal inhibition (%) of 91 ± 6, 97 ± 3, 97 ± 3 and 92 ± 6, respectively. Given orally, the HEs of species of Phyllanthus caused a significant antinociceptive profile, but they were about one-tenth to one-twentieth as potent when given intraperitoneally. However, the HEs of Phyllanthus failed to affect formalin-induced paw oedema and did not interfere with the performance of animals in the rota-rod test. Naloxone (5 mg kg−1) completely reversed the analgesic effect caused by morphine (5 mg kg−1), but had no effect against the analgesic effect of the HE of Phyllanthus. Furthermore, the HEs of Phyllanthus in contrast to morphine had no analgesic effect in either tail-flick or hot-plate tests.
Taken together, these findings confirm and extend our previous results and indicate that all studied HE of species of plant belonging to the genus Phyllanthus exhibit potent and long-lasting antinociceptive activity in several models of pain, including the neurogenic algesic component of the formalin test. The mechanism underlying their analgesic profile is presently unknown.