bluuebunny/crossref_metadata_2025 huggingface dataset:
Polyethylene glycol: its adverse gastric effects in rats
Authors: Cho C H , Hui W M , Liao N X , Liu X G , Lam S K , Ogle C W
Published: April 2011

The effects of polyethylene glycol (PEG) on gastric function and on lesion formation, evoked by topical applications of absolute ethanol to an ex-vivo stomach chamber preparation have been examined. Parenteral injection (i.p. or s.c.) of PEG with different molecular weights (PEG 300, 400 or 4000), dose-dependently reduced the gastric mucosal blood flow and volume of gastric secretion; these effects were greater in rats given PEG by the i.p. route, which also lowered acid output. Topical application of 1·5 mL absolute ethanol produced severe gastric mucosal injury, which was exacerbated by PEG; this lesion-aggravating effect was higher in the i.p.-injected groups. These findings indicate that when PEG is given by injection, it can adversely affect gastric function and increase the damaging action of alcohol. It is suggested that the use of PEG as a vehicle for injection should be re-assessed.
MK−801 antagonizes the lethal action of centrally and peripherally administered cypermethrin in mice and rats
Authors: Chugh Vati , Sankaranarayanan A , Sharma P L
Published: April 2011

The present study investigated the effect of MK−801, an N-methyl-d-aspartate antagonist, on the convulsant lethal action of cypermethrin administered centrally or peripherally. Cypermethrin produced severe convulsions and death in a dose-dependent manner. MK−801 (0·5, 1 and 2 mg kg−1, intraperitoneally) significantly increased the onset time of convulsions and decreased the mortality in the peripherally treated cypermethrin group. MK-801 (1·0 and 2·0 mg kg−1) attenuated the convulsant action of cypermethrin (50 μg, intracerebroventricularly) significantly. Survival rate was also increased significantly. However, MK−801 (0·5 mg kg−1) did not produce any significant protective effect against centrally administered cypermethrin. These results suggest excitatory amino acids to be a target for pyrethroid-induced neurotoxicity.
Epi-fluorescence Microscopy and Image Analysis Used to Measure Diffusion Coefficients in Gel Systems
Authors: Henry B T , Adler J , Hibberd S , Cheema M S , Davis S S , Rogers T G
Published: April 2011

A method using epi-fluorescence microscopy and image analysis has been developed to follow and quantify the diffusion of fluorescent compounds through gels. Two mathematical approaches were employed to calculate diffusion coefficients. The spatial resolution provided by the fluorescence microscope allowed diffusion to be followed over very short distances; accordingly diffusion coefficients were obtained within minutes, even for slowly diffusing systems. The method was successfully applied to the diffusion of macromolecules into agar, carbopol and mucus gel systems.
Effect of Oily Vehicles on Absorption of Mepitiostane by the Lymphatic System in Rats
Authors: Ichihashi Teruhisa , Kinoshita Haruki , Takagishi Yasushi , Yamada Hideo
Published: April 2011

[14C]Mepitiostane in various vehicles was administered to the small intestine of anaesthetized rats with cannulated thoracic ducts, and the effect of lipids on lymphatic absorption was examined. The extent of lymphatic absorption was greatest when administered in triolein and sesame oil, which are triglycerides of long-chain fatty acids. Absorption in the presence of other vehicles was in the order of 10% Tween 80 aqueous solution > monolein > oleic acid ∼ oleic acid/monolein (2:1 mol/mol) > aqueous suspension. Differences between the extents of lymphatic absorption of mepitiostane in the various formulations were not due to variation in the lymph flow but to the increased secretion of chylomicron and very low density lipoproteins. During absorption of mepitiostane from the small intestine, oil affected not only the penetration into epithelium cells and the metabolism in them, but also the partition between blood and lymph.
Effect of Bile on Absorption of Mepitiostane by the Lymphatic System in Rats
Authors: Ichihashi Teruhisa , Kinoshita Haruki , Takagishi Yasushi , Yamada Hideo
Published: April 2011

The effects of bile and site of gastrointestinal absorption on the lymphatic absorption of the highly lipophilic drug, mepitiostane were examined using thoracic duct-cannulated rats. The lymphatic absorption from the small intestine was very small in the absence of bile compared with that when bile was present. The lymphatic absorption was greatest when drug was administered to the upper small intestine with bile, was smaller for the lower regions of the small intestine, and was negligible for the stomach and the large intestine. A correlation was observed between the extent of lymphatic absorption and the secretion of chylomicron and very low density lipoproteins after administration to various regions with or without bile. The portal absorption data of mepitiostane confirmed that site specificity occurs in the partition of drug between blood and lymph.
Effects of Salicylate and Other Enhancers on Rectal Absorption of Erythropoietin in Rats
Authors: Mizuno A , Ueda M , Kawanishi G
Published: April 2011

To develop a new treatment for patients with anaemia in which erythropoietin (EPO) can be given without injection, the effects of promoters of the rectal absorption of EPO were studied. Recombinant human (rHu) EPO (5000 units) in a dosing solution or in a rectal suppository was placed in the rectum of healthy rats and changes in serum EPO levels were monitored by an enzyme-linked immunosorbent assay. Without a promoter, rHuEPO was not absorbed. Sodium glycocholate, sodium caprate, and sodium salicylate in the solution of rHuEPO increased the absorption of rHuEPO. Sodium salicylate or sodium caprate in the suppository with rHuEPO also increased its absorption. The bioavailability of rHuEPO in a suppository containing 5% sodium salicylate compared with that by an intravenous injection was 1·2%. rHuEPO given in rectal suppositories containing sodium salicylate and inserted once a day for 6 consecutive days increased erythropoiesis in peripheral blood.
In-vivo Blood-brain Barrier Transport of a Novel Adrenocorticotropic Hormone Analogue, Ebiratide, Demonstrated by Brain Microdialysis and Capillary Depletion Methods
Authors: Shimura Takesada , Tabata Shigeru , Terasaki Tetsuya , Deguchi Yoshiharu , Tsuji Akira
Published: April 2011

The transport of ebiratide, a novel adrenocorticotropic hormone (ACTH) analogue, [H-Met-(O2)-Glu-His-Phe-d-Lys-Phe-NH(CH2)8-NH2], through the blood-brain barrier was directly demonstrated in-vivo. [125I]Ebiratide (16·9 MBq mL−1) or [14C]sucrose (29·2 MBq mL−1) known to be restrictively transported through the blood-brain barrier was infused into the rat internal carotid artery at a flow rate of 50 μL min−1 for 10 min, and after 15 min infusion the distribution volume of each compound in the brain parenchyma was determined by the capillary depletion method. The distribution volume of [125I]ebiratide was 167·8 ± 62·2 μL (g brain)−1, which was about seven times higher than that of [14C]sucrose (24·9 ± 4·0 μL g brain)−1, indicating the uptake of ebiratide into brain parenchymal cells. During the infusion into the internal carotid artery, brain microdialysis was simultaneously performed to directly collect the brain interstitial fluid as the dialysate. Radioactivity was detected in the dialysate during the [125I]ebiratide infusion and HPLC analysis of the dialysate revealed that the intact ebiratide accounted for ≥ 80% total radioactivity. The concentrations of [125I]ebiratide and [14C]sucrose in the brain interstitial fluid were estimated based on the relative recovery obtained in the in-vitro recovery study. The brain interstitial fluid/internal carotid arterial blood concentration ratio for [125I]ebiratide was determined to be 1·47 × 10−2 ± 0·17 × 10−2 and was about eight times higher than that for [14C]sucrose (1·92 × 10−3 ± 0·36 × 10−3), indicating significant transport of ebiratide to the brain interstitial fluid. Accordingly, it was demonstrated that ebiratide is taken up into the brain in the intact form possibly via an absorptive-mediated transport through the blood-brain barrier.
Failure of tetrodotoxin to inhibit the prostaglandin-induced secretory response of rat small intestine in-vitro
Authors: Hardcastle J , Hardcastle P T
Published: April 2011

Tetrodotoxin (TTX, 10 μm) did not inhibit prostaglandin E2 (PGE2)-stimulated increases in electrical activity in intact or stripped sheets of rat small intestine, although it reduced basal electrical activity in the intact preparation. Basal and PGE2-stimulated cAMP production by enterocytes isolated from the small intestine was unaffected by TTX. Thus its reported ability to inhibit prostaglandin-induced fluid secretion in-vivo does not appear to represent a direct interaction of the neurotoxin with the mechanism of prostaglandin action at the enterocyte.
The effect of temperature and pH on the deacetylation of diamorphine in aqueous solution and in human plasma
Authors: Barrett David A , Dyssegaard Astrid L P , Shaw P Nicholas
Published: April 2011

The effect of temperature on the kinetics of the deacetylation of diamorphine and 6-monoacetylmorphine was studied in human plasma. Diamorphine was rapidly and quantitatively degraded to 6-monoacetylmorphine with initial half-lives of 354, 18 and 3 min at temperatures of 4, 25 and 37°C, respectively. Further deacetylation to morphine was not detected. In aqueous solution, diamorphine was quantitatively degraded to give 6-monoacetylmorphine as the major product and morphine as a minor product, the rate of deacetylation being dependent on temperature and pH. At pH 4·0 and 5·6 diamorphine had a half-life of greater than 14 days at all temperatures but at alkaline pH diamorphine was rapidly deacetylated. The rate of deacetylation of 6-monoacetylmorphine was consistently slower than that of diamorphine under identical conditions of pH and temperature. A method is described for the rapid stabilization and subsequent assay of diamorphine in plasma which will prevent errors in estimation of the drug due to unwanted hydrolysis.
The pharmacokinetics of oral itraconazole in AIDS patients
Authors: Smith D , Van De Velde V , Woestenborghs R , Gazzard B G
Published: April 2011

To test the hypothesis that absorption of orally administered itraconazole may be reduced in patients with the Acquired Immunodeficiency Syndrome (AIDS), 8 patients with AIDS were given two 100 mg capsules of itraconazole for 15 days. Plasma levels were measured by HPLC hourly for the first 8 h following ingestion, then at 24, 48, 72 and 96 h on days 1, 8 and 15. Peak plasma levels occurred after approximately 4 h. Mean peak plasma concentrations were 446 ± 196 and 530 ± 214 ng mL−1 at days 8 and 15. The area under the curve over 24 h (AUC0–24) was 2105 ± 1241, 7679 ± 3838 and 8748 ± 4385 ng mL−1 h for days 1, 8 and 15, respectively. Steady-state was achieved after one week of dosing. There was no evidence of hepatotoxicity and one patient stopped itraconazole due to a rash. It may be concluded that the absorption of oral itraconazole capsules is reduced in AIDS patients, by a factor of approximately 50%, when compared with normal volunteers. AIDS patients may require higher doses of itraconazole than used in non-AIDS patients to achieve comparable plasma levels.
Some Features of Cannabis Plants Grown in the United Kingdom from Seeds of Known Origin
Authors: Pitts J E , Neal J D , Gough T A
Published: April 2011

The cannabinoid content of UK-grown plants (up to the 6th generation) from Moroccan, Sri Lankan and Zambian seedstock was determined by TLC, GLC and HPLC. All plants from the 5th and 6th series resembled their parents, and UK-grown plants were always much greener than those grown overseas. Cannabinoid content remained broadly typical of the source countries. However, tetrahydrocannabinolic acid (THCA) consistently predominated over tetrahydrocannabinol (THC) to a far greater extent than in the original plants; the THCA/THC ratio was 17 in UK-grown plants compared with 2·0 in the plants from the original areas. Two types of plant emerged from the Moroccan seedstock, one tending to increased cannabidiol (CBD), the other tending to zero levels of this component. The first generation Sri Lankan plants revealed one type of plant with an increased CBD/THC ratio (1·7 compared with 0·11) but this returned to the original value in the succeeding generations. Other Sri Lankan plants had low or undetectable levels of CBD. Moroccan and Sri Lankan CBD-rich plants did not contain cannabichromene, although this cannabinoid was found in THC-rich plants. Zambian plants did not appear to show such a pattern. Zambian seedstock plants had total tetrahydrocannabivarin (diol and acid) levels greater than THC but the ratio was progressively reversed in succeeding generations. The study concludes that the ratios of particular cannabinoids is greatly influenced by the environment.
The Effects of Various Peptides on Human Isolated Gut Muscle
Authors: Bennett A , Stamford I F , Sanger G J , Bloom S R
Published: April 2011

The effects of eleven peptides of gastrointestinal origin have been studied on the contraction, relaxation and spontaneous activity of circular and longitudinal muscle strips from different regions of the human gastrointestinal tract. The effects varied with the peptides and sometimes with the region and muscle layer. There was either contraction, no effect, or relaxation and/or inhibition of an acetylcholine-induced contraction. Responses to some peptides are consistent with the possibility that they may contribute directly to the control of motility: galanin, neurotensin and substance P might be involved in contraction, and vasoactive intestinal peptide, peptide histidine isoleucine and peptide histidine methionine might be inhibitory transmitters.
Antiarrhythmic, Electrophysiological and Haemodynamic Effects of Prolonged Oral Dosing with Org 7797 in the Anaesthetized Rat
Authors: Delbressine L , Harris N , Kane K A , Muir A W , Winslow E
Published: April 2011

The antiarrhythmic, electrophysiological and haemodynamic effects of chronic oral administration of Org 7797 ((16α,17β)-17-methylamino-oestra-1,3,5(10)-triene-3,16-diol-(Z)-2-butonedioate) were studied in rats. During dosing (10 mg kg−1 twice a day for 10 days) no effects on the electrocardiogram, monitored in conscious animals, were observed despite modest reductions (15–18%) in the maximum rate of depolarization of papillary muscle excised 1 or 6 h after completion of the dosing regime. Following anaesthesia, Org 7797 reduced the severity of arrhythmias induced by coronary artery occlusion and prevented the accompanying decrease in the ventricular fibrillation threshold (VFT) at 1 h after completion of dosing. By 6 h the effect on VFT had waned but protection against ischaemia-induced arrhythmias was retained despite a substantial decrease in Org 7797 plasma levels. Drug treatment did not modify arterial blood pressure, heart rate or stroke volume. We conclude that Org 7797 given chronically via the oral route exerts antiarrhythmic actions which may, at least in part, be due to sodium-channel block. In addition, our results suggest the presence of an active metabolite. The protective effects of Org 7797 were seen in the absence of electrocardiographic or haemodynamic changes suggesting that multiple oral doses of Org 7797 do not compromise normal cardiac function.
The Long Term Stability of Mechlorethamine Hydrochloride (Nitrogen Mustard) Ointment Measured by HPLC
Authors: Cummings J , MacLellan A , Langdon S J , Smyth J F
Published: April 2011

HPLC has been applied to determine the stability of mechlorethamine hydrochloride (nitrogen mustard) formulated as an ointment in white soft paraffin (10 mg drug, 50 g paraffin and 1 mL acetone). A new solubilization technique is described for extraction of the drug from the ointment for HPLC analysis which has an extraction efficiency of 76·1% with a coefficient of variation of 10·4%. Stored at 4°C the drug content of the ointment remained stable for at least 84 days and stored at 37°C the drug content remained stable for at least 40 days. In comparison aqueous solutions of mechlorethamine at the same concentration, fully degraded after 4 days. These data will aid hospital pharmacists decide on a standardized protocol for the controlled usage of the ointment which is both safe and cost-effective.
Stability of GR63178A, a Novel Pentacyclic Pyrroloquinone Anticancer Compound, in Aqueous Solutions and Biological Fluids
Authors: French Raymond C , Cummings Jeffrey , Nicolson Margaret , Smyth John F
Published: April 2011

The effect of temperature, pH, light, drug concentration and aeration on the stability of aqueous solutions of GR63178A, a novel anticancer compound, has been investigated. The effect of light upon the stability of GR63178A in a clinical infusion system and in biological fluids, has also been investigated. A high performance liquid chromatographic assay was used to separate the parent compound from a number of degradation products. Data presented here demonstrate that GR63178A is stable in aqueous solutions at normal ambient temperatures in neutral or alkaline pH ranges. The compound is unstable when exposed to light (t½ 3·2–233 min) and shows an inverse relationship between concentration and rate of degradation. The drug is also unstable under acidic conditions, but shows a more limited spectrum of degradation products than those arising from photolysis.
Controlled Release of Oral Drugs from Cross-linked Polyvinyl Alcohol Microspheres
Authors: Thanoo B C , Sunny M C , Jayakrishnan A
Published: April 2011

A new technique for the preparation of cross-linked polyvinyl alcohol (PVA) microspheres containing various drugs is described. An aqueous solution of PVA containing various concentrations of glutaraldehyde was dispersed as droplets in liquid paraffin using a suitable stabilizing agent. Cross-linking of PVA droplets with glutaraldehyde was induced by an acid catalyst (HCl) which was produced by the addition of small quantities of benzoyl chloride into the dispersion medium. Microspheres containing drugs such as aspirin, griseofulvin and nicotinic acid were prepared by carrying out the cross-linking reaction in the presence of such drugs. The drug release studies were carried out in simulated gastric and intestinal fluids without enzymes at 37°C. It was observed that increase in the cross-linking density of the microspheres reduced the drug release rate considerably, suggesting that the release profiles could be controlled by changing the cross-linking density. It was also observed that a higher rate of release was obtained from smaller beads.
Oral Sustained-release Drug Delivery Systems using Polycarbonate Microspheres Capable of Floating on the Gastric Fluid
Authors: Thanoo B C , Sunny M C , Jayakrishnan A
Published: April 2011

Polycarbonate microspheres loaded with aspirin, griseofulvin and p-nitroaniline were prepared by a solvent evaporation technique. High drug loading (> 50%) was achieved by this process. Drug-loaded microspheres were found to float on simulated gastric fluid and intestinal fluid. Drug-release studies were carried out in these fluids at 37°C. Increasing the drug to polymer ratio in the microspheres increased both their mean particle size and the release rate of the drugs. It was concluded that sustained delivery of drugs could be effected using this matrix.
Red Blood Cell Partitioning, Protein Binding and Lipophilicity of Six Phenothiazines
Authors: Marroum P J , Curry S H
Published: April 2011

Hexane-water partition coefficients, pKa values, protein binding and red blood cell partitioning were studied with six phenothiazine drugs. Red cell partitioning was independent of drug concentration, and there was no correlation between partitioning and physicochemical characteristics. Red cell partitioning could be used indirectly to estimate protein binding, but two potential pitfalls of general importance were found. Failure to consider drug binding of glassware and haematocrit changes were shown to induce incorrect estimates of both red cell partitioning and protein binding, as well as hexane-water partition coefficients.
Fc-Receptor-mediated Targeting of Antibody-bearing Liposomes Containing Dideoxycytidine Triphosphate to Human Monocyte/Macrophages
Authors: Betageri G V , Black C D V , Szebeni J , Wahl L M , Weinstein J N
Published: April 2011

Liposomes bearing surface-attached antibody (L-Ab) molecules can be used for various purposes including the immunospecific delivery of drugs or other materials to antigenic target cells. In this study, L-Ab were prepared to deliver an anti-human immunodeficiency virus (HIV) drug, dideoxycytidine triphosphate (ddCTP) to human monocyte/macrophages. Cells of the monocyte/macrophage lineage are an important reservoir of HIV-1. A mouse monoclonal antibody IgG2a was labelled with 125I and modified using N succinimidyl-3-(2-pyridyldithio)propionate (SPDP) as a heterobifunctional reagent in order to conjugate with liposomes to produce a covalent bond (thioether). SPDP-modified antibody was incubated with liposomes containing 5 mol% of maleimido phenyl butyrate phosphatidylethanolamine (MPB-PE) at room temperature (21°C) for 24 h. L-Ab were separated from free and aggregated antibodies by centrifugation. L-Ab were characterized by measuring particle size and binding to anti-mouse IgG-sepharose. Ninety five per cent of the liposomal (L-Ab) lipid label was bound to anti-mouse IgG-sepharose, whereas only 7% of plain liposomes were bound, indicating non-specific binding. Uptake of L-Ab was measured in human monocyte/macrophages as a function of time and compared with that of plain liposomes. The uptake increased with time and it was 4–6 times greater than that of plain liposomes although part of that effect may have been due to unreacted MPB groups.
Effects of Vanadate on Responses of Guinea-pig Isolated Trachea to Spasmogens
Authors: Cortijo J , Santamaría P , Antón M , Villagrasa V , Morcillo E
Published: April 2011

The effects of vanadate on the contractility of the guinea-pig isolated trachea was examined. Vanadate (0·1 Mm) produced a sustained contraction that was abolished in Ca2+-free EGTA (0·1 Mm)-containing physiological salt solution but was resistant to verapamil (1 μm). Vanadate (0·1 Mm) depressed tracheal responses to CaCl2 (in Ca2+-free depolarizing solution), KCl, acetylcholine, histamine and 5-hydroxytryptamine. For vanadate (10 μm), the inhibition of spasmogenic responses only reached statistical significance for histamine and 5-hydroxytryptamine. Caffeine (1 Mm)-induced spasm (trachea at 20°C in the presence of indomethacin (2·8 μm)) was not affected by vanadate (10 μm-0·1 Mm). Vanadate (0·1 Mm) slightly depressed the responses to KCl (50 Mm), acetylcholine (1 Mm), histamine (1 Mm) or 5-hydroxytryptamine (0·1 Mm) observed in Ca2+-free EGTA (0·1 Mm)-containing physiological salt solution. Vanadate (0·5 Mm) depressed Ca2+ (20 μm)-induced contraction of trachea which had been chemically skinned of its plasmalemmal membranes. The mechanism of the inhibitory effect of vanadate on tracheal responses to a variety of spasmogens remains obscure, but, under in-vitro conditions, vanadate clearly does not induce hyper-reactivity of airway smooth muscle to spasmogens.
Calcium Antagonism and Structure-affinity Relationships of Terfenadine, a Histamine H1 Antagonist, and Some Related Compounds
Authors: Zhang M Q , Caldirola P , Timmerman H
Published: April 2011

Calcium channel affinity of terfenadine and its optical isomers was determined by the displacement of [3H]nitrendipine on rat cerebral cortex membranes. Terfenadine showed a pKd of 6·36±0·03 whereas its R(+)-isomer (VUF4567) had a pKd value of 6·39±0·03 and the S(–)-isomer (VUF4568) had a pKd of 6·40 ± 0·04. The same affinity between the enantiomers suggests that the binding domain on the membrane is not sterically restricted towards the part of the molecule in which the chiral centre is present. The characteristics of terfenadine in regulating [3H]nitrendipine binding were similar to those of some other diphenyl-alkylamine type calcium antagonists. It allosterically altered the binding affinity for nitrendipine and acted at the same site linked to the calcium channel as gallopamil. A structure-affinity relationship among a group of terfenadine analogues is discussed.
Urinary excretion of hexafluoroisopropanol glucuronide and fluoride in patients after sevoflurane anaesthesia
Authors: Jiaxiang Ni , Sato Nobuyoshi , Fujii Kohyu , Yuge Osafumi
Published: April 2011

The excretion of sevoflurane metabolites in the urine collected every 12 h after sevoflurane anaesthesia was measured by ion exchange chromatography. A metabolite, which was converted on incubation with glucuronidase to hexafluoroisopropanol was detected in the urine. The maximum excretion was found in the first 12 h after anaesthesia, none was found in the last collection 3 days after anaesthesia. The excretion half-life for the metabolite was calculated to be 55 h. A significant increase in the urinary excretion of organic and inorganic fluoride was also observed during the first 12 h after anaesthesia. The cumulative organic and inorganic fluoride excretion in the 3 days after sevoflurane anaesthesia was 1588 and 856 μmol, respectively (ratio = 1·85). The excreted half-lives for organic and inorganic fluoride were calculated to be 4028 and 2069 min, respectively. Our study showed that a hexafluoroisopropanol glucuronide is excreted in the urine, and the major part of urinary metabolites of sevoflurane, organic and inorganic fluoride, are excreted within 2 days of sevoflurane inhalation in man.
Intraduodenal delivery of intrinsically and extrinsically labelled CaCO3 in the rat: effect of solubilization on calcium bioavailability
Authors: Kanerva R L , Webb D R , Andon M B , Smith K T
Published: April 2011

The dissolution of CaCO3 before intraduodenal administration was found to be an important factor determining calcium (Ca) bioavailability. Extrinsically and intrinsically labelled 47CaCO3 preparations were sequentially dissolved by serial additions of HCl. Aliquots of these preparations were collected before (no HCl added) and during the solubilization process and administered intraduodenally to rats. Whole body 47Ca retention 72 h post-dose was used as a measure of Ca bioavailability. Although dissolution of CaCO3 significantly increased Ca bioavailability (p < 0·001), Ca from both intrinsically and extrinsically labelled CaCO3 was absorbed and retained to some extent without prior acid dissolution. Due to a disproportionately high concentration of 47Ca on the particle surface, extrinsically labelled 47CaCO3 overestimated bioavailability when unsolubilized or partially solubilized CaCO3 preparations were used (P < 0·05). These data indicate that dissolution is a determining factor for Ca bioavailability from CaCO3. Incomplete dissolution will significantly limit but not completely prevent Ca bioavailability. The disintegration and dissolution characteristics of commercial CaCO3 preparations, which vary widely, may produce important differences in Ca absorption.
Effect of Thyrotropin-releasing Hormone on Pentobarbitone-induced Sleep in Rats: Continuous Treatment with a Sustained Release Injectable Formulation
Authors: Hashimoto Tadatoshi , Wada Takeo , Fukuda Naohisa , Nagaoka Akinobu
Published: April 2011

The mode of action and the time course of the effects of continuous thyrotropin-releasing hormone (TRH) treatment using a two-week sustained release injectable formulation of TRH-containing copoly(±)-lactic/glycolic acid) microspheres (TRH-SR) on pentobarbitone-induced sleeping time were studied in rats. Subcutaneous treatment with TRH-SR at doses corresponding to 0·05 and 0·2 mg of TRH kg−1 day−1 caused a dose-related shortening of pentobarbitone-induced sleeping time with a minimum effective dose (MED) of 0·05 mg kg−1 day−1, without affecting the body weight gain. On the other hand, the MED of TRH when given as a bolus subcutaneous injection was 40 mg kg−1. The effect of TRH-SR treatment was blocked by intraperitoneal scopolamine (0·1 mg kg−1) and mecamylamine (2 mg kg−1) but not by scopolamine methyl bromide (0·1 mg kg−1). The results indicate that continuous TRH treatment using TRH-SR causes shortening of pentobarbitone-induced sleeping time at doses lower than those required using bolus injection and probably by a mechanism involving the central cholinergic system.
Kinetic Evaluation of the Ciliotoxicity of Methyl- and Propyl-p-hydroxybenzoates Using Factorial Experiments
Authors: Jian L , Po A Li Wan
Published: April 2011

The ciliotoxicity of methyl-p-hydroxybenzoate (methyl paraben, MHB) and propyl hydroxybenzoate (propyl paraben, PHB) was investigated. It is shown that at the concentrations used (0·28 and 0·38 Mm) PHB exerted only mild toxicity. The MHB solutions used (1·18 and 2·36 Mm) were much more ciliotoxic. There was, however, an order of magnitude difference in the concentrations used as a result of constraints imposed by their differing aqueous solubilities. There was no evidence of synergism in the ciliotoxicity of the two compounds when the MHB concentration was raised from 1·18 to 2·36 Mm and the PHB concentration was raised from 0·28 to 0·38 Mm in a 22 factorial experiment. At those levels the two compounds showed additive effects. On the other hand, clear synergism was evidenced by the fact that the ciliotoxicity of both MHB and PHB was dependent on whether the cilia were exposed to each hydroxybenzoate singly or in combination. The results combined with those of an earlier study, indicate that it is not possible to improve the selectivity of antimicrobial activity without also increasing ciliotoxicity.
Suppressive Effects of Hyaluronic Acid on Elastase Release from Rat Peritoneal Leucocytes
Authors: Akatsuka Masahiro , Yamamoto Yumiko , Tobetto Kenji , Yasui Tadashi , Ando Takao
Published: April 2011

Effects of hyaluronic acid on the release of elastase from rat peritoneal leucocytes were studied by measuring the leucocyte elastase activity using a synthetic peptide substrate. Leucocyte elastase release was induced by opsonized zymosan, 12-O-tetradecanoyl phorbol-13-acetate (TPA) and N-formyl-l-methionyl-l-leucyl-l-phenylalanine combined with cytochalasin B. Calcium ionophore A23187 potentiated the action of TPA on leucocyte elastase release, whereas hyaluronic acid inhibited leucocyte elastase release regardless of the method of stimulation. Inhibitory effects of hyaluronic acid were dependent on its concentration and molecular weight. Hyaluronic acid of the highest molecular weight (2·0 × 106) indicated a potent inhibitory effect on elastase release. Our present findings suggest that hyaluronic acid may elicit an anti-inflammatory effect by inhibiting leucocyte elastase-dependent pathological processes.
Differential effects of the (+)- and (–)-gossypol enantiomers upon Entamoeba histolytica axenic cultures
Authors: González-Garza María Teresa , Matlin Stephen A , Mata-Cárdenas Benito D , Said-Fernández Salvador
Published: April 2011

The in-vitro anti-amoebic effects of (±)-, (+)-, (–)-gossypol and emetine were tested against axenic trophozoites from five Entamoeba histolytica strains. The (–)-isomer was more active than the racemate and the (+)-isomer. These results indicate that the gossypol anti-amoebic activity is mainly due to its content of (–)-gossypol in all strains tested.
Absence of desensitization to the relaxant activity of streptozotocin in isosorbide dinitrate-tolerant rat aorta
Authors: Uma Serdar , BalcioḡLu Aygül
Published: April 2011

The effect of in-vitro isosorbide dinitrate (ISDN)-induced tolerance on the vasodilatory actions of streptozotocin, a nitric oxide containing compound, and papaverine was studied in rat aortic strips precontracted by phenylephrine. Aortas made tolerant to ISDN remained fully responsive to streptozotocin but exhibited a greater response to low concentrations of papaverine compared with control strips. Methylene blue produced parallel displacement to the right of the relaxant concentration-effect curves of both ISDN and streptozotocin, whereas responses to only low concentrations of papaverine were significantly antagonized. These results indicate that the relaxant activity of streptozotocin is due to the stimulation of guanylate cyclase and impaired activity of this enzyme is not likely to be the operating mechanism for nitrate tolerance. It is also suggested that the vasodilating action of papaverine is partly dependent on the tissue cGMP level.
Antidiarrhoeic activity of quercitrin in mice and rats
Authors: Gálvez J , Crespo M E , Jiménez J , Suárez A , Zarzuelo A
Published: April 2011

Quercitrin, a flavonoid isolated from Euphorbia hirta, shows antidiarrhoeic activity at doses of 50 mg kg−1, against castor oil- and PGE2-induced diarrhoea in mice, but not when magnesium sulphate is used as a cathartic agent. It also delays rat small intestinal transit if this is accelerated with castor oil. However, the flavonoid does not modify the fluid transport across the colonic mucosa when it is administered intraluminally, either in normal conditions or when this transport is altered by PGE2 or sodium picosulphate. However, quercetin, the aglycone of quercitrin, increases the colonic fluid absorption only in the presence of secretagogue compounds, such as PGE2 and sodium picosulphate. It is concluded that the antidiarrhoeic activity of quercitrin is due to its aglycone, quercetin, which is released by the glycoside in the intestine.
Investigation of Synergism between Combinations of Ciprofloxacin, Polymyxin, Sulphadiazine and p-Aminobenzoic acid
Authors: Richards R Michael E , Xing Dorothy K L
Published: April 2011

Subinhibitory concentrations of combinations of any two of ciprofloxacin, colistin (or polymyxin B), sodium sulphadiazine and p-aminobenzoic acid were shown by checkerboard minimum inhibitory concentration determinations to have synergistic inhibitory activity against Pseudomonas aeruginosa and to have either synergistic or additive activity against Staphylococcus aureus. In addition, sulphadiazine plus either ciprofloxacin or polymyxin showed markedly enhanced killing activity against both P. aeruginosa and S. aureus. p-Aminobenzoic acid plus either ciprofloxacin or polymyxin also demonstrated enhanced killing activity against P. aeruginosa but these combinations were less effective in enhancing activity against S. aureus. Ciprofloxacin in combination with polymyxin had a marked synergistic effect against P. aeruginosa but only a slight synergistic effect against S. aureus. These findings indicate a potential usefulness for the synergistic combinations against P. aeruginosa and S. aureus in the clinical situation; that is, they indicate an extended role for sulphonamides and support a potential role for p-aminobenzoic acid as enhancers of the activity of primary antibacterial agents such as ciprofloxacin and polymyxin. We suggest that for a second antibacterial to enhance the activity of ciprofloxacin, it may be necessary for the second antibacterial to increase cell permeability so increasing bacterial uptake of ciprofloxacin.
Post-UV Survival and Mutagenesis in DNA Repair-proficient and -deficient Strains of Escherichia coli K-12 Grown in 5-Azacytidine to Inhibit DNA Cytosine Methylation: Evidence for Mutagenic Excision Repair
Authors: Radnedge L , Pinney R J
Published: April 2011

Inhibition of cytosine methylation by growth in 5-azacytidine (5-azaC), did not affect the sensitivities to DNA damage induced by exposure to ultraviolet light (UV) of Escherichia coli K-12 strains AB1157 dcm+, which is fully DNA repair-proficient, LR68 (a dcm derivative of ABU57), JC3890 dcm+ uvrB, deficient in error-free excision repair, TK702 dcm+ umuC, deficient in error-prone repair, or TK501 dcm+ uvrB umuC, which lacks both excision repair and error-prone repair. However, growth in 5-azaC increased the post-UV survival of strains AB2463 recA(Def), AB2470 recB and AB2494 lexA(Ind−), which are deficient in the induction or expression of recombination repair or error-prone repair of DNA. Spontaneous mutation frequencies were increased in strains LR68, AB2463, AB2470 and AB2494 by growth in 5-azaC, but remained unaltered in strains AB1157, JC3890, TK702 or TK501. Growth in 5-azaC significantly increased UV-induced mutation frequencies in strains AB2463 and AB2470, significantly reduced UV-induced mutation in strain JC3890, but had little effect on UV-induced mutation in the other strains. The results suggest that 5-azaC may induce a normally error-free DNA repair pathway to become error-prone and therefore genotoxic.
Treatment of Antigen-induced Arthritis in Rabbits with Liposome-entrapped Methotrexate Injected Intra-articularly
Authors: Foong W C , Green K L
Published: April 2011

Rabbits with a bilateral antigen-induced arthritis were injected intra-articularly in one joint with methotrexate as the free drug or entrapped in liposomes. Free methotrexate (1 mg) injected as a single dose at the time of antigen challenge, suppressed the development of joint swelling and the rise in skin surface temperature of treated joints by 20–30% compared with contralateral control arthritic joints. The beneficial effect of methotrexate occurred within 24 h of injection and was maintained for at least 56 days. However, methotrexate was ineffective in suppressing arthritis when injected 7 days after antigen challenge. Liposomal methotrexate suppressed the development of arthritis at a dose one-tenth that of the free drug and it was also effective in suppressing arthritis of 7 days duration, although significant beneficial effects of liposomal methotrexate were delayed for 10 to 14 days after injection. Neither free nor liposomal methotrexate was effective in suppressing an established arthritis, having no significant effect on joint swelling or skin surface temperature when injected 21 and 35 days after antigen challenge. At the end of the study, 8 or 9 weeks after induction of arthritis, the joints were examined morphologically and histologically. Free methotrexate generally had no significant effect on joint pathology. However, liposomal methotrexate suppressed the development of synovial hyperplasia, cellular infiltration and the erosion of cartilage and bone when injected at the time of antigen challenge or 7 days later, but affected none of these parameters in an established arthritis of 3 weeks duration.
Quinine impairs quinidine clearance in rat perfused liver
Authors: Mihaly George W , Scott Haydn , Hyman Mark K , Morgan Denis J , Smallwood Richard A
Published: April 2011

We have examined the disposition of the cinchona alkaloids quinine and quinidine in the rat recirculating isolated perfused liver preparation. When administered as separate 1 mg doses, the hepatic clearances of quinine and quinidine were similar to the hepatic perfusate rate of 10 mL min−1. When 1 mg of each was administered simultaneously, mean hepatic clearance of quinine was unchanged (9·00 ± 2·20 mL min−1 separate dosage, n = 7; 6·87 ± 1·77 mL min−1 simultaneous dosage, n = 7; P > 0·05). By contrast, mean hepatic clearance of quinidine was reduced significantly by concomitant quinine (10·6 ± 1·72 mL min−1 separate dosage, n = 7; 4·82 ± 1·25 mL min−1 simultaneous dosage, n = 7; P < 0·05). There was no significant difference in volumes of distribution when each alkaloid was administered separately (131 ± 46 mL quinine, 129 ± 21 mL quinidine; P > 0·05) but concomitant quinine administration increased quinidine volume of distribution to 169 ± 30 mL (P < 0·05). Four further experiments with simultaneous dosages of 0·5 mg of each alkaloid produced similar findings, indicating that the interactions did not derive from nonlinear drug disposition.
K+ Concentration influences methohexitone inhibition of K+-stimulated release of [3H]noradrenaline from minislices of rat cerebral cortex
Authors: Jones C A , Silvers K M
Published: April 2011

This study investigated the effect of methohexitone, a barbiturate anaesthetic, with variation of the K+ concentration used to stimulate [3H]noradrenaline release from superfused minislices of rat cerebral cortex. The amount of [3H]noradrenaline released by K+-stimulation depended on the concentration of K+ used (increasing release was seen at 10–50 Mm K+). Methohexitone (10−7-3 × 10−4  m) added to the superfusing medium did not alter the basal efflux of [3H]noradrenaline, but high concentrations inhibited K+-stimulated release. Using 12·5 Mm K+, inhibition of release was observed only at 10−4  m methohexitone (48% inhibition); the effect of 25 Mm K+ was reduced by 3 × 10−5  m (72% inhibition) and higher concentrations while release stimulated by 50 Mm K+ was inhibited by 10−5  m methohexitone (30% inhibition) and higher concentrations.
Properties of Human Albumin Microparticles Prepared by a Chilled Cross-linking Technique
Authors: Oner L , Groves M J
Published: April 2011

Examination of conditions needed to form albumin microparticles (in the 1–5 μm diam. size range) by glutaraldehyde cross-linking, at low temperature (–15°C), suggested that the particles formed very rapidly over a short time scale and at low concentrations of cross-linking reagent. Detailed analysis showed that the particles increased in size with time of reaction and with an increase in glutaraldehyde concentration. Evaluation of the particle matrix using a dilute trypsin digestion process suggested that the above factors may influence the internal composition since the particles dissolved less rapidly than might be anticipated from a consideration of particle diameter alone.
Statistical Moments in Pharmacokinetics: Models and Assumptions
Authors: Dunne Adrian
Published: April 2011

The modelling basis of statistical moments in pharmacokinetics is considered and the associated assumptions and restrictions highlighted. Both deterministic and statistical models are described and they are seen to give identical results on the basis of equivalent assumptions. It is shown that it is not necessary to assume that all kinetic processes are first order and that some of the pharmacokinetic parameters may be dependent on the dose of administered drug and on the route of administration.
A Pharmacological Comparison of the Receptors Mediating Contractile Responses to 5-Hydroxytryptamine in the Rat Isolated Caudal Artery and Fundic Strip
Authors: Growcott James W , Cox Barry , Blackburn Thomas P
Published: April 2011

Contractile responses to 5-hydroxytryptamine (5-HT) and to a number of 5-HT-receptor agonists have been compared on the rat isolated caudal artery and stomach fundic strip. On the caudal artery, 5-HT was the most potent agonist tested. The 5-HT1-like agonist, 5-carboxamidotryptamine (5-CT), was less potent than 5-HT and produced a lower maximum response. 8-Hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and RU24969 (5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)1H indole) were inactive as agonists and 8-OH-DPAT was not an antagonist. Ketanserin, ICI 169,369 (2-(2-dimethylaminoethyl-thio)-3-phenylquinoline hydrochloride) and ICI 170,809 (2-(2-dimethylamino-2-methylpropylthio)-3-phenylquinoline hydrochloride) were competitive antagonists of 5-HT on this preparation, indicating that 5-HT is acting via 5-HT2 receptors. In contrast, all the agonists produced contractions of the fundic strip (rank order of potency, 5-HT = 5-CT > RU24969 > 8-OH-DPAT). The maximum response to RU24969 was significantly lower than the maximum responses to the other agonists. Ketanserin was only a weak antagonist of 5-HT in the fundic strip, demonstrating that 5-HT2 receptors were not involved, but ICI 169,369 and ICI 170,809 were non-surmountable antagonists of 5-HT responses, as were methysergide and methiothepin. Since ICI 169,369 and ICI 170,809 are devoid of activity at 5-HT3 and 5-HT4 receptors, then these two subtypes would not appear to be implicated, a view that was confirmed in the case of 5-HT3 receptors by experiments using ondansetron. Since radioligand binding studies have shown that ICI 169,369 and ICI 170,809 have high affinity for 5-HT1C sites, α-methyl-5-HT, an agonist claimed to be selective for 5-HT1C and 5-HT2 receptors, was also tested on the fundic strip in the presence of ketanserin. This compound acted as an agonist and was antagonized in a competitive manner by ICI 170,809. Therefore, these results suggest that the receptors mediating contractile responses to 5-HT in the rat fundic strip are more similar to the 5-HT1C subtype than any of the other subtypes that have been described previously.
Synthesis, Properties, and Intratumoral Evaluation of Mitoxantrone-loaded Casein Microspheres in Lewis Lung Carcinoma
Authors: Knepp W A , Jayakrishnan A , Quigg J M , Sitren H S , Bagnall J J , Goldberg E P
Published: April 2011

Smooth, round, uniform bovine casein microspheres of 1–5 and 10–20 μm size were readily prepared by a steric stabilization technique previously developed in this laboratory for synthesis of albumin microspheres. The avid phagocytic uptake of casein and albumin microspheres was demonstrated with fluorescein-labelled microspheres using a macrophage-like mouse myelomonocytic leukaemia cell line. Post-synthesis loading of 25% mitoxantrone was achieved for casein microspheres containing 20% polyglutamic acid. Preliminary intratumoural chemotherapy experiments with a mouse Lewis lung carcinoma indicated that mitoxantrone and mitoxantrone-loaded casein-polyglutamic acid microspheres exhibited lower toxicity when administered intratumorally.
Effects of age on α1-adrenoceptor subtypes in the heart ventricular muscle of the rat
Authors: Gascón Silvia , Dierssen Mara , Màrmol Frederic , Vivas Nuria M , Badia Albert
Published: April 2011

The effects of ageing on α1-adrenoceptor subtypes have been examined in heart ventricular muscle of young (2–3 months) and middle-aged (18 months) Sprague-Dawley rats. Radioligand binding studies with [3H]prazosin revealed an age-related loss of binding sites (Bmax 56·7 ± 1·93 fmol (mg protein)−1 age 2 months vs 31·7 ± 2·45 fmol (mg protein)−l age 18 months) not followed by changes in the dissociation constant value (Kd 0·16 ± 0·03 nm age 2 months and 0·10 ± 0·03 nm age 18 months). Competition curves with WB 4101 showed two distinct sites with different affinities, the proportion of sites with high affinity being similar for both age groups (22·2 ± 1·89% vs 17·8 ± 1·96% for animals aged 2 and 18 months, respectively). Agonist displacement curves of [3H]prazosin indicate the existence of two different affinity sites for the agonist, that are maintained regardless of the ageing process (Rhigh= 16·2 ± 1·54% and Rlow = 83·8 ± 1·89% in rats aged 2 months and Rhigh= 16·3 ± 3·23% and Rlow = 83·7 ± 3·95% in rats aged 18 months). The fractional inactivation of α1-adrenoceptors by chloroethylclonidine resulted in a loss of [3H]prazosin specific binding, and a percentage of 22·5 ± 0·95 and 22·6 ± 4·2 of remaining binding sites for the groups of 2 and 18 months of age, respectively. The percentage of chloroethylclonidine-insensitive [3H]prazosin binding sites was similar to those with high affinity for WB 4101. The present study confirms a decline of α1-adrenoceptors with increasing age and reveals that the equilibrium of the expression of the two existing subpopulations of the receptor is maintained during ageing.