bluuebunny/crossref_metadata_2025 huggingface dataset:
Penetration of diazepam and the non-peptide CCK antagonist, L-364, 718, into rat brain
Authors: Pullen R G L , Hodgson O J
Published: April 2011

Interest in the actions of the peptide cholecystokinin (CCK) has led to the design and synthesis of several non-peptide CCK antagonists, the most recent being that produced by Merck Sharp & Dohme and designated L-364, 718. This can be viewed as modified D-tryptophan linked to diazepam (1-methyl-3-(2-indoloyl)amino-5-phenyl-3H-1,4-benzodiazepin-2-one) 1.
Intravenous kinetics and metabolism of [15,16-3H]naltrexonium methiodide in the rat
Authors: Misra A L , Pontani R B , Vadlamani N L
Published: April 2011

After a 4 mg kg−1 bolus intravenous dose of [15,16-3H]naltrexonium methiodide to the rat, brain to plasma concentration ratios of the compound were 0.031 to 0.228 between 0.25 to 6 h after injection and the t½β; in plasma and brain were 2.92 and 7.61 h, respectively. Ethyl acetate-extracted radioactivity due to metabolites in plasma decayed with t½β; 1.83 h and the ratios of plasma concentration of metabolites to quaternary compound between 0.25 and 6 h were 0.014–0.026. Only unconjugated 7,8-dihydro-14-hydroxynormorphine, naltrexone and traces of 7,8-dihydro-14-hydroxynormorphinone were the metabolites in plasma. Naltrexone (but not normetabolites) was present only in traces in brain up to 0.5 h after injection and not at later times.
Particulate contaminants of intravenous medications and infusions
Authors: Backhouse C M , Ball P R , Booth Sharon , Kelshaw Margaret A , Potter S R , Mccollum C N
Published: April 2011

Particulate contamination in small volume parenteral medications has been studied and compared with that found in a selection of large volume infusions. Particle counts in 39 commonly used small volume medications and 7 large volume infusions were performed by an automated light blockage method (HIAC) or by optical microscopy. Based on these results and a random survey of drug therapy of intensive care patients, it is concluded that the contribution of intravenous medications to the total particle load received by such patients is likely to be many times greater than from infusion fluids. Until firm evidence regarding the harmful systemic effects of drug particles is available and the manufacturing regulations adjusted appropriately, final in-line filtration of infusions immediately proximal to the intravenous cannula should be considered when drugs are being given intravenously.
Effects of a 5-lipoxygenase inhibitor, REV-5901, on leukotriene and histamine release from human lung tissue in-vitro
Authors: Tennant Carolyn M , Seale J Paul , Temple Diana M
Published: April 2011

REV-5901, α-pentyl-3-(2-quinolinylmethoxy)benzene-methanol, is an arylmethylphenyl ether derivative which inhibits 5-lipoxygenase activity of leukocytes. Its effects on the release of leukotrienes, induced by antigen and calcium ionophore, from human lung tissue in-vitro have been examined. At 1 and 10 μM it significantly inhibited the release of leukotrienes induced by both stimuli. At 10 μM it also inhibited antigen-induced histamine release. These results suggest that REV-5901 may be useful in clinical disorders such as asthma in which leukotriene release may be involved.
Effect of pyridoxine on prostaglandin synthesis in rabbit kidney medulla slices
Authors: Fujimoto Yohko , Nishioka Kazuyuki , Ohtani Noboru , Aihara Midori , Fujita Tadashi
Published: April 2011

Pyridoxine stimulated the generation of prostaglandin E2 in rabbit kidney medulla slices. Moreover, pyridoxine in the presence of aspirin reduced the release of linoleic acid, but enhanced the release of arachidonic acid from the medulla slices as compared with aspirin alone, indicating that the enhancement of prostaglandin E2 formation elicited by pyridoxine may be ascribed to an increased conversion of linoleic acid to arachidonic acid. These results suggest that pyridoxine can be an important modulating factor in prostaglandin synthesis by the kidney.
Differences in the promotion mechanism of the colonic absorption of antipyrine, phenol red and cefmetazole
Authors: SHIGA MASAHARU , HAYASHI MASAHIRO , HORIE TOSHIHARU , AWAZU SHOJI
Published: April 2011

The promotion of antipyrine, phenol red and cefmetazole absorption by sodium ethylenediaminetetraacetate (EDTA-Na) as a paracellular promoter, diethyl maleate (DEM) as a transcellular promoter, and sodium taurocholate (TC-Na), whose promotion mechanism is still unclear, has been investigated by the rat in-situ colonic loop technique. All these promoters increased AP absorption and water influx from the lumen to the blood. Ouabain treatment suppressed the increase in antipyrine absorption and water influx induced by TC-Na and EDTA-Na, but did not modify the enhancing effect of DEM. Thus, the promotion mechanism of TC-Na may be similar to that of EDTA-Na. Phenol red and cefmetazole absorption were increased by TC-Na and EDTA-Na but not by DEM. Accordingly, phenol red and cefmetazole absorption appears to be promoted via paracellular but not transcellular routes. The collection of blood for plasma samples reduced the influx of water which had been increased by TC-Na or EDTA-Na. Consequently, the enhancement in antipyrine plasma concentration by these promoters was reduced to the control level. The inhibitory mechanism for this is discussed on the basis of the blood-flow limitation of antipyrine and water absorption.
Anticholinergic activity of the dopamine receptor agonist, TL-68 (N,N-dipropyl-2-aminotetralin)
Authors: Sahin Inci , Ilhan Mustafa
Published: April 2011

The anticholinergic properties of a dopamine receptor agonist, a non-hydroxylated derivative of N,N-dipropylaminotetralin (TL-68), were evaluated using the guinea-pig isolated tracheal strip and rat phrenic nerve-diaphragm preparations. TL-68 competitively antagonized carbachol-induced contractions in guinea-pig trachea with a pA2 value of 5.88 ± 0.05. In the rat phrenic nerve-diaphragm preparation, TL-68 was found to be inactive in blocking nicotinic cholinergic receptors.
Influence of water deprivation on the disposition of paracetamol
Authors: Zafar N U , Niazi S , Jung D
Published: April 2011

The effect of acute (96 h) water deprivation on the disposition of paracetamol (acetaminophen) has been examined in male Sprague-Dawley rats. Plasma and urinary concentrations of the drug and its two major metabolites, the glucuronide and sulphate, were determined by a sensitive and specific high performance liquid chromatographic assay. Following an intravenous dose of 100 mg kg−1 of paracetamol, no significant changes were found in the elimination rate constant (k), the mean residence time (MRT), total plasma clearance (Cl) and the apparent volume of distribution at steady-state (Vss). However, rats deprived of water for 96 h excreted a larger percentage of the administered dose as the glucuronide conjugate (15.3 vs 7.9%) and a smaller percentage as unchanged paracetamol (7.3 vs 20.7%) in the urine. In addition, there was a significant two-fold increase in the partial metabolic clearance to paracetamol glucuronide. Water deprivation also led to a significant reduction in the renal clearance of paracetamol accompanied by an increase in the renal clearance of the glucuronide.
Influence of time and chloride ions on the interaction of cisplatin with human albumin in-vitro
Authors: Momburg R , Bourdeaux M , Sarrazin M , Chauvet M , Briand C
Published: April 2011

The interaction of cis-dichlorodiammineplatinum (II) (cisplatin) with human serum albumin (HSA), dissolved in phosphate buffer with or without sodium chloride (0ṁ1 M) has been examined at pH 7ṁ4 and μ = 0ṁ154. Equal volumes of cisplatin and HSA solutions were incubated at 37 °C for various times and filterable platinum concentrations versus time measured by flameless atomic absorption spectrophotometry. Binding kinetics differed depending on the buffer solutions used and on the time elapsing between cisplatin dissolution and outset of incubation with HSA. Experimental data were fitted to a theoretical equation used to calculate the number of nucleophilic sites per HSA molecule. Titrations of the HSA sulphydryl group content before and after incubation with a cisplatin solution were made, from which it was shown that the lone SH-group of the HSA macromolecule is involved in cisplatin binding. We also studied HSA's sensitivity towards denaturing agents when it was complexed with cisplatin. This sensitivity was decreased upon cisplatin binding. Also, the binding capacities of HSA and the HSA-Pt(II) complex to both tryptophan and warfarin were compared to determine the possible influence of cisplatin upon the binding to HSA of other drugs; this influence was negligible.
Binding of chlorpromazine, phenytoin and aspirin to the erythrocytes and lipoproteins in whole human blood
Authors: Tamura Akira , Kawase Fumito , Sato Takashi , Fujii Tatsuzo
Published: April 2011

The quantitative binding of 14C-labelled chlorpromazine, phenytoin or aspirin (at 10 μM) to blood cells and plasma lipoproteins in whole human blood or to the washed erythrocytes in an isotonic protein-free medium has been studied. The fractions of chlorpromazine, phenytoin and aspirin bound to the blood cells in whole blood amounted to about 40, 14 and 2% of the total amount added, and those to the lipoproteins amounted to 7, 2 and 1%, respectively. Their binding to the washed erythrocytes in protein-free medium was 95, 76 and 40%, respectively. Their octanol: water partition coefficients were 214, 170 and <0ṁ1, respectively. These results suggest that the amphiphilic drugs with relatively high hydrophobicity may be bound to the blood cells, mainly to erythrocytes, to considerable extents when administered clinically, and also that their binding to plasma lipoproteins may not be negligible.
The Interaction of Dopexamine with Various Drugs and Excipients in Parenteral Solutions
Authors: Pereira-Rosario Ronald , Utamura Toshiko , Perrin J H
Published: April 2011

The interaction of dopexamine hydrochloride with various excipients and other drugs in parenteral solutions has been investigated by microcalorimetry. The interaction with heparin sodium, in particular, is significant. The interaction is strongest in parenterals containing glucose and is eliminated in normal saline. Divalent cations are more effective than monovalent ones in eliminating the reaction, which is apparently ionic in nature.
Biotransformation of Primary Nicotine Metabolites: Metabolism of R-(+)-[3H-N′-CH3; 14C-N-CH3] N-Methylnicotinium Acetate—The Use of Double Isotope Studies to Determine the In-vivo Stability of the N-Methyl Groups of N-Methylnicotinium Ion
Authors: Pool William F , Crooks Peter A
Published: April 2011

The in-vivo metabolism of R-(+)-[3H-N′-CH3; 14C-N-CH3]-N-methylnicotinium acetate (NMN) was studied in the guinea-pig to determine the in-vivo stability of the N-methyl and N′-methyl groups of this primary nicotine metabolite. The results showed that N-demethylation does not occur. However, losses of 34 and 36%, respectively, of the 3H label in the N′-CH3 group of urinary NMN and the secondary metabolite, N-methyl-N′-oxonicotinium ion (NMNO), were observed. These results suggest that biotransformation of NMN may involve either an initial N′-demethylation step to N-methylnornicotinium ion (NMNor) followed by N′-methylation back to NMN, or the formation of an N′-methylene iminium species, which may be reductively converted back to NMN.
Binding of Amitriptyline to α1-Acid Glycoprotein and its Variants
Authors: Eap C B , Cuendet C , Baumann P
Published: April 2011

Binding studies have been performed between amitriptyline and i) native α1-acid glycoprotein (AAG); ii) its desialylated form; iii) its two variants, S-AAG and F-AAG; and iv) a mixture of S-AAG and F-AAG. Scatchard analysis revealed the presence of two classes of binding sites on AAG. For native AAG, the first class (of high affinity) has an association constant (Ka1) of 1.5 × 106 L mol−1 and a number of binding sites per mole of protein (n1) of 0.25, while the second class (of low affinity) has a Ka2 of 3.2 × 104 L mol−1 and a n2 of 0.94. Similar data were found for desialylated AAG. S-AAG and F-AAG do not differ in their association constants measured with amitriptyline, but in their number of binding sites per mole of protein (n): S-AAG: n1 = 0.56, n2 = 0.52; F-AAG: n1 = 0.17, n2 = 0.71. These results confirm those of a previous study, in which a higher affinity of S-AAG towards various basic drugs in comparison with F-AAG has been found.
Relaxant and β2-adrenoceptor blocking activities of labetalol, dilevalol, amosulalol and KF-4317 on the rat isolated aorta
Authors: Doggrell Sheila A
Published: April 2011

The KCl-contracted rat aorta is relaxed by labetalol, dilevalol, amosulalol and KF-4317. These relaxations are not reversed by ICI 118,551 at 10−6 M and, therefore, are not due to β-adrenoceptor agonism. At 10−7 M, labetalol, dilevalol, amosulalol and KF-4317 were β2-adrenoceptor antagonists as they inhibited the relaxant responses of rat aorta to procaterol.
Solubilization Kinetics of a Triglyceride/n-Alkane Mixture in a Non-ionic Surfactant Solution
Authors: Carroll B J , Doyle P J
Published: April 2011

The kinetics of solubilization in a non-ionic surfactant solution of pure n-hexadecane, pure triolein and a mixture of the two oils have been investigated. The rates were determined from observations of the dissolution of a single, microscopic droplet, using a drop-on-fibre technique. Conditions were such that negligible saturation of the micellar surfactant with solubilizate occurred. The rate of solubilization of each of the pure oils was found to be independent of time, hexadecane solubilization on a volume basis being about 8 times as rapid as that for triolein. The rate of solubilization of a mixture of the two oils, having a volume fraction 0.69 for triolein, was found to vary in the medium term, the rates apparently being steady both initially and (at a lower value) in the long term. These observations can be related quantitatively to the rates found for the pure oils.
The effect of hydrochlorothiazide on the composition of renal papillary interstitial fluid in the rat
Authors: Shirley D G , Skinner J , Walter S J
Published: April 2011

The effect of chronic hydrochlorothiazide administration on the composition of renal papillary interstitial fluid was investigated in the rat. Hydrochlorothiazide alone had no effect on papillary composition. However, when the sodium depletion that usually accompanies thiazide treatment was minimized by allowing the rats access to hypertonic NaCl solution, hydrochlorothiazide administration resulted in significant reductions in papillary osmolality, and sodium and potassium concentrations. It is suggested that the effects of hydrochlorothiazide on the renal papilla might be mediated by thiazide-induced hypokalaemia, and that under normal circumstances these effects are masked by the concomitant sodium depletion.
Twenty-one hormones fail to inhibit the brain to blood transport system for Tyr-MIF-1 and the enkephalins in mice
Authors: Banks William A , Kastin Abba J
Published: April 2011

Tyr-MIF-1 (Tyr-Pro-Leu-Gly-amide) and methionine enkephalin are transported intact across the blood-brain barrier by a saturable, stereospecific system. This system has been found to be modulated by a few non-peptide substances and by certain conditions such as ageing and some stresses. We investigated the possibility that hormones structurally unrelated to Tyr-MIF-1 and the enkephalins might also be capable of modulating this transport. Twenty-one hormones were tested including steroids, proteins, glycoproteins, peptides, and thyroid hormones, in doses ranging from 0.01 pmol to 1 nmol/mouse by injecting each hormone directly into the lateral ventricle simultaneously with [125I]Tyr-MIF-1. No clear effect on transport could be established for any of the substances at the doses tested. None of these substances seemed able to act as competitive inhibitors, to share their respective transport systems with Tyr-MIF-1, or to modulate immediately the saturable transport system.
Dopamine and apomorphine do not modulate the uptake of [3H]D-aspartate in the rat striatum in-vitro
Authors: O'Connor Ian , Cowburn Richard F , Hardy John A , Fowler Christopher J
Published: April 2011

Sodium-dependent [3H]D-aspartate uptake was measured in rat striatal homogenates. The uptake was inhibited by both L- and D-glutamate, with IC50 values of 5.6 and 224 μM, respectively. Dopamine (10−7–10−4 M), apomorphine (10−7 M), sulpiride (10−6 M) or a combination of dopamine and sulpiride were found not to affect the observed uptake of [3H]D-aspartate. Thus, the in-vitro dopaminergic modulation of high affinity glutamate uptake reported in the literature is not found when [3H]D-aspartate is used instead of [3H]L-glutamate.
Characterization of Sodium Carboxymethylcellulose-Gelatin Complex Coacervation by Chemical Analysis of the Coacervate and Equilibrium Fluid Phases
Authors: Koh Geok-Lay , Tucker Ian G
Published: April 2011

The complex coacervation of sodium carboxymethylcellulose (SCMC) and gelatin has been characterized by chemical analyses of the coacervate and equilibrium fluid phases. The phenol-sulphuric acid (for SCMC) and Lowry (for gelatin) assays were used. Chemically analysed coacervate yield was used to predict optimum coacervation conditions, which occurred at a SCMC-gelatin mixing ratio of 3:7 at pH 3.5. The effects of pH, colloid mixing ratio and total colloid concentration on coacervate yield and composition were studied. The colloid mixing ratio, at which the peak coacervate yields occurred varied with coacervation pH. Increase in the total colloid concentration suppressed coacervation, resulting in a coacervate of higher water content. A similar coacervation mechanism was seen for two viscosity grades SCMC. However, because of the different degree of substitution of these two grades the SCMC-gelatin coacervates had different SCMC contents.
The Effects of Inclusions and Conditions of Storage on the Mechanical Properties of Maize Starch and Methylcellulose Films
Authors: Ononokpono Okon E , Spring M S
Published: April 2011

Films of methylcellulose and gelatinized maize starch were tested in tension, with and without 0.01–10% of additive in the film. The effects of these inclusions on the physical properties of the films have been found to be statistically significant in almost every case. The films, with and without inclusions, have also been conditioned at four different relative humidities and the behaviour of these films has also been considered. In general films were weakened by the presence of additives particularly at higher concentrations. The properties of methylcellulose films were changed most at specific concentrations of the inclusions, this effect was not found with maize starch films. Plasticization of maize starch films was not achieved.
The Distribution of Doxorubicin in Mice Following Administration in Niosomes
Authors: Rogerson A , Cummings J , Willmott N , Florence A T
Published: April 2011

Large multilamellar non-ionic surfactant vesicles (niosomes) with diameters of around 800–900 nm prepared from a C16 triglyceryl ether with and without cholesterol and containing doxorubicin (Adriamycin) were administered to S180 tumour-bearing NMRI mice by bolus injection. Although in-vitro drug release from cholesterol-containing niosomes is delayed, in-vivo there was little difference between the two preparations when plasma levels were compared. As previously observed, half-lives of the drug were prolonged compared with free solution profiles. Liver uptake was not significantly affected by niosome encapsulation of doxorubicin. There is minor accumulation of drug in the lung, perhaps because of aggregation of the vesicles and their physical entrapment. Tumour levels of drug were higher following administration of cholesterol-containing niosomes and this was reflected in the more effective reduction in tumour growth. Metabolism of doxorubicin is altered by niosomal administration, but more studies are required before the significance of the metabolic data can be assessed.
The effect of capsule size and density on transit through the proximal colon
Authors: Parker G , Wilson C G , Hardy J G
Published: April 2011

Colonic transit of radiolabeled capsules has been monitored in 18 healthy subjects using gamma scintigraphy. The capsules ranged in volume from 0.3–1.8 cm3 and in density from 0.7–1.5 gcm−3. The capsules were administered after an overnight fast and entered the colon, on average, 5 h after dosing. Transit rates through the proximal colon were independent of capsule density. Any effect due to capsule volume was small when compared with intersubject variations in transit rates. Within 10 h of entering the colon 80% of the units had reached the splenic flexure. These findings have implications in the design of non-disintegrating, sustained release dosage forms.
Paracetamol Confers Resistance to Ethanol-induced Gastric Mucosal Damage in Rats
Authors: Poon Y K , Cho C H , Ogle C W
Published: April 2011

Paracetamol given orally or subcutaneously did not produce any observable gastric mucosal damage, nor did it change the acidity of the residual secretion in rat stomachs. However, it delayed the gastric emptying rate and increased the residual volume of gastric secretion. Pretreatment with paracetamol 250 mg kg−1 significantly prevented ethanol-induced gastric ulceration. Although it did not influence ethanol-stimulated acid secretion, it increased the mucosal mucus content in the ethanol-treated animals. The findings suggest that the protective mechanism of paracetamol against ethanol-induced damage is likely to be due to improved gastric mucosal integrity, through an increase in the adherent mucosal mucus which protects the underlying delicate cellular structures.
Inhibition of the Multiplication of Enveloped and Non-enveloped Viruses by Glucosamine
Authors: Delgadillo R A , Berghe D A Vanden
Published: April 2011

Glucosamine can inhibit the development of viral cytopathogenic effect and the production of infective viral particles of both enveloped and non-enveloped viruses. The extent of antiviral activity is dependent on drug concentration, composition of the culture medium and type of cell host.
Actions of Buspirone in a Putative Model of Anxiety in the Mouse
Authors: Costall B , Kelly M E , Naylor R J , Onaivi E S
Published: April 2011

In a two-compartment box divided into a dark area and a brightly illuminated white area, mice taken from a dark environment showed aversion to the light and exhibited preference for exploratory rearings and line crossings in the black area. The peripheral administration of buspirone, and its injection into the dorsal raphe nucleus, lead to an increased time spent in the white area associated with enhanced exploratory behaviour with a decreased incidence of rearings and line crossings in the black section. In contrast, the injection of 5-hydroxytryptamine and 2-methyl-5-hydroxytryptamine into the dorsal raphe nucleus increased exploratory behaviour in the black section with decreased activity in the white area: the effects of 2-methyl-5-hydroxytryptamine were antagonized by buspirone administered peripherally. Ritanserin, methysergide, metergoline and cyproheptadine failed, in non-sedative doses, to influence exploratory behaviour in the two-compartment system and ritanserin and methysergide also failed to antagonize the effects caused by 2-methyl-5-hydroxytryptamine. It is concluded that in the mouse model the ability of buspirone to reduce the aversive response to a brightly illuminated area may reflect an anxiolytic action, that the dorsal raphe nucleus may be an important locus of action, and that the effects of buspirone may reflect an interaction at 5-hydroxytryptamine receptors.
Characterization of the sphericity of particles by the one plane critical stability
Authors: Chapman S B , Rowe R C , Newton J M
Published: April 2011

A method has been developed to characterize the roundness of particles in terms of the angle necessary to tilt a plane such that the particles would roll, the ‘one plane critical stability’. The method is based on determination of the centre of gravity of the particle from a digitized image of the coordinates of its outline and computing the angle necessary to incline a plane such that the centre of gravity moves outside the boundary of the particle. The method is particularly applicable to differentiate between the various shapes formed during the production of spherical granules by extrusion/spheronization.
Actions of amrinone and milrinone on the guinea-pig ileum
Authors: Stone T W , Paton D M
Published: April 2011

The pharmacological activity of the cardiotonic agents amrinone and milrinone has been examined on the isolated guinea-pig ileum. Both compounds antagonised the presynaptic inhibitory action of adenosine on electrically evoked contractions, milrinone being the more potent. Higher concentrations of amrinone or milrinone produced contractions of the ileum which were prevented by atropine. Contractile responses to adenosine 5′-monophosphate were not inhibited by atropine. It is concluded that amrinone and milrinone can antagonise some effects of purines but this does not represent their only pharmacological action.
Evaluation of the Sorbent Suspension Reciprocating Dialyser in the Treatment of Overdose of Paracetamol and Phenobarbitone
Authors: Shihab-Eldeen Aida A , Peck Garnet E , Ash Stephen R , Kaufman Geraldine
Published: April 2011

Poisoning with paracetamol (acetaminophen) and phenobarbitone is a common occurrence in the United States and Europe. The removal efficiency of these drugs by a sorbent suspension reciprocating dialyser (SSRD) has been investigated. The SSRD is a parallel plate dialyser with a reciprocating blood flow and free mobile sorbent suspension composed of charcoal and zeolites. This arrangement provided a system with minimal sorbent saturation. High performance liquid chromatography was used for the quantification of the drugs in aqueous and serum fluids. The in-vitro removal efficiency of the dialyser was studied by dialysing a large volume of the drug in solution for 12 to 16 h. The removal efficiency remained relatively constant up to 10 h of dialysis. The in-vivo dialysis studies were performed using normal dogs. Large doses of the drugs were administered orally or intravenously to achieve high blood levels. The clearance values obtained from these studies were comparable with, or in excess of, the values reported in the literature for conventional dialysers. The major advantage of the SSRD is the ability of the unit to be used for prolonged dialysis and to provide a system with minimal sorbent saturation due to mixing and interchange of sorbent granules next to the membrane surface.
Cardiovascular and Renal Actions of Calcium Channel Blocker Chemical Subgroups: a Search for Renal Specificity
Authors: Barrett Richard J , Wright Kathryn F , Taylor David R , Proakis Anthony G
Published: April 2011

The diuretic and natriuretic responses to structurally distinct classes of Ca2+ channel blockers have been compared, to determine whether any agent provoked K+-sparing natriuresis, and to assess the relation of such responses with drug effects on blood pressure. Conscious normotensive Sprague-Dawley rats received vehicle or one of the following drugs in an oral saline load (40 mL kg−1): nifedipine, nimodipine, nitrendipine, prenylamine, cinnarizine, flunarizine, diltiazem, verapamil, hydrochlorothiazide, amiloride, or hydralazine, at doses from 0.316 to 100 mg kg−1. Urine was collected for 6 h. Blood pressure was monitored directly in parallel studies. Diltiazem (31.6, 100 mg kg−1) and flunarizine (100 mg kg−1) enhanced urine and electrolyte excretion in spite of marked hypotension; diltiazem was the only drug to produce dose-related renal responses. In contrast, equihypotensive doses of hydralazine and nifedipine produced overt urine and electrolyte retention. Nitrendipine and prenylamine (0.316 mg kg−1 each) produced slight diuresis or natriuresis without altering blood pressure; higher doses had no effect. The 31.6 mg kg−1 doses of verapamil, nitrendipine, and nimodipine markedly reduced blood pressure, but neither enhanced nor limited urine and electrolyte excretion. Cinnarizine failed to produce any cardiovascular or renal effects. Diuretic responses evoked by the Ca2+ channel blockers were not class-specific, showed no tendency towards sparing K+, were generally weaker than those produced by low doses of amiloride or hydrochlorothiazide, and were dissociable from drug-induced changes in blood pressure.
A Three Dimensional Receptor Model of the Dopamine D2 Receptor from Computer Graphic Analyses of D2 Agonists
Authors: Manallack David T , Beart Philip M
Published: April 2011

Four potent D2 agonists were employed to define a primary pharmacophore for the D2 receptor. Hypothetical receptor points, representing interaction points on a receptor were built on to each molecule. These points and the nitrogen atom were averaged to give the coordinates (Å) of the primary pharmacophore: R1 (0.00, 3.50, 0.00), R2 (0.00, −3.50, 0.00), R3 (5.79, 2.06, 0.00), and nitrogen (5.13, −0.63, 0.37). Eight structural classes of D2 agonists were then superimposed on to the primary pharmacophore to aid in the location of secondary binding sites. The secondary sites include two lipophilic clefts, an area of steric bulk, a region to hydrogen bond ‘meta’ hydroxy groups and a ‘critical region’ accepting methoxy and halogen substituents but not hydroxy substituents. The model has the potential to design and predict activity of novel D2 agonist compounds.
The stable prostacyclin-analogue, iloprost, unlike prostanoids and leukotrienes, potently stimulates cyclic adenosine monophosphate synthesis of primary astroglial cell cultures
Authors: Seregi Andras , Schobert Angelika , Hertting Georg
Published: April 2011

The effect of different eicosanoids on adenosine-3′, 5′-cyclic-monophosphate (cAMP) accumulation in primary astroglial cell cultures prepared from newborn rat brain was studied. The stable prostacyclin-analogue, iloprost, effectively stimulated cAMP synthesis in a concentratioin-dependent, saturable manner, the EC50 being about 3 × 10−8 M. Prostaglandin (PG) E2 was less potent, without reaching plateau even at 10−5 M. Prostaglandins D2 and F2α, and the stable thromboxane A2-analogue, U 46619, as well as leukotrienes (LT) B4, C4, D4 and E4 were not effective and did not attenuate basal or isoprenaline (10−8 M)-stimulated astroglial cAMP formation. This is the first indication for the existence of a prostacyclin receptor coupled positively to the adenylate cyclase in astrocytes. Other eicosanoids are unlikely to be involved in receptor-mediated regulation of astroglial cAMP levels.
Metabolism of fenfluramine to norfenfluramine in guinea-pigs
Authors: Fuller Ray W , Snoddy Harold D , Perry Kenneth W
Published: April 2011

After injection of fenfluramine into guinea-pigs, the N-dealkylated metabolite norfenfluramine was present in brain at higher concentrations and persisted longer than the parent drug, fenfluramine. Contrary to a claim in previous literature, the guinea-pig does metabolize fenfluramine to norfenfluramine, hence the ability of fenfluramine to cause acute and long-term depletion of brain 5-hydroxytryptamine in this species does not prove that fenfluramine, instead of nonfenfluramine, can produce these effects.
Cardiovascular effects of intracerebro-ventricular bradykinin and melittin in the rat
Authors: Thomas G Roger , Hiley C Robin
Published: April 2011

The cardiovascular effects of intracerebroventricular (i.c.v.) bradykinin and melittin were investigated in the anaesthetized rat. Bradykinin, 30 μg, increased mean arterial pressure by 15 mmHg and this was the result of an increase in peripheral resistance; heart rate and cardiac output were unchanged. Tissue blood flow was lower in the skin and spleen in the animals given bradykinin than the controls. Significant increases in tissue vascular resistance occurred in the skin and several organs of the splanchnic region, the spleen, stomach, large intestine and the pancreas/mesentery. Melittin infusion gave a biphasic response in systemic blood pressure in which a depressor response was followed by a pressor phase; the pressor stage was accompanied by an increase in heart rate. Since melittin is a stimulant of membrane bound kallikrein, the results lend limited support to the hypothesis that there is a kallikrein-kinin system endogenous to the central nervous system which is involved in cardiovascular regulation.
Differences in the characteristics of opioid receptor binding in the rat and marmoset
Authors: Yeadon M , Kitchen I
Published: April 2011

The density of μ and δ opioid binding sites in homo-genates of rat and marmoset brain was determined using radio-labelled peptides with high receptor selectivity. In addition the affinity of μ and δ receptor binding of five drugs of the fentanyl series was measured. The ratio of μ:δ sites was similar within each species but the total receptor binding capacity in the rat was double that of the marmoset. The binding affinities for the δ site were dissimilar between the species and supports the hypothesis that the structure of this receptor shows phylogenetic differences. In contrast, μ site binding affinity was identical in rat and marmoset.
Prostaglandin synthetase inhibitors in feverfew
Authors: Pugh W J , Sambo K
Published: April 2011

The IC50 values for the in-vitro inhibition of the prostaglandin synthetase (bovine seminal vesicle mitochondrial fraction) mediated PGE2 production from arachidonic acid by parthenolide, michefuscalide and chrysanthenyl acetate were 11.0 ± 0.44, 121 ± 0.51 and 14.2 ± 0.58 μM (mean ± 95% confidence limits), respectively.
Thermal Characterization of Drug/Polymer and Excipient/Polymer Interactions in Some Film Coating Formulation
Authors: Okhamafe Augustine O , York P
Published: April 2011

Some probable consequences of the dissolution/migration of a major solid dosage component in or into an applied film coating during or after a film coating operation have been investigated using free films of hydroxypropyl methylcellulose (HPMC) and polyvinyl alcohol (PVA) incorporating small amounts of either lactose (a diluent) or ephedrine hydrochloride (a drug). Intrinsic features of the films such as softening, glass transition, crystallinity and melting were examined by differential scanning calorimetry and thermomechanical analysis. Generally, the results indicate that ephedrine hydrochloride exhibited plasticizing activity in both HPMC and PVA films. On the other hand, incorporation of lactose produced an opposite effect (stiffening) in PVA films as demonstrated by increased glass transition temperature and crystallinity. On the basis of these findings, it was proposed that the undesired presence of a component of a solid dosage core in the applied film coating could significantly alter its end-use properties such as diffusivity and the incidence of film coating defects. It was also shown that the application of the relationship of Moelter & Schweizer (1949) in the evaluation of the plasticizer efficiency of non-homologous additives could pose problems of interpretation.
Chemical Reactivity of Aluminium-based Pharmaceutical Compounds used as Phosphate-binders
Authors: Cargill Robert W , Dutkowskij Michael , Prescott Ann , Fleming Laura W , Stewart William K
Published: April 2011

Several aluminium-containing substances, including antacids used as phosphate-binders in treating renal failure, have been analysed in-vitro under different pH conditions for the release of Al3+ ions and for binding of phosphate. Control experiments on different forms of pure aluminium hydroxide validated the methods. At pH 2 it was the most amorphous forms which released Al3+ most rapidly. These aluminium ions, available for absorption by the patient, were released from all antacids tested, but no firm phosphate-binding was detected while the pH remained at 2. Phosphate was bound at pH 8, by adsorption onto the surface of aluminium hydroxide. No significant amounts of free Al3+ exist in solution at pH 8, since at that pH aluminium hydroxide is precipitated. The most amorphous forms of this solid were the most efficient phosphate-binders. Alumino-silicate salts require prior exposure to acid to produce free Al3+ before they can act as phosphate-binders, whereas amorphous aluminium hydroxide acts as an efficient phosphate-binder without prior exposure to acid. Chemical principles are employed to show why aluminium release and phosphate-binding are separate and independent processes. Methods are proposed for maximizing the activity of phosphate- binders in-vivo, while minimising aluminium release.
Unequal Disposition of Enantiomers of the Organic Cation Oxyphenonium in the Rat Isolated Perfused Liver
Authors: Feitsma Karla G , Drenth Ben F H , de Zeeuw Rokus A , Oosting Roelof , Meijer Dirk K F
Published: April 2011

This paper describes the results of pharmacokinetic experiments in the rat isolated perfused liver with enantiomers of oxyphenonium. The study was performed with the [14C]methyl labelled compounds. In this preparation both metabolism and biliary excretion were significantly different for the (+)- and the (-)-isomer. Hepatic uptake rate was similar, but total biliary excretion (including metabolites) of the (-)-isomer was only 55% compared with the excretion of the (+)-isomer. In line with these data, after 2 h only 30% of the dose of the (+)-isomer and over 50% of the dose of the (-)-isomer was still found in the liver, predominantly in the form of metabolites. The metabolic profile was investigated using ion pair TLC. At least two metabolites were detected in bile for both enantiomers. However, unchanged (-)-oxyphenonium persisted for longer in bile, indicating either a more rapid canalicular transport of the (+)-isomer and/or a more rapid metabolism of (+)-oxyphenonium to cholephilic metabolites.
The Pharmacokinetics and Pharmacodynamics of a New Thromboxane Synthetase Inhibitor, 6-(1-Imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (DP-1904), in Man after Single Oral Administration
Authors: Tanaka Makoto , Ono Kenji , Takegoshi Toshio , Shiozawa Tomoo , Suzuki Tomoyoshi , Nii Shigenori , Shibata Hisao
Published: April 2011

The pharmacokinetics of DP-1904, a new potent and selective thromboxane synthetase inhibitor and its effects on ex-vivo prostanoid formation were studied in Japanese normal male volunteers, who received orally a single 10, 20, 50, 100, 200, 400 or 800 mg dose. The drug was well tolerated by all subjects without evidence of any adverse reactions. The absorption of DP-1904 from gastro-intestinal tract was rapid. After oral doses of 10–800 mg of the drug given to volunteers in the fasted state, the mean maximum drug concentrations in plasma (Cmax) (mean ± s.e., n = 5) of 0·215 (± 0·041), 0·399 (± 0·037), 1·47 (± 0·22), 2·86 (±0·22), 4·66 (±0·58), 7·28(±0·72) and 16·9 (±2·6) μgmL−1 were reached within 1 h. DP-1904 concentrations declined monophasically after Cmax with half lives of 30–40 min. These half lives were independent of the administered doses. The mean area under the concentration-time curves (AUCs) increased from 0·398 (±0·038) to 30·0 (±2·7) μgh. mL−1 as the dose increased from 10 to 800 mg. Linear relations between the doses and Cmax and AUCs were observed. The correlation coefficients for Cmax and AUC were 0·930 and 0·960, respectively. The apparent oral clearance (CL/F) and renal clearance (CLR) did not change significantly as dose increased from 10 to 800 mg. The kinetics of DP-1904 proved to be linear in the dose range studied. The urinary excretion of DP-1904 was also independent of the administered dose, and about half of the dose was recovered in urine as unchanged form within 48 h after administration. The elimination of the drug was fast and almost complete within 6 h after dosing. On the other hand, only 0·5% of the dose was excreted into faeces as intact DP-1904 up to 48 h after 400 mg oral dose. Food intake delayed the absorption of DP-1904 but did not significantly modify its pharmacokinetics. Serum thromboxane B2 levels (the stable metabolite of thromboxane A2) were reduced more than 90% within 0·5 h after all doses studied. DP-1904 had a long duration of inhibitory activity and there was still more than 80, 90 and 95% suppression at 12 h after 200, 400, and 800 mg doses, respectively.
Dual Effects of Zinc Sulphate on Ethanol-induced Gastric Injury in Rats: Possibly Mediated by an Action on Mucosal Blood Flow
Authors: Cho C H , Chen B W , Poon Y K , Ng M M T , Hui W M , Lam S K , Ogle C W
Published: April 2011

The present study examines the protective effect of zinc sulphate against ethanol-induced gastric mucosal ulcers in rats. Absolute ethanol decreased the gastric mucosal blood flow and produced haemorrhagic lesions in the glandular mucosa. Zinc sulphate preincubation in an ex-vivo stomach chamber preparation prevented the formation of ethanol-induced lesions and attenuated the decrease of blood flow produced by ethanol. Subcutaneous injection of the same doses of the drug at 15 and 30 min before ethanol exposure, markedly reduced the blood flow and also aggravated ethanol-induced gastric injury; however, when injected at 23 and 24 h before ethanol administration, zinc sulphate protected against lesion formation but had no effect on the vascular changes induced by ethanol in the gastric glandular mucosa. These findings show that the antiulcer effect of zinc sulphate occurs only when the drug is given orally, or injected s.c. 23 and 24 h before ethanol challenge. Furthermore, this protective action is probably not entirely mediated by preservation of the gastric mucosal blood flow.
The influence of monoamine oxidase activity on the release of noradrenaline by tyramine
Authors: Brandão F , Araújo D , Monteriro J Guilherme
Published: April 2011

The influence of monoamine oxidase (MAO) activity on the kinetic characteristics of noradrenaline (NA) release evoked by tyramine has been examined. Dog splenic artery strips were incubated with [3H]NA after inhibition of catechol-O-methyl-transferase (COMT) and of extraneuronal uptake. In some experiments MAO was also inhibited. The strips were then perifused for 200 min. Some strips were exposed to tyramine (1·5, 40 and 3240 μmol L−1) from the 100th to the 200th min of perifusion. In control experiments (i.e. in the absence of tyramine) most of the [3H]NA accumulated in the strips (83% of tissue activity) and did not contribute to the efflux. The value of this “bound fraction” (the NA located at a site(s) from which it could not be displaced by a simple concentration gradient) was the same whether or not MAO was inhibited. At all concentrations, tyramine mobilized only one NA compartment. Increasing the concentration of tyramine resulted in a decrease of the “bound fraction”, which became negligible for the highest concentration of tyramine used (3240 μmol L−1), regardless of MAO being inhibited or not. However, for the lower concentrations of tyramine, MAO inhibition resulted in an increase in the amine’s releasing effect. The formation of 3,4-dihydroxy-phenylglycol (DOPEG) increased with increase of tyramine from the 1·5 to 40 μmol L−1 concentration, but not beyond. The ratio NA/DOPEG increased for all concentrations of tyramine. Thus, it was not possible to exclude an inhibitory effect of tyramine on MAO activity with the highest concentration used.
The relevance of the presence of certain synthetic steroids in the aquatic environment
Authors: Aherne G W , Briggs R
Published: April 2011

Norethisterone and ethinyloestradiol concentrations in sewage effluent, reservoirs, rivers and potable water have been estimated at less than 20 ng L−1, a value unlikely to present a significant risk to human health.
Methodology for a Better Evaluation of the Relation Between Mechanical Strength of Solids and Polymorphic Form
Authors: Kopp S , Beyer C , Graf E , Kubel F , Doelker E
Published: April 2011

In order to evaluate the role played by polymorphism in the mechanical strength of solid dosage forms (e.g. compressed tablets) and minimize the influence of other factors (such as compaction force, porosity, particle size, and possibly crystal habit), a melted disc technology was developed. With this technique, tablet-shaped discs of zero porosity were prepared by melting powder and subsequent crystallization in the desired modifications. Taking phenobarbitone as a model drug, different methods were used to get discs of forms I, II and III and the amorphous form. Mechanical properties of the discs were assessed, primarily through their bending strength. The Vickers hardness number was also determined for some specimen discs and monocrystals. Results showed that the amorphous form and form III of phenobarbitone gave the toughest discs and would be therefore the most suitable materials to manufacture coherent tablets. Moreover, the various preparation methods used resulted in discs of different internal structures. Both crystal size and crystal habit significantly affected the physical properties of the tested materials.
Lack of Mixed Agonist-Antagonist Properties of [Gln8-Gly31]-βh-EP-Gly-Gly-NH2 and [Arg9,19,24,28,29]-βh-EP in the Rat Vas Deferens Neuroeffector Junction: Studies with Naloxone, β-Funaltrexamine and ICI 174,864
Authors: Valenzuela Raúl , Li The Late Choh Hao , Huidobro-Toro J Pablo
Published: April 2011

The 1–27 truncated fragment of βh-endorphin (βh-EP) as well as [Gln8,Gly31]-βh-EP-Gly-Gly-NH2 or [Arg9,19,24,28,29]-β-EP exhibited opiate agonist activity in the rat vas deferens bioassay; the potency of these peptides was 3 to 6 times less than that of βh-EP. None of these compounds exhibited any degree of antagonism towards the inhibitory action of βh-EP. Naloxone antagonized and reversed the inhibitory action of βh-EP and its analogues though with varying potencies. The apparent naloxone-pA2 value for βh-EP was 8·94; that for [Gln8-Gly31]-βh-EP-Gly-Gly-NH2 was 8·08 and that for [Arg9,19,24,28,29]-βh-EP was 8·38. β-Funaltrexamine (β-FNA) potently antagonized the inhibitory action of βh-EP following non-equilibrium kinetics. Tissue preincubation with 10 nM β-FNA for 60 min followed by extensive washing caused a 10-fold increase in the βh-EP IC50. However, 10 nM β-FNA caused only a 1·2 increase in the IC50 of [Gln8,Gly31]-βh-EP-Gly-Gly-NH2 and a 4·1 -fold increase in the IC50 of [Arg9,19,24,28,29]-βh-EP. In contrast, preincubation of the tissue with 3 βM ICI 174,864 did not modify the potency of βh-EP or its structural analogues. However, a 60 min pretreatment with 10 μM β-FNA followed by the addition of 3 μM ICI 174,864 revealed a further decrease in the potency of the opiopeptins compared with tissues exposed to β-FNA alone or ICI 174,864 alone. In conclusion, the inhibitory action of these peptides is remarkably sensitive to β-FNA antagonism; in addition the peptides act as pure opiate agonists in marked contrast with the agonist-antagonist properties described in the CNS.
Distribution of dissociation constant values of muscarinic agonists
Authors: Lucchelli Adele , Boselli Cinzia , Grana Enzo
Published: April 2011

The frequency distributions of dissociation constant values of some muscarinic agonists (carbachol, muscarone and cis-2-methyl-5-trimethylammoniummethyl-1,3-oxathiolane) obtained on guinea-pig ileum and atria and rat urinary bladder have been examined to see if the means of the dissociation constant values and the statistical tests for their significance, should be based on geometric rather than on arithmetic means. For the three compounds the distributions on a logarithmic scale did not significantly deviate from normality while the distributions on an arithmetic scale tended to deviate from normality.