bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of 6-hydroxydopamine on the metabolism of endogenous octopamines and catecholamines
Authors: Ibrahim Kamal E , Williams Clyde M
Published: April 2011

The daily excretion in rat urine of o-(OHMA) (0.2), m-(MHMA) (0.9), p-(PHMA) hydroxymandelic acid (78), vanillylmandelic acid (VMA) (3.5) and homovanillic acid (30 μg day−1), terminal metabolites of the isomeric octopamines and catecholamines, has been determined by gas chromatography-mass spectrometry. Chemical sympathectomy with 6-hydroxydopamine (i.p.) caused the daily output of each acid (except OHMA) to drop by 50% and that of PHMA was restored to normal the most rapidly after cessation of treatment. These results indicate that m-and p-(but not o-) octopamine coexist with catecholamines in sympathetic nerve terminals, are subject to the same compensatory biosynthetic mechanism following chemical sympathectomy and that p-octopamine has the highest turnover rate of these biogenic amines in the rat.
The nasal absorption of sodium cromoglycate in the albino rat
Authors: Fisher A N , Brown K , Davis S S , PARR G D , Smith D A
Published: April 2011

The intranasal absorption of sodium cromoglycate has been investigated in the adult male COBS/Wistar rat. Sodium cromoglycate (1 mg kg−1) was instilled into the nasal cavities and for comparison animals were also similarly dosed intravenously or sublingually. Serial samples of blood or bile were collected. After intravenous administration, the area under the plasma concentration curve (AUC0-∞) was 32 μg min ml−1 corresponding to a plasma clearance of 13 ml min−1 and an elimination rate constant of 0.049 min−1. Plasma concentrations of radioactivity after intranasal administration rose to a mean peak of 0.3 μg ml−1 approximately 20 min after dosing and fell to 0.03 μg ml−1 at 3 h. The AUC0-3 was 19 μg min ml−1 corresponding to an absorption of 60% over 3 h. The absorption rate constant (ka) was 0.059 min−1. The total amount of sodium cromoglycate excreted in bile after intravenous administration was 56%. The amount of compound excreted in the bile was 30% after intranasal administration corresponding to an absorption of 53%. Plasma and bile data therefore show good agreement. Total excretion in the bile over 3h after sub-lingual administration was 3%, demonstrating that this route made no significant contribution to the intranasal results. The absorption of sodium cromoglycate is independent of variations in the technique including changes in the orientation of the rat or blocking of the nasopalatine. The techniques used minimized other competing nasal clearance processes such as mucociliary clearance.
Inhibition of mouse epidermal 12-lipoxygenase by 2,3,4-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-l,4-benzoquinone (AA861)
Authors: Nakadate Teruo , Yamamoto Satoshi , Aizu Eriko , Kato Ryuichi
Published: April 2011

2,3,5-Trimethyl-6-(12-hydroxy-5, 10-dodecadiynyl)-1.4-benzoquinone (AA861) strongly inhibited epidermal lipoxygenase activity which was determined by the formation of [14 C]12-hydroxy-5,8,10,14-eicosatetraenoic acid by incubating [l4 C]arachidonic acid with cytosol fraction of epidermal homogenate of ***CD-1 mice. AA861 failed to inhibit epidermal cyclooxygenase activity. The present results indicate that AA861 is a potent inhibitor of 12-lipoxygenase in mouse epidermis (IC50 1.9 μM).
Effect of dopaminergic drugs on striatal acetylcholine concentration
Authors: Sethy Vimala H , Wenger Dora
Published: April 2011

Striatal acetylcholine concentration was determined after administration of varying doses of apomorphine, (+)-PPP and (-)-PPP to rats. (+)-PPP at 3 and 10 mg kg−1 is a dopamine agonist, whereas (-)-PPP at 0.3 and 3 mg kg−1 is a dopamine antagonist in the striatum.
Effects of interacting variables on the tensile strengths and disintegration times of paracetamol tablets
Authors: Bangudu A B , Pilpel N
Published: April 2011

The effects of separately varying the packing fraction (P), the proportions of microcrystalline cellulose, Avicel (A) and alginic acid, disintegrant (D), on both the tensile strengths and disintegration times of paracetamol tablets are in the order P » A » D. The combined effects of these variables on both tensile strength and disintegration time are A x P » D x P > A x D.
Indirect dopaminergic effects of tofisopam, a 2,3-benzodiazepine, and their inhibition by lithium
Authors: Chopin Philippe , Stenger Antoine , Couzinier Jean-Pierre , Briley Mike
Published: April 2011

Tofisopam, a 2,3-benzodiazepine, has been shown to have anxiolytic activity. However, in contrast to the widely used 1,4-benzodiazepines, it has no anticonvulsant, sedative or muscle relaxant effects. Tofisopam enhanced the behavioural actions of various dopaminergic drugs, both direct agonists, such as apomorphine (climbing behaviour in mice), and indirect agonists, such as (+)-amphetamine and amineptine (jumping behaviour in mice). Chronic treatment with lithium abolished the tofisopam-induced increase in the activity of these dopaminergic drugs. Thus tofisopam appears to induce acutely an increase in the sensitivity of central dopaminergic receptors which can be prevented by pretreatment with lithium.
Phenobarbitone enhances [35S]TBPS binding to extensively washed rat cortical membranes
Authors: Honoré Tage , Drejer Jørgen
Published: April 2011

Pentobarbitone and phenobarbitone enhance [35S]TBPS binding to extensively washed rat cortical membranes with ED50 values of 15 and 120 μM, respectively, indicative of an interaction with the chloride ionophore part of the GABA-receptor different from the TBPS binding site, but allos-terically coupled to this site.
Polymorphism in metoclopramide hydrochloride and metoclopramide
Authors: Mitchell A G
Published: April 2011

Metoclopramide hydrochloride (MCPHCl.H2O) and metoclopramide base (MCP) have been studied by DSC, thermomicroscopy, X-ray diffraction and infrared spectroscopy. MCPHCl.H2O does not readily lose water of crystallization either from the solid state or from the melt, but depending on the conditions, dehydration can give rise to two anhydrous polymorphs, MCPHCl/Form I (mp 187 °C) and MCPHCL/Form II (mp 155 °C). Form I crystallizes from the melt of Form II and not by a reversible solid-solid transition. The anhydrous hydrochloride therefore shows monotropic polymorphism where Form I is the stable polymorph and Form II, a metastable polymorph. Thermal analysis of MCP shows that the base exists as two enantiotropic polymorphs. The transition of the form stable at room temperature (MCP/Form I) to the form stable at high temperatures (MCP/Form II mp 147 °C) occurs extremely rapidly at 125 °C but the reverse process requires one month at room temperature ($22 °C). It is therefore possible to compare the X-ray diffraction powder patterns and infrared spectra of MCP Forms I and II.
Properties of amiodarone monolayer spread at the air–water interface
Authors: Ferreira Jeanine , Brasseur Robert , Chatelain Pierre , Ruysschaert Jean-Marie
Published: April 2011

Surface pressure measurements demonstrate that, over a wide range of pH, amiodarone forms a stable monolayer at the air–water interface. The area found to be occupied by an amiodarone molecule was compared with a theoretical prediction based on a conformational analysis, making it possible to assemble amphiphilic molecules. The intrinsic ionization constant of amiodarone in an aqueous environment pKi = 8.7 ± 0.5 was evaluated from surface potential measurements.
Plasma concentrations and pharmacokinetics of midazolam during anaesthesia
Authors: Crevat-Pisano P , Dragna S , Granthil C , Coassolo P , Cano J P , Francois G
Published: April 2011

Midazolam and 1-hydroxymidazolam plasma concentrations have been monitored and pharmacokinetic parameters of midazolam estimated during anaesthesia induced and Maintained by its repeated injection according to two protocols (3 × 0.3 mg kg−1 at 45 min intervals or an induction dose of 0.3 mg kg−1 with maintenance doses of 0.15 mg kg−1 at 30 min intervals). Minimum plasma concentrations of midazolam measured just before each injection were 258.8 ± 108.4 ng ml−1 for the first protocol and 353.1 ± 55.2 ng ml−1 for the second protocol; maximum midazolam concentrations, measured 5 min after the last administration, were 1103.1 ± 237.9 ng ml−1 and 743.0 ± 103.2 ng ml−1, respectively, suggesting that a continuous infusion of midazolam after a loading dose should be better than repeated injections at keeping the concentration close to the sedative level of 400 ng ml−1. The estimated pharmacokinetic parameters were similar to those already published, except for the β elimination half-life of midazolam (3.24 ± 0.90 h for protocol 1 and 3.34 ± 1.47 h for protocol 2) which was slightly longer than that reported for single dose studies. The comparison of plasma determinations, obtained either by gas-liquid chromatography or by a radioreceptor assay technicjue, clearly showed that 1-hydroxymidazolam, even after repeated midazolam administration, was not present at a concentration sufficient to affect the overall pharmacological activity of the parent drug.
Pharmacological characterization of the postsynaptic α-adrenoceptors in human uterine artery
Authors: Ribeiro C A Fontes , Macedo Tice A
Published: April 2011

Prazosin and yohimbine were used to differentiate postjunctional α-adrenoceptors in the human uterine artery in-vitro. Two postjunctional α-adrenoceptor subtypes were distinguished by the affinities of the receptor for yohimbine and prazosin. The pA2 for prazosin was 8.91 against phenylephrine with a slope not significantly different from unity (0.91), and the pA2 for yohimbine was 7.25 against naphazoline and 8.70 against clonidine, with slopes not significantly different from unity (1.11 and 1.18, respectively). Yohimbine was not very active against phenylephrine, while prazosin was very active against the mixed and selective α2-adrenoceptor agonist noradrenaline and clonidine; the intercepts of the Schild plot were 8.80 and 8.82 but with slopes significantly less than unity (0.77 and 0.67, respectively). Prazosin competitively antagonized phenylephrine at the α1-adrenoceptor, whereas yohimbine competitively antagonized naphazoline and clonidine at the α2-adrenoceptor. It is concluded that both α1- and α2-adrenoceptors are present in the human uterine artery.
Some pharmacokinetic characteristics of furafylline, a new 1,3,8-trisubstituted xanthine
Authors: Segura Jordi , Garcia Inocencio , Tarrus Emili
Published: April 2011

After administration of furafylline, a, 1,3,8-trisubstituted xanthine, to beagle dogs at 0.5 and 10 mg kg−1 an elimination half-life 2–10 times longer than that of theophylline was observed. The kinetics were dose-dependent but no phase I metabolites were detected. When the compound was given orally to humans at a dose of 1.3–1.9 mg kg−1 a mean β elimination half-life of 48.1 ± 10.8 h was obtained after an initial distribution phase. Evidence of non-linear kinetics for plasma levels below 0.6 μg ml−1 was also obtained. Other 1,3,8-trisubstituted xanthines, may also have a lower elimination rate than theophylline.
The effect of media and other variables on the BP solution rate test for slow lithium carbonate tablets
Authors: Wall B P , Parkin J E , Sunderland V B
Published: April 2011

The British Pharmacopoeial test for assessing the solution rate of slow lithium carbonate tablets has been evaluated using ‘controlled release’ tablets containing 400 mg of lithium carbonate. No significant differences in lithium release were found when the volume of media used in the test was reduced from 250 ml to 200 ml, the final stage of the test in pH 6.8 phosphate buffer reduced from 5 to 3 h, the number of tablets in each thimble reduced from three to one, or the prescribed phosphate buffers replaced with phthalate and Tris, respectively. A four-fold increased concentration of phosphate in the phosphate buffers used resulted in a significant retardation in lithium solution rate. This was not attributable to an ionic strength effect but possibly to the formation of trilithium phosphate at the interface. Dissolution studies using the USP Basket Method showed a significantly slower release rate of one tablet into 900 ml of phosphate buffer compared with Tris buffer. This difference was markedly increased when three tablets were investigated in 200 ml of similar media. These differences were considered to be due to the formation of the much less soluble trilithium phosphate in the phosphate buffers.
Polysorbate 20 as a drug release regulator in ethyl cellulose film coatings
Authors: Lindholm Tuula , Lindholm Bengt-Åke , Niskanen Mervi , Koskiniemi Jaakko
Published: April 2011

Tablet coatings of hydrophobic ethyl cellulose have been made more hydrophilic by the addition of a non-ionic surfactant, polysorbate (Tween) 20, to the film. As its content increased, so did the release of sodium salicylate from the coated tablets. With a certain content of surfactant and specific thickness of the tablet coat, zero order release kinetics were observed. Leaching of the polysorbate 20 occurred from all formulations. Scanning and transmission electron micrographs showed that the structure of the coats consisted of several layers parallel to the tablet surface. Polysorbate 20 was seen as small drops in some coats.
Effect of urapidil on rat brain catecholamine synthesis
Authors: Pugsley T A , Myers S
Published: April 2011

The effects of urapidil, a clinically effective antihypertensive drug, on the in-vivo rate of synthesis of rat brain noradrenaline (NA) and dopamine (DA) was determined. A significant dose-dependent increase in dopa concentration by urapidil after dopa decarboxylase inhibition by NSD 1015 was observed in brain stem (3–30 mg kg−1 i.p.) and striatum (10–30 mg kg−1 i.p.), indicating increased NA and DA turnover, respectively, most probably a result of central blockade of brainstem α1-adrenergic and striatal DA receptors. These results indicate that urapidil may possibly exert its central hypotensive action in part by a reduced influence on brain stem NA, thus reducing central sympathetic outflow.
Does naloxone induce relaxation of guinea-pig airway smooth muscle?
Authors: Soulioti A M A , Leonard M , Rodger I W
Published: April 2011

The effects of the opiate receptor antagonist naloxone were investigated on isolated preparations of guinea-pig trachealis contracted with either histamine, methacholine or KC1. The commercially available solution of naloxone (Narcan) induced concentration-dependent relaxation of the contracted airway preparations. In stark contrast, aqueous solutions of naloxone were without any significant relaxant effect. Aqueous solutions of the preservatives (methyl and propyl hydroxybenzoate) present in the vehicle used in the commercial formulation of naloxone mimicked exactly the relaxant effects induced by Narcan. Thus, naloxone does not directly induce relaxation of airway smooth muscle. The effects of Narcan can be solely attributed to the activity of the preservatives present in the vehicles. The mechanism underlying the bronchodilator activity of methyl and propyl hydroxybenzoate is unknown but is not related to receptor blockade or to alterations in the intracellular levels of cyclic AMP.
Compounds extracted from feverfew that have anti-secretory activity contain an α-methylene butyrolactone unit
Authors: Groenewegen W A , Knight D W , Heptinstall S
Published: April 2011

Extracts of feverfew inhibit secretion of granular contents from platelets and neutrophils and this may be relevant to the therapeutic value of feverfew in migraine and other conditions. In this investigation we fractionated an extract of feverfew and obtained eleven fractions with anti-secretory activity. The active fractions, together with two fractions that were devoid of anti-secretory activity, were examined using 1H NMR and infrared spectroscopy. All the active fractions (but neither of the inactive fractions) contained compounds with an α-methylene butyrolactone unit. Five compounds that contain this unit were identified as parthenolide, 3-β-hydroxyparthenolide, secotanapartholide A, canin and artecanin, all of which are sesquiterpene lactones. It is very likely that these and other sesquiterpene lactones that contain an α-methylene butyrolactone unit are responsible for the anti-secretory activity in extracts of feverfew.
Antipyrine kinetics following partial blood exchange with Fluosol-DA in the rat
Authors: Shrewsbury Robert P , White Sonja G , POLLACK Gary M , Wargin William A
Published: April 2011

The effects of partial blood exchange with Fluosol-DA on hepatic microsomal oxidative metabolism have been studied in the rat. Antipyrine clearance (Cl) was used as an in-vivo measure of the activity of the mixed function oxidase system. Rats were partially exchanged with Fluosol-DA and dosed with antipyrine at selected time intervals following exchange. No change in antipyrine Cl was observed at 0.5 h, but there was a statistically significant decrease at 24 h and then an increase by more than 50% relative to control at 48 and 72 h. These data indicate that the effects of Fluosol-DA on hepatic function are time-dependent and that Fluosol-DA has the potential both to inhibit and to enhance hepatic metabolism. The possibility of altered hepatic metabolism should be considered when patients transfused with Fluosol-DA are given drugs primarily metabolized by the mixed function oxidase system.
Calculated and actual changes in β-adrenoceptor number associated with increases in rat and guinea-pig cardiac sensitivity
Authors: Chess-Williams Russell G , Broadley Kenneth J , Sheridan Desmond J
Published: April 2011

Chronic catecholamine depletion induced by reserpine pretreatment of rats, or 6-hydroxydopamine pretreatment of guinea-pigs, resulted in an enhanced sensitivity of isolated papillary muscles to isoprenaline. This hypersensitivity was accompanied by l.41-(rats) and 1.52-fold (guinea-pigs) increases in the number of [3H]dihydroalprenolol binding sites, without changes in binding affinity. An equation was derived for calculation of increases in receptor number. Application of this showed that substantially greater increases in receptor number were required (2.32- to 4.04-fold) to account for the degree of supersensitivity observed.
On the binding of cinmetacin and indomethacin to human serum albumin
Authors: Montero M T , Pouplana R , García S , Valls O
Published: April 2011

The binding of two non-steroidal anti-inflammatory drugs, indomethacin and cinmetacin, to human serum albumin was studied by dynamic dialysis at 37 °C and pH 7.4. Cinmetacin is bound more than indomethacin. The affinity constant for the primary binding site is 4.28 × 106 M−1 for cinmetacin and 1.4 × 106 M−1 for indomethacin. The protein binding of indomethacin is decreased in the presence of cinmetacin.
Functional evidence for altered activity of gabaergic receptors following chronic desipramine treatment in rats
Authors: Borsini Franco , Giuliani Sandro , Meli Alberto
Published: April 2011

The antinociceptive effect of subcutaneous 4,5,6,7-tetrahydroisoxazol[5,4-c]pyridin-3-ol (THIP) or (±)-baclofen, measured as reaction time of rats placed on a plate heated to 55 °C, was assessed after a single or the last repeated (18 consecutive days) dose (5 mg kg−1 once daily) of subcutaneous desipramine. Baclofen (10 mg kg−1)-induced antinociception was reduced by acute and unaffected by chronic desipramine treatment. On the contrary, THIP (20 mg kg−1)-induced antinociception was unaffected by acute and reduced by chronic desipramine.
α-Adrenoceptor blocking activity of fenoldopam (SK&F 82526), a selective DA1 agonist
Authors: Nakamura Shigeru , Kohli Jai D , Rajfer Sol I
Published: April 2011

The α-adrenoceptor blocking activity of fenoldopam (SK&F 82526), a selective dopamine vascular receptor (DA1) agonist, was evaluated in isolated segmental preparations of rabbit aorta, dog mesenteric and rabbit splenic arteries. Fenoldopam, in concentrations ranging from 10−6 to 10−4 M, produced parallel, dextral shifts of concentration-contractile response curves to noradrenaline. Slopes of the Schild regression lines were not significantly different from unity in the three vessels. pA2 values for fenoldopam in the rabbit aorta, dog mesenteric and rabbit splenic arteries were 5.48 ± 0.08, 5.78 ± 0.05, and 5.20 ± 0.05, respectively. In experiments where the drug was added to the bathing medium before exposing the vascular segments to the irreversible α-adrenoceptor antagonist, phenoxybenzamine, fenoldopam provided nearly complete protection against α-adrenoceptor blockade. These results demonstrate that fenoldopam possesses α-adrenoceptor antagonist activity and competes with α-phenoxybenzamine, for occupancy at the same receptor site.
Effect of some centrally administered putative amino acid neurotransmitters on carrageenan-induced paw oedema in rats
Authors: Bhattacharya S K , Sarkar M K
Published: April 2011

The possible modulatory effect of central amino acid neurotransmitters on carrageenan-induced paw inflammation has been investigated in rats. Eight putative amino acid neurotransmitters were administered intracerebroventricularly and their effect on the peripheral inflammation was noted. The inhibitory amino acid transmitters, GABA, glycine and taurine attenuated the peripheral oedema, while the excitatory amino acid transmitters, glutamic acid and aspartic acid had a pro-inflammatory effect. However, the other putative amino acid neurotransmitters, proline and alanine (inhibitory) and cysteic acid (excitatory) did not affect carrageenan-induced oedema.
Lack of effect of omeprazole, a potent inhibitor of gastric (H++ K+) ATPase, on hepatic lysosomal integrity and enzyme activity
Authors: Grinpukel Susan , Sewell Richard , Yeomans Neville , Mihaly George , Smallwood Richard
Published: April 2011

The substituted benzimidazole, omeprazole, is a potent inhibitor of the ATP-dependent proton pump of the parietal cell. Since there is accumulating evidence that hepatic lysosomes also possess an ATP-dependent proton pump system to maintain internal acidification, and since antibodies to the putative lysosomal proton pump protein are immunologically similar to the parietal cell (H+ + K+) ATPase, we studied the effects in rats of six days of omeprazole treatment on hepatic lysosomal function. Omeprazole, 5 mg kg−1, a dose five times the ED50 for gastric acid secretion inhibition in rats, did not alter the activity of three representative lysosomal enzymes in liver (acid phosphatase, β-galactosidase and N-acetyl-β-glucosaminidase) nor did it alter lysosomal enzyme latency, a measure of the integrity of the lysosomal membrane. Furthermore, bile flow and the secretion of lysosomal enzymes into bile were also unaffected by omeprazole. These data indicate that in rats short-term treatment with omeprazole, in doses that markedly inhibit gastric acid secretion, has no major biological effect on liver lysosomal integrity and lysosomal enzyme activity.
Correlation between in-vitro microsomal enzyme activity and whole organ hepatic elimination kinetics: analysis with a dispersion model
Authors: Roberts Michael S , Rowland Malcolm
Published: April 2011

A new model, the dispersion model of hepatic elimination, is applied to the correlation between in-vitro microsomal data and corresponding rat isolated perfused liver data for a number of drugs reported in the literature, whose extraction ratio varies over the range of 0.01 to 0.995. The dispersion model described the data better than either the ‘well-stirred’ model or the ‘parallel-tube’ model, two other widely used models of hepatic elimination. The experimental data support the concept that elimination of solutes is affected by is a considerable dispersion on passage through the liver.
The prediction of compatibility/incompatibility in blends of ethyl cellulose with hydroxypropyl methylcellulose or hydroxypropyl cellulose using 2-dimensional solubility parameter maps
Authors: Rowe R C
Published: April 2011

Typical two dimensional solubility parameter maps for ethyl cellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose have been constructed using literature data. The maps of the polymers showed some degree of overlap indicating some mutual compatibility. Compatibility between ethyl cellulose and hydroxypropyl cellulose was greater than between ethyl cellulose and hydroxypropyl methylcellulose. The maps may also be used to predict the effect of added plasticizers.
Polyalkyl cyanoacrylate nanocapsules
Authors: el-Samaligy M S , Rohdewald P , Mahmoud H A
Published: April 2011

In-situ polymerized methyl cyanoacrylate (MCA), ethyl cyanoacrylate (ECA), and butyl cyanoacrylate (BCA) were used to prepare nanocapsules of fluorescein or doxorubicin as markers by a w/o emulsion interfacial polymerization technique. Different concentrations of MCA were also used to show the effect of monomer concentration. The nanocapsules were characterized by electron microscopy, particle size analysis, holding capacity and in-vitro release of the marker substances. After selection of the polymerization solvent system, nearly spherical nanocapsules were obtained using each of the monomers. Most of the nanocapsules prepared were in the particle size range 500–1500 nm diameter. They were able to hold 55–74% of the marker initially present in aqueous solution. In-vitro dissolution studies showed that release of marker was retarded variably in an increasing order from nanocapsules containing MCA, ECA then BCA. Increasing the concentration of the monomer in the nanocapsules led to retardation of marker release.
Effect of thermal history on the glassy state of indapamide
Authors: Serajuddin Abu T M , Rosoff Morton , Mufson Daniel
Published: April 2011

The effects of thermal history, e.g. cooling rate, annealing, etc., on the thermal behaviour of indapamide glass were determined by differential scanning calorimetry (DSC). The glass was prepared by heating indapamide crystals (m.p. 162 °C) to 180 °C., and then cooling the melt to room temperature. The glass transition temperature (Tg) of the material was 98 °C. An endotherm, due to thermal relaxation of the glass, was observed in the DSC thermogram when indapamide glass was prepared by slow cooling or was annealed isothermally at a temperature below Tg. Such enthalpy relaxation may be observed during ageing of pharmaceutical glasses and might influence their physicochemical properties.
Enhanced serum concentrations of Ara-C using suppositories containing tetrahydrouridine as a deamination inhibitor of Ara-C
Authors: Liversidge G G , Nishihata T , Engle K K , Higuchi T
Published: April 2011

Rectal bioavailability of Ara-C (serum AUC 4 h: 65 μg h−1 ml−1) administered in a suppository formulation containing tetrahydrouridine (a deamination inhibitor) and sodium salicylate (an adjuvant) to dogs was better than that from a suppository formulation without tetrahydrouridine (serum AUC 4 h: 18 μg h−1 ml−1).
Isoprenaline-induced changes in activity of the endogenous inhibitor of cAMP-dependent protein kinases under conditions of β-adrenoceptor supersensitivity
Authors: Zawilska J , Szmigielski A
Published: April 2011

Isoprenaline-induced changes in activity of an endogenous, specific inhibitor of cAMP-dependent protein kinases (type I inhibitor) under conditions of experimental supersensitivity of β-adrenoceptors were investigated in rat hippocampus and brain stem. Both subchronic administration of reserpine (2.5 mg kg−1, i.p., 4 days, once daily) and i.c.v injections of 6-hydroxydopamine (250 μg/ventricle, bilaterally, 48 h apart), which are known to increase β-adrenoceptor sensitivity in the rat brain, markedly enhanced the response of the type I inhibitor activity to isoprenaline. To obtain a significant decrease of type I inhibitor activity in the examined brain structures of these animals, doses of isoprenaline 2–5 times lower than in control groups had to be used. It is suggested that the isoprenaline-induced decrease of type I inhibitor activity might be used as an index of central β-adrenoceptor reactivity in-vivo.
The formation and characterization of hydrocortisone-loaded poly((±)-lactide) microspheres
Authors: Cavalier M , Benoit J P , THIES C
Published: April 2011

The solvent evaporation process has been used to form hydrocortisone-loaded microspheres from poly((±)-lactide) (PLA) and a lactide-glycolide copolymer (65/35). Methylene chloride was the casting solvent. Partially hydrolysed (88%) poly(vinyl alcohol) and methylcellulose were used as aqueous phase emulsifiers. Methylcellulose was preferred, because it gave stable emulsions as the amount of hydrocortisone being encapsulated increased whereas poly(vinyl alcohol) did not. With methylcellulose as the emulsifier, a broad size range of spherical microspheres containing up to 50% (w/w) hydrocortisone could be prepared. Thermal and X-ray analyses established that poly((±)-lactide) microspheres containing hydrocortisone retained thermal events characteristic of both materials. This is evidence that such microspheres contain, to some extent, crystalline hydrocortisone domains dispersed in a PLA matrix. But most of the encapsulated drug was molecularly dispersed in the PLA glass. The stability of hydrocortisone in microspheres was evaluated in different storage conditions: no degradation of drug was found. The release of hydrocortisone from 250–350 μm diameter microspheres into agitated 37°C water (nitrogen atmosphere) was determined by HPLC analysis. The microspheres evaluated had initial hydrocortisone payloads of 12 to 47% (w/w). The rate of drug release increased as the initial drug payload carried by the microspheres increased. The release data are not adequately described by zero order, first order, or square-root-of-time release kinetics. Drug release from microspheres that contain 12% (w/w) hydrocortisone approached a plateau value well below the amount of drug actually carried by the microspheres. This is particularly true for hydrocortisone encapsulated in lactide-glycolide polymer.
The role of lipid peroxidation in acute doxorubicin-induced cardiotoxicity as studied in rat isolated heart
Authors: Julicher R H M , Sterrenberg L , Bast A , Riksen R O W M , Koomen J M , Noordhoek J
Published: April 2011

Doxorubicin induces an acute cardiotoxicity that becomes manifest in isolated hearts as a deterioration in mechanical function. The oxidative component in this myocardial damage has been investigated. The effects of doxorubicin on the activity of superoxide dismutase and the capacity of the glutathione system, factors of the cellular protective mechanism against free radicals, were examined in rat isolated heart. Doxorubicin was found to reduce the capacity of the protective mechanisms. Whether oxidative membrane damage due to excessive free radical formation plays a role in the pathogenesis of the acute cardiotoxic action of doxorubicin was also examined. Its acute effect on myocardial contraction amplitude, frequency of beating, coronary flow and on the above mentioned biochemical parameters was compared in rat hearts sufficient or deficient in vitamin E. Peroxidation of lipids was measured as the formation of malondialdehyde, one of the final products of this process. Vitamin E deficiency neither aggravated the decrease in the capacity of the cellular protective factors nor worsened the reduction in myocardial function. Nor did induction of lipid peroxidation by doxorubicin occur in vitamin E-deficient hearts. It was concluded that lipid peroxidative damage most probably is not decisive in the development of the acute cardiomyopathy in rats.
Monoamine oxidase activities in dissociated cell fractions from rat skeletal muscle
Authors: Lyles Geoffrey A , Archer David R
Published: April 2011

Collagenase was used to dissociate rat skeletal muscle (gastrocnemius) into its constituent cells, from which a myocyte fraction enriched in striated muscle cells, and a non-myocyte fraction containing cells of connective tissue and vascular origin, were prepared. The activities of amine oxidase enzymes and alkaline phosphatase (AP) were then assayed in these fractions, and also in homogenates prepared from corresponding samples of non-dissociated tissue. The specific activities of the semicarbazide-sensitive amine oxidase (SSAO) and AP were considerably higher (30 to 35-fold) in non-myocyte than in myocyte fractions. AP is generally considered to be present predominantly in vascular cells of skeletal muscle, with little, if any, in skeletal muscle cells themselves. Thus, the results obtained may indicate a similar localization for SSAO activity. Support for this came from histochemical studies, which showed staining for SSAO primarily over the walls of larger blood vessels in the muscle. Unlike SSAO and AP, were marked differences in MAO-A activity between myocyte and non-myocyte fractions were not found, suggesting that MAO-A is more probably a constituent of cells within both fractions.
Pulmonary absorption of carboxyfluorescein in the rat
Authors: Woolfrey S G , Taylor G , Kellaway I W , Smith A
Published: April 2011

The pulmonary absorption of the fluorescent marker 6-carboxyfluorescein (CF) has been characterized. CF was administered intratracheally (i.t.) as a fluid instillate to pentobarbitone-anaesthetized rats at doses of 0.5 and 2 mg kg−1. The absorption was characterized by both model-independent and model-dependent pharmacokinetic analyses of blood concentration data with reference to previous intravenous (i.v.) studies. The mean fraction available (F) of CF was 90 and 112% with a mean absorption time of 107 and 109 min for the lower and higher doses, respectively. The terminal half-life for the i.t. administered CF (73 and 83 min for the 0.5 and 2 mg kg−1 doses, respectively) was significantly longer (P < 0.001) than after i.v. dosing (18 min). This indicates a slow pulmonary absorption of CF. Blood concentration-time profiles could not be adequately described by models involving a simple first-order absorption process; a model incorporating two simultaneous first-order inputs gave a much better description, its absorption rate constants differing by almost two orders of magnitude.
Autonomic regulation involved in the ocular hypotensive action of (β-adrenergic blocking agents
Authors: Alkondon M , Ray A , Sen P
Published: April 2011

The effects of racemic propranolol and some related drugs on the intraocular pressure (IOP) were studied after topical application in rabbits. These drugs produced a significant reduction in IOP with the following order of potency: (−)-propranolol > timolol > (±)-propranolol > sotalol > (+)-propranolol > pranolium. Pretreatment of rabbit eyes with atropine significantly antagonized the ocular hypotensive action of (±)-propranolol, timolol and pranolium. Both (±)-propranolol and timolol produced a significant increase in pupil diameter in the presence of a submydriatic dose of atropine. The activities of monoamine oxidase and carbonic anhydrase were unaffected by (±)-propranolol, timolol and pranolium in-vitro. It is concluded from the results that both cholinergic and adrenergic mechanisms may be involved in the ocular hypotensive effects of the drugs.
The effect of temperature on the plasto-elasticity of some pharmaceutical powders and on the tensile strengths of their tablets
Authors: Esezobo S , Pilpel N
Published: April 2011

Measurements have been made of the stress relaxation (SR) during, and of the elastic recovery (ER) after, compression of four directly compressible excipients, and of chloroquine diphosphate and of a paracetamol tablet formulation at temperatures between −10 and +65 °C and of the tensile strengths of the tablets produced. It was found that at a fixed packing fraction, the stress relaxation and tensile strength of all the materials increased and the ratio ER/SR decreased as the compression temperature was raised. Tensile strength was inversely proportional to ER/SR at all the temperatures studied. Values for the activation energies (Eo) of bonding between particles for all the materials were derived from plots of the log of tensile strength and of log SR/ER versus the reciprocal of the absolute temperature. The values of Eo obtained from the latter plots tended to be higher than from the former by a factor of between 1.5 and 4.5.
Characterization of in-vitro drug release and biological activity of methotrexate-bovine serum albumin conjugates
Authors: Halbert G W , Florence A T , Stuart J F B
Published: April 2011

Two series of methotrexate (MTX)-bovine serum albumin (BSA) conjugates have been prepared containing either 96 ± 16 mg (mean ± s.d.) or 32 ± 13 mg of MTX per gram of conjugate. The conjugates released MTX in-vitro in a biphasic manner, the release rate being dependent on the quantity of MTX in the conjugate and on the pH of the release medium. An initial rapid release over 6 h appears to be due to physically adsorbed MTX with the slower secondary release due to covalently bound drug. The conjugates retain a degree of antineoplastic activity in-vitro, but this might be related to the small fraction of MTX that is tightly physically bound.
Auranofin inhibits the active uptake of bile acid by rat ileum
Authors: Hardcastle J , Hardcastle P T , Kelleher D K
Published: April 2011

Auranofin in the mucosal fluid inhibited the active Na+-dependent absorption of taurocholic acid by everted sacs of rat ileum. It did not however, affect the passive uptake of taurocholic acid by sacs of mid-intestine. The inhibition by auranofin of active bile acid absorption could result from its previously demonstrated ability to inhibit Na+, K+-ATPase activity. A reduction in the reabsorption of bile acids by the ileum may contribute to the diarrhoea experienced by some patients taking auranofin.
Effect of moderate haemodilution with Fluosol-DA or normal saline on low-dose phenytoin and (±)-5-(4-hydroxyphenyl)-5-phenylhydantoin kinetics
Authors: Shrewsbury Robert P , Lewis Lee M , Oliver Sharon R
Published: April 2011

Phenytoin kinetics were determined in the rat following moderate (50%) blood exchange with either Fluosol-DA or normal saline. Rats received an intravenous phenytoin dose (10 mg kg−1) 0ṁ5, 24, 48, or 72 h after exchange and were compared with non-exchanged controls. Phenytoin t1/2 was not altered by exchange with either fluid. Its Cl and Vd were decreased and AUC increased 24, 48, and 72 h after saline exchange and 24 h after Fluosol-DA exchange. (±)-5-(4-Hydroxyphenyl)-5-phenylhydantoin (HPPH), a major metabolite of phenytoin, showed a decreased t1/2 and VHPPH 24, 48, and 72 h after exchange with either fluid; t1/2 was also reduced 0ṁ5 h after Fluosol-DA exchange. The decreased Vd and VHPPH may result from changes in cardiac output secondary to haemodilution, or may represent a redistribution in the microcirculation. Fluosol-DA appears to enhance phenytoin and HPPH metabolism 48 and 72 h after exchange.
Interactions of trimebutine with guinea-pig opioid receptors
Authors: Roman François , Pascaud Xavier , Taylor John E , Junien Jean-Louis
Published: April 2011

Affinities of trimebutine (TMB) and N-desmethyl trimebutine (NDTMB) for mu, delta and kappa opioid receptor subtypes have been examined using specific 3H-ligands and guinea-pig membrane. TMB and NDTMB showed a relative higher affinity for the mu receptor subtype although they were, respectively, 30-and 48-fold less active than morphine. The receptor selectivity index for mu, delta and kappa were 100:12:14ṁ4 for TMB, 100:32:25 for NDTMB and 100:5:5 for morphine. The sodium shift ratio was 14 for TMB, 10 for NDTMB and 37 for morphine. These data show that (unlike morphine, a pure mu agonist) TMB and NDTMB can be classified as weak opioid agonists and confirm that peripheral opioid receptors mediate their gastrointestinal motility effects.
Effect of age on gastrointestinal and hepatic first-pass effects of levodopa in rats
Authors: Iwamoto Kikuo , Watanabe Jun , Yamada Mika , Atsumi Fumie , Matsushita Tomoko
Published: April 2011

Presystemic elimination of levodopa (20 mg kg−1) has been studied in 5- to 104-week-old male Wistar rats. The gastrointestinal and hepatic contribution to the overall first-pass effect was estimated separately after the drug had been administered intravenously, orally and intraportally. The contribution of the gut to the overall first-pass effect of this drug was greater than that of the liver in any age-group of the rats. Both the overall and intestinal first-pass effects of levodopa were greatest in 11-week-old rats and relatively small in both young (between weeks 5 and 7) and aged (between weeks 52 and 104) rats. In contrast, the hepatic first-pass effect did not show any significant age-dependent change. Age-related change in the jejunal blood flow could not explain the unique age-dependence in the intestinal first-pass metabolism of levodopa. However, the present age-dependence in the oral systemic availability of this drug between adult (11 weeks) and aged (52 to 104 weeks) rats was found to be similar to the tendency that has been reported between normal adult subjects and aged patients with Parkinson's disease.
The differential cytotoxicity of antiseptic agents
Authors: Blenkharn J I
Published: April 2011

The cytotoxicity of the antiseptic agents noxythiolin and chlorhexidine has been evaluated in-vitro using a range of tissue culture cell lines of differing degrees of neoplasticity. Noxythiolin appeared more cytotoxic than did chlorhexidine when tested against established neoplastic cell lines. By contrast, noxythiolin was not cytotoxic to normal control (non-neoplastic) cells. For chlorhexidine, the cytotoxic activity against control cells was similar to that observed for neoplastic cell lines. The results confirm an earlier observation of limited antitumour activity of noxythiolin solutions and, on the basis of differential cytotoxicity, confirm that noxythiolin is free from adverse effects against normal tissues and is safe for use as an antimicrobial agent applied to peritoneal surfaces and the healing wound.
Water distribution in creams prepared using cetostearyl alcohol and cetrimide
Authors: Rowe R C , Bray D
Published: April 2011

The water distribution in an antiseptic cream formulation prepared using cetostearyl alcohol and cetrimide has been studied using thermogravimetric analysis, differential scanning calorimetry, ultracentrifugation and scanning electron microscopy. In addition to a free water phase two types of interlamellarly fixed water were found, one associated with the liquid crystalline network around the oil droplets and one associated with the liquid crystalline network of the bulk. The latter was in equilibrium with the free water and can be classed as freely drainable.
The biliary excretion of acenocoumarol in the rat: stereochemical aspects
Authors: Thijssen H H W , Baars L G M
Published: April 2011

Within 24 h, 50% of a single dose of the acenocoumarol enantiomers was recovered in bile and 20% in urine of Wistar rats. The elimination products were mainly (>90%) the 6- and 7-hydroxyacenocoumarol as conjugates in the bile but free in the urine. Only R-acenocoumarol, free and conjugated, was excreted in bile. There were no gross differences between the enantiomers in metabolic pattern or in the amount of metabolites formed. A significant difference was observed for the biliary excretion of the 7-hydroxy metabolite; the ratio of free and conjugated 7-hydroxyacenocoumarol was three times higher for the S-than for the R-isomer. An unknown third metabolite was recovered in bile in higher amounts with the S- than with the R-acenocoumarol. Only traces of this metabolite were recovered from urine. The data show an extensive biliary excretion of acenocoumarol and demonstrate stereoselective mechanisms in the excretion processes.
Stereoselective blockade of central [3H]5-hydroxytryptamine binding to multiple sites (5-HT1A, 5-HT1B and 5-HT1C) by mianserin and propranolol
Authors: Alexander Beverley S , Wood Martyn D
Published: April 2011

The interaction of the enantiomers of mianserin and propranolol with the binding of [3H]5-hydroxytryptamine ([3H]5-HT) to the 5-HT1A, 5-HT1B and 5-HT1C sites, and with the binding of [3H]ketanserin to the 5-HT2 site, has been evaluated in rat brain membranes. A stereoselective interaction at the 5-HT1A, 5-HT1B and 5-HT1C sites was demonstrated for both compounds, with (-)-mianserin being a more potent displacer than (-)–mianserin and (-)-propranolol being more potent than (+)-propranolol. Only mianserin interacted in a stereoselective manner with the 5-HT2 site, (+)-mianserin being the more potent isomer. The stereoselective association of mianserin and propranolol with the 5-HT1A, 5-HT1B and 5-HT1C sites may prove useful in the characterization of these sites.
Gastric ulcerogenicity of non-steroidal anti-inflammatory drugs in mice with mucosa sensitized by cholinomimetic treatment
Authors: Rainsford K D
Published: April 2011

A novel technique is described for the assay of acute gastric irritancy of non-steroidal anti-inflammatory drugs (NSAIDs) in mice in which (a) the gastric mucosa is sensitized to the irritant actions of the drugs by coadministration of bethanechol chloride to increase acid and pepsin production, and (b) the area and number of haemorrhagic lesions in the glandular mucosa is measured quantitatively by visual image analysis. The technique has been used to assess the acute gastric irritancy of 20 NSAIDs in mice. In relation to published values for their acute and chronic anti-inflammatory activities, drugs with low relative gastric irritancy (e.g. carprofen, chloroquine, diclofenac, fenbufen, tenoxicam, tilomisole) were differentiated from the drugs of higher relative irritancy.
A quantitative assessment of the reactivity of the fatty alcohols with cetrimide using immersion calorimetry
Authors: Rowe R C
Published: April 2011

The reactivity of the fatty alcohols with cetrimide has been quantitatively assessed using immersion calorimetry. In all cases the reaction was endothermic i.e. it had a positive enthalpy. For the n-alcohols the reactivity, as evaluated by the rate of enthalpy change, decreased with increasing chain length although branching on the tetradecanol and hexadecanol resulted in a higher reactivity. Adding 1-octadecanol to 1-hexadecanol resulted in an increased reactivity rising to a maximum for mixtures containing 20–40% w/w 1-octadecanol. The results have been interpreted in terms of the polymorphic form of the alcohol.
The effect of digoxin dosage on the digoxin—quinidine interaction in the bile duct-cannulated rat
Authors: Hewick D S , Ostenfeld T
Published: April 2011

Pretreating anaesthetized bile duct-cannulated rats with 9 mg kg−1 quinidine significantly decreased the cumulative biliary excretion of digoxin and its metabolites after 10 or 100 μg kg−1 [3H]digoxin, although the effect was more marked in animals receiving the high dose of digoxin. In contrast, however, although quinidine pretreatment raised plasma radioactivity levels by 50–80% in animals given the higher dose of digoxin, no significant effect on circulating plasma levels was observed in rats receiving 10 μg kg−1 digoxin. Generally, quinidine had no statistically significant effect on other aspects of digoxin disposition, although with both digoxin doses there were trends towards a reduction in the direct intestinal secretion and urinary excretion of digoxin-derived radioactivity with an increase in tissue levels of radioactivity (apart from the small intestine wall where concentrations were reduced). The radioactivity in the bile after 100 or 10 μg kg−1 digoxin comprised about 25 and 33% of digoxin and digoxigenin bis-digitoxoside, respectively, as well as appreciable amounts of the mono-digitoxoside and a highly polar component. This metabolite profile was unaffected by quinidine. The influence of cardiac glycoside dosage shown by the present work indicates that the digoxin—quinidine interaction and possibly analogous interactions involving other cardiac glycosides, may not always be readily detectable from plasma concentration data.