bluuebunny/crossref_metadata_2025 huggingface dataset:
An HPLC assay procedure of sensitivity and stability for measurement of acetylcholine and choline in neuronal tissue
Authors: Barnes N M , Costall B , Fell A F , Naylor R J
Published: April 2011

A method is presented for the sensitive and specific determination of acetylcholine and choline in neuronal tissue. The method is based on the separation of acetylcholine and choline by reversed-phase HPLC, passing the eluent into a post-column reactor containing choline oxidase and acetylcholinesterase covalently bound to vinyl sulphone bonded onto a hydroxyethyl methacrylate support, and electrochemical detection of the hydrogen peroxide formed. The limit of detection of the procedure is 1 pmol for acetylcholine and 500 fmol for choline. The excellent baseline stability of the method ensures the rapid and reliable processing of a large number of samples.
The effect of blending time on particle adhesion in a model interactive system
Authors: Kulvanich Poj , Stewart P J
Published: April 2011

The adhesive tendency of drug particles in a model drug carrier interactive system increased with blending time. The degree of interaction was measured using a centrifuge technique; the resultant adhesion profile of per cent retained on the carrier versus the square of the speed of rotation was a logarithmic normal function that allowed the determination of the S50 to characterize the adhesion tendency. The relative degree of adhesion of the drug particles in the interactive mixtures and the rate to attain adhesion saturation in the interactive system during the mixing process was markedly different for the three mixtures studied. The increased adhesive tendencies during blending were probably associated with triboelectrification of the drug and carrier particles.
Lack of inotropic selectivity of phosphodiesterase enzyme inhibitors in-vitro
Authors: Smith George W , Hall Janet C , West Philip A
Published: April 2011

Phosphodiesterase enzyme (PDE) inhibitors form a diverse category of chemical structures which display positive inotropic activity, but it is unclear as to how force/rate selective these are on the heart. In this study several recently developed PDE inhibitors, almost all of which are selective for the cardiac PDE III isoenzyme, were compared with the xanthine PDE inhibitor IBMX and with ouabain and the direct and indirect adenylate cyclase activators, forskolin and isoprenaline, respectively. These compounds were active in increasing paced guinea-pig left atrial force, the order of potency being: isoprenaline > ouabain > forskolin > pimobendan > IBMX > sulmazole > buquineran > carbazeran > milrinone > piroximone > amrinone. Ro 13-6438 and enoximone were however, both inactive. With the exception of buquineran and carbazeran, which produced bradycardia and were therefore force specific, all of the recently discovered PDE inhibitors increased the rate of contraction of the right atria and they were rate selective to the same extent as IBMX, isoprenaline and forskolin. Sulmazole, the only force selective PDE inhibitor of the compounds studied, was intermediate between IBMX and ouabain in force/rate selectivity and pimobendan showed no selectivity. Since both these agents also possess other actions, then these results suggest that in general, PDE III inhibitors do not show advantageous force selectivity in guinea-pig atria.
Coprecipitation of Enzymes with Water Soluble Starch—An Alternative to Freeze-drying
Authors: Randén Lennart , Nilson Jerker , Edman Peter
Published: April 2011

Krill proteases were prepared in solid form from a partially purified extract by coprecipitation of the enzymes with water-soluble starch in an organic solvent at 22°C. The precipitation did not affect the activity of the enzymes. The recovery of proteolytic activity was 100%. The thermostability of the krill proteases increased when incorporated in the starch precipitate. No reduction in enzymatic activity could be seen after storage at +50°C for 99 days. After milling the coprecipitate could be dispensed. The enzyme preparation consisted of irregular needle-shaped particles. This simple precipitation technique offers an alternative to freeze-drying or spray-drying.
Binding of Organic Cations to Brush Border Membrane from Rat Small Intestine
Authors: Saitoh Hiroshi , Kawai Shinji , Iseki Ken , Miyazaki Katsumi , Arita Takaichi
Published: April 2011

The binding of six organic cations (chlorpromazine, promethazine, imipramine, diphenhydramine, methochlorpromazine and propantheline) to the brush border membrane isolated from rat small intestine has been investigated. The cations were bound to the membrane to varying extents, the order of binding being chlorpromazine > promethazine > methochlorpromazine > imipramine > propantheline > diphenhydramine. There was no relation between binding and the chloroform-water partition coefficient. Chlorpromazine binding was significantly decreased in the presence of imipramine, methochlorpromazine and propantheline. Anionic compounds (indomethacin and xanthene-9-carboxylic acid) did not affect chlorpromazine binding. High and low affinity binding of the cations to the intestinal brush border membrane was demonstrated with Scatchard plots and Hill plots. Imipramine and methochlorpromazine inhibited chlorpromazine binding at both binding sites. From the results, it was suggested that the organic cations tested were specifically bound to common binding sites on the brush border membrane.
Application of difference spectroscopy to the determination of some pharmaceutically important nitro compounds
Authors: Hassan S M , El-Din M Sharaf , Belal F , Sultan M
Published: April 2011

A simple and selective spectrophotometric method for the determination of some pharmaceutically important nitro compounds has been developed. The suggested method depends upon the spectral changes induced by reduction using either Zn/HCl or Zn/NH4Cl. The different experimental parameters were studied and incorporated into the procedure. The mean percentage recovery ranged from 99 to 101. The proposed method was applied to the determination of the studied compounds in dosage forms, and the results obtained were compared favourably with those given with the compendial ones.
Uterine inhibitory effect of reticuline
Authors: Martin M L , Sagredo J A , Morais J M , Montero M J , Sanchez M T , Roman L San
Published: April 2011

Reticuline, the most abundant benzylisoquinoleic alkaloid of Laurobasidium lauri, exerts a uterine inhibitory effect mainly related to a decrease in the concentration of cytosolic calcium available for contraction.
The in-vitro percutaneous absorption of glycerol trioleate through hairless mouse skin
Authors: Moloney Stephen J
Published: April 2011

The chemical composition of the aqueous receptor fluid in one-chambered diffusion cells used for in-vitro percutaneous absorption studies has been shown to significantly affect the apparent extent of absorption of the triglyceride, glycerol trioleate. Using murine skin samples it was found that the addition of albumin to the receptor fluid resulted in an increase in the apparent extent of absorption, while the presence of the bacteriostatic agent thiomersal resulted in a decrease. The viability of the skin samples had no effect on absorption. It was determined that the chemical species in the receptor fluid was the free fatty acid. Albumin presumably bound the fatty acid, therey creating a sink which enabled the fatty acid to partition from the skin into the receptor fluid.
Effect of Butylated Hydroxyanisole on Hepatic Glucuronidation and Biliary Excretion of Drugs in Mice
Authors: Gregus Zoltan , Klaassen Curtis D
Published: April 2011

Inhibition of glucuronidation by depletion of UDP-glucuronic acid from liver impairs the hepatobiliary transport of glucuronidated xenobiotics. However, it is not known if enhancement of hepatic glucuronidation increases the biliary excretion of these compounds. Therefore, the effect of treatment with butylated hydroxyanisole (BHA), which increases hepatic glucuronidation capacity, on the biliary excretion of compounds undergoing glucuronidation was studied in mice. BHA-feeding (1% for 10 days) increased hepatic UDP-glucuronic acid content by 240% and enhanced hepatic UDP-glucuronosyltransferase activities (expressed per kg body weight) toward valproic acid, phenolphthalein, iopanoic acid and bilirubin 220, 180, 120 and 60%, respectively. BHA treatment did not influence the biliary excretion of unmetabolized cholephils, phenol-3,6-dibromphthalein disulphonate and phenolphthalein glucuronide, but enhanced that of phenolphthalein (+108%), iopanoic acid (+63%) and bilirubin (+33%) as glucuronides. However, these increases were apparent only in the initial phase of excretion. In contrast, BHA markedly decreased (−43%) the biliary excretion of valproic acid glucuronides. Simultaneously, BHA increased the urinary excretion of the glucuronides of phenolphthalein (+48%), iopanoic acid (+450%) and valproic acid (+150%). A shift in the distribution of iopanoic acid and valproic acid and metabolites from liver to kidney was also apparent in BHA-fed mice. Thus, enhanced glucuronidation does not facilitate the biliary excretion of all glucuronidated compounds and only transiently increases others. It is likely that this phenomenon is the result of the glucuronides readily entering the plasma and being excreted by the kidney.
Biochemical Characterization of a New Highly Cardioselective β-Adrenoceptor Antagonist
Authors: Gobbi Marco , Mennini Tiziana , Ratti Emiliangelo
Published: April 2011

P0160 (1-phenyl-3-(2-(3-(2-cyanophenoxy)-2-hydroxypropyl)amino) ethylhydantoin HCl) is an aryloxypropanolamine which contains a ureido group as part of the hydantoin ring. This molecule was synthesized to obtain a more cardioselective β-adrenoceptor blocker. Preliminary data have shown that it is as potent as propranolol and four times more cardioselective than atenolol in pharmacological tests in-vitro and in the conscious rat. In the present study we evaluated the interaction of P0160 with β-adrenoceptors by radioreceptor binding studies and by measuring adenylate cylase activity coupled to β-adrenoceptors. The data indicate that P0160 binds with nanomolar affinity to β-adrenoceptors labelled with [3H]DHA in the rat heart, but with micromolar affinity in the rat lung. Its binding is stereospecific, the S-(−)isomer being 200 times more active than the R-(+) form. P0160′s selectivity between cardiac β1- and β2-receptors was 1388, about 60 times that for metoprolol. Analysis of the thermodynamic characteristics of P0160′s interaction with rat heart β-adrenoceptors indicated antagonist properties of the same order of magnitude as propranolol, as confirmed by adenylate cyclase studies. These data indicate that P0160 is a potent, specific and selective β1-adrenoceptor antagonist, and give a molecular explanation for the cardioselective activity found in pharmacological tests.
The Use of a Perfluorochemical Emulsion as a Vascular Perfusate in Drug Absorption
Authors: Takahashi Hideaki , Nishikawa Masahiko , Hayashi Masahiro , Awazu Shoji
Published: April 2011

In-vitro simultaneous luminal and vascular perfusion using the perfluorochemical emulsion, FC-43 emulsion, as a vascular perfusate, was examined for drug absorption in rat jejunum. The intestinal membrane in this system was found to retain its normal barrier functions for drug transport, as evident from the following: (i) stable absorption clearance of tritiated water and salicylic acid at steady-state, (ii) agreement of this clearance with that by in-situ single-pass luminal perfusion, (iii) active transport of D-glucose and its inhibition by phloridzin and (iv) normal glutamate pyruvate transaminase activity in the intestinal mucosa. FC-43 emulsion gave a more normal absorption site blood flow than the usual vascular perfusate containing erythrocytes and albumin in Krebs-Henseleit bicarbonate buffer solution. Consequently, this emulsion was useful for examining the contribution of blood flow resistance toward drug absorption. The rate-limiting steps of absorption of tritiated water, antipyrine and salicylic acid were examined by perfusion using FC-43 emulsion. The absorption of tritiated water was almost completely blood flow-limited and its absorption clearance may possibly be an approximated absorption site blood flow. The contribution of blood flow resistance to total resistance for antipyrine absorption exceeded that for salicylic acid absorption.
Increase in Mouse Brain Regional Noradrenaline Turnover after L-Dopa Administration
Authors: Gibson Candace J
Published: April 2011

Noradrenaline (NA) and its major metabolite, 3-methyl-4-hydroxyphenylethylene glycol (MHPG) were measured by HPLC with electrochemical detection in five mouse brain regions after L-dopa treatment. Noradrenaline concentration increased significantly, by 30–40%, in the three terminal regions of the locus coeruleus; cortex, hippocampus and cerebellum, but did not change in hypothalamus and brainstem. In mice whose central NA levels had been depleted by prior treatment with the neurotoxin, DSP-4, remaining NA neurons in these terminal regions were still able to respond with an increase in NA after L-dopa loading. The NA metabolite, MHPG, increased several-fold in all five regions in both saline and DSP-4-pretreated mice. Thus, L-dopa may be a useful precursor of NA in specific brain regions, particularly when NA is depleted.
The Response of the Intestinal Mucosa to Prostaglandin E2 during Withdrawal from Morphine
Authors: Coupar Ian M , Hardcastle Jacqueline , Hardcastle Peter T
Published: April 2011

Experiments were designed to determine whether the diarrhoea characteristic of morphine withdrawal results from an enhanced sensitivity of the intestinal mucosa to PGE2. Rats (250–300 g) were made morphine-dependent by subcutaneous injection of an emulsion releasing 300 mg morphine HCl over 48 h. In-vivo, the transintestinal potential difference (PD) responses to PGE2 (4.6–46 μg kg−1 i.v.), which reflect increased Cl secretion, were significantly larger in withdrawn (morphine emulsion, 10 mg kg−1 naloxone s.c.) compared with non-dependent animals (emulsion only, naloxone s.c, P < 0.05). Muscle-stripped intestinal sheets from dependent animals incubated with naloxone (10−5 mol L−1) in-vitro did not demonstrate a greater electrical response (PD, short circuit current) to PGE2 (1.4 × 10−6 mol L−1) than sheets taken from non-dependent animals. In-vitro preparations from animals withdrawn in-vivo did not respond differently from tissue taken from non-dependent animals (naloxone 10 mg kg−1 s.c, 10−4 mol L−1 in medium, in both groups). This occurred in whole sheets of intestine as well as sheets without attached muscle. Jejunal fluid absorption in-vivo was lower in withdrawn animals than in non-dependent animals. However, the responses to intra-arterial infusion of PGE2 were similar in both groups with 2 μg min−1 inhibiting absorption and 4 μg min−1 inducing secretion. In-vivo, PGE2-induced Cl secretion appears to be enhanced during withdrawal although net fluid transport is not altered, suggesting different effects of the withdrawal process on the electrogenic Cl secretory and neutral NaCl absorptive mechanisms.
Inhibitory Effect of Glycyrrhetinic Acid Derivatives on Arachidonic Acid-induced Mouse Ear Oedema
Authors: Inoue Hideo , Mori Takeo , Shibata Shoji , Koshihara Yasuko
Published: April 2011

The inhibitory effects of glycyrrhetinic acid and its derivatives were examined on arachidonic acid (AA)-induced ear oedema in mice. Of the compounds, dihemiphthalate derivatives of 18β-olean-12-ene-3β, 30-diol (IId, IId′), 18β-olean-9(11)12-diene-3β, 30-diol (IIIa, IIIa′) and olean-11,13(18)-diene-3β, 30-diol (IVa, IVa′) showed a strong inhibition of ear oedema on both topical (ID50, 1.9, 2.8 and 1.7 mg/ear, respectively) and oral (ID50, 90, 130 and 88 mg kg−1, respectively) administration. Topical ID50 values were approximately the same potency as nordihydroguaiaretic acid (ID50, 2.1 mg/ear). Given topically these compounds were also capable of inhibiting PGE2 and LTC4 formation at an early stage of AA-induced ear oedema. However, glycyrrhetinic acid (Ia) and deoxoglycyrrhetol (IIa), the fundamental skeletons of the derivatives, showed no detectable inhibition of oedema at a dose of 1 mg/ear (topical) or 200 mg kg−1 (oral). The most effective time for the topical administration of the compound IId against ear oedema was 0–30 min before AA application; this is different from dexamethasone which requires a time lag for reaction. The results suggest that the inhibitory effect of the hemiphthalate compounds (IId, IId′, IIIa, IIIa′, IVa and IVa′) is a direct action, and does not involve the anti-inflammatory action of steroids mediated by the secondary formation of a reactive protein.
Pharmacokinetic evaluation of local drug delivery: the intratesticular and intrarenal administration of acenocoumarol in the rat
Authors: Daemen M J A P , Vervoort-Peters H T M , Thijssen H H W
Published: April 2011

According to theory, the regional increase in drug concentration during target organ directed drug delivery as compared with systemic drug delivery is related to the quotient of the clearance of the drug and the blood flow of the target organ. We investigated the steady-state pharmacokinetic disposition of S-acenocoumarol in plasma, liver, testis, and kidney following its administration (constant rate infusion by an osmotic minipump) directly into the testis or the kidney of rats. The effects of clearance induction (phenobarbitone treatment) on the disposition of the drug were also investigated. The results confirm the theory of target-directed drug delivery.
Binding studies on two functional cardioselective antimuscarinic compounds
Authors: Choo L K , Mitchelson F
Published: April 2011

Vecuronium and himbacine are antimuscarinic compounds which in functional studies exhibited a ca 6- and 10-fold higher potency at cardiac muscarininc receptors than at ileal muscarininc receptors. However in binding studies both compounds failed to differentiate between [3H](−)-QNB binding sites in guinea-pig atrial and ileal muscle homogenates. In the latter experiments, the dissociation constants of vecuronium in atria and ileum and that of himbacine in ileum were lower than the values determined functionally. The basis for the lack of cardioselectivity in binding studies is not known. These compounds add to the list of functional cardioselective muscarinic receptor antagonists that failed to display selectivity in binding studies with [3H](−)-QNB.
Flavonoids, leucocyte migration and eicosanoids
Authors: Mascolo N , Pinto A , Capasso F
Published: April 2011

Quercetin reduced the concentration of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in the pleural exudate induced in rats by 1% carrageenan given intrapleurally. Leucocyte migration in the exudate was also reduced by the flavonoid. Inhibition of eicosanoids and leucocytes in the exudate was dose-related. Quercetin also reduced LTB4 synthesis in cells stimulated with ionophore A23187, either ex-vivo or in-vitro. A similar, though less active, mode of action was found with quercitrin, while apigenin and luteolin reduced leucocyte accumulation and PGE2 formation, but not LTB4–formation.
Naltrexone and the behavioural action of clonidine in normotensive and spontaneously hypertensive rats
Authors: van den Buuse M , Henneveld H , de Jong W
Published: April 2011

The present experiments were aimed at the behavioural effects of clonidine and the possible involvement of opiate systems therein. Previous work had shown that opiate antagonists could block the effects of clonidine on blood pressure. In the open-field, clonidine treatment induced a decrease in ambulation and rearing activity. This effect was similar in normotensive Wistar and Wistar-Kyoto rats and in spontaneously hypertensive rats. In neither strain did naltrexone pretreatment influence the behavioural action of clonidine, however. These results do not lend support to the proposed interaction between opiate systems and the central effects of clonidine.
Zacopride: anxiolytic profile in rodent and primate models of anxiety
Authors: Costall B , Domeney A M , Gerrard P A , Kelly M E , Naylor R J
Published: April 2011

Zacopride, a substituted benzamide derivative, was compared with diazepam in three models of experimental or provoked anxiety. The drug’s action (i) in reducing aversion to a brightly lit environment was assessed in mice using a two compartment black and white test box system, (ii) in disinhibiting a suppressed behaviour was measured in the rat social interaction test under high light/unfamiliar conditions and (iii) in antagonizing a defensive response in the marmoset was assessed using the threat of a human presence. Both zacopride and diazepam enhanced exploratory behaviour and social interaction in the mouse and rat models and antagonized the defensive response in the marmoset, zacopride being 100 times more potent than diazepam. It is concluded that the 5-HT3 receptor antagonist, zacopride, alters rodent and primate behaviour in a manner consistent with that of an anxiolytic agent.
Anticholinesterase activity of prolactin: correlation with analgesia
Authors: Ramaswamy S , Regunathan S , Bapna J S
Published: April 2011

The possible inhibitory effect of prolactin on serum cholinesterase activity has been examined. Prolactin given to mice inhibited the enzyme’s activity in a dose-related fashion. This inhibition was not reversed by naloxone. A significant correlation was observed between the anticholinesterase and analgesic activity of prolactin. The findings suggest that prolactin may exert its cholinomimetic activity by inhibition of cholinesterase. A significant contribution by the cholinergic activity, which was independent of the opioid system, was indicated in the analgesic effect.
Rate-controlled Absorption Enhancement of Rectally Administered Cefazolin in Rats by a Glyceride Mixture (MGK)
Authors: van Hoogdalem Ewoud J , Stijnen Anna M , de Boer Albertus G , Breimer Douwe D
Published: April 2011

The enhancing effect of the medium chain glyceride preparation MGK on the rectal absorption of the cephalosporin antibiotic cefazolin sodium was evaluated in relation to the rate of delivery. Cefazolin sodium proved to be absorbed to a small extent (15 to 27%) after rectal administration without MGK. Bolus administration with MGK enhanced rate and extent of cefazolin sodium absorption, resulting in a bioavailability of 57 ± 26%. Linear infusion of 3 mg cefazolin sodium with MGK in 32 min produced complete absorption of the antibiotic (102 ± 7%), but absorption occurred slower in comparison with bolus delivery. The rate of administration proved to be an important variable of the absorption enhancing effect of MGK.
Glycogenolysis in the Rat Isolated Perfused Liver as a Measure of Chemically Induced Liver Toxicity
Authors: Nishihata Toshiaki , Ikawa Chie , Saitoh Yukiko , Sakai Kiyoshi
Published: April 2011

The relationship between chemically induced glycogenolysis and decreased thiol content in the rat isolated, perfused liver has been examined. Chemicals such as 2,4-dinitrophenol (DNP), diethyl maleate, alchohols and anti-inflammatory agents (except for sodium salicylate) accelerated glycogenolysis. Protein thiol loss correlated well with a marked increased rate of glucose release. Non-protein thiol loss, without significant loss of protein thiol, caused by a slight increase in the rate of glycogenolysis compared with controls. Since it has been reported that protein thiol loss rather than non-protein thiol loss is correlated to liver cell injury, a marked glucose release from the perfused liver may be a convenient measure of hepatic toxicity for a variety of chemicals.
Particulate contamination in solutions of antibiotics packed as dry powders in vials
Authors: Alexander D M , Veltman A M
Published: April 2011

The particulate contamination in 12 formulations of antibiotic solutions in vials packed as dry powders from five South African sources has been analysed quantitatively using a HIAC PC 320 light blockage particle analyser linked to a CMB 60 sensor. Results showed that the level of particulate contamination fell well within the limits set by the USP XXIst Edition for Small Volume Parenterals although four formulations contained some particles ≥50 μm. There was no apparent difference between the quality of the same antibiotics from different sources or between vials of the same antibiotics packed in different strengths.
The effect of moisture on the cohesive properties of microcrystalline celluloses
Authors: Heng Paul W S , Staniforth John N
Published: April 2011

A comparative evaluation of two microcrystalline celluloses, Avicel PH101 and Emcocel, revealed some differences in their cohesive properties at different moisture contents. A new method of sandwich rheometry was used to evaluate the cohesive properties of different powder masses. The force required to cause shear failure of a rough-surfaced blade in a powder bed was recorded. Avicel PH101 was found to be more cohesive than Emcocel at moisture contents less than 30 wt%, whereas at higher moisture contents the cohesive behaviour was comparable.
Presynaptic changes promoted by alloxan diabetes in the cat isolated heart
Authors: Ladosky E M P , Fonteles M C
Published: April 2011

Adrenergic presynaptic functions were evaluated in the cat isolated perfused heart preparation. The sympathetic nerve endings were labelled with [3H]noradrenaline ([3H]NA) and the effect of electric neural stimulation was determined in the presence of drugs which inhibit neuronal or extraneuronal uptake, or which antagonize α-adrenoceptors. [3H]NA overflow was measured in control and diabetic cats and was significantly increased by electric neural stimulation on both conditions. Perfusion with 0.1 μM phentolamine increased transmitter overflow in control hearts but failed to do so on organs obtained from alloxan-treated cats. The data provide evidence that in alloxan diabetic cats there is an abnormality of the adrenergic synapse.
Intracerebroventricularly administered bradykinin augments carrageenan-induced paw oedema in rats
Authors: Bhattacharya S K , Rao P J R Mohan , Das Neeta , Gupta G Das
Published: April 2011

Intracerebroventricular (i.e.v.) administered bradykinin (2.5 and 5.0 μg/rat) was found to augment carrageenan-induced acute paw oedema throughout the 4 h post-carrageenan observation period. The effect was statistically significant with the higher dose. The pro-inflammatory effect of i.c.v. bradykinin was antagonized following pretreatment with hemicholinium and atropine ethoiodide administered i.c.v., drugs that reduce central cholinergic activity. Similarly, central administration of drugs that inhibit the synthesis of eicosanoids, hydrocortisone, diclofenac and paracetamol, also attenuated the pro-inflammatory effect of bradykinin. The findings indicate that the inflammation-promoting effect of centrally administered bradykinin involves the central prostaglandin and cholinergic neurotransmitter systems.
The therapeutic effect of sodium stibogluconate in BALB/c mice infected with Leishmania donovani is organ-dependent
Authors: Carter K C , Baillie A J , Alexander J , Dolan T F
Published: April 2011

A study of the antileishmanial efficacy of sodium stibogluconate was carried out in BALB/c mice. The drug was administered to Leishmania donovani-infected animals on days 7 and 8 post-infection in one of three forms; free (40–50 mg Sbv Kg−1), liposomal, or niosomal (6.4–8.0 mg Sbv Kg−1) drug. On day 14 post-infection counts of the number of parasites present in the liver, spleen and bone marrow of treated and control animals showed that although all three drug preparations significantly reduced parasite numbers in the liver (≃99% suppression) they had little effect on those residing in the spleen or bone marrow. The carrier forms of the drug were therefore significantly more effective than free drug in reducing liver parasite burdens. Increasing the concentration and the number of doses of free drug (maximum of 500 mg Sbv Kg−1), and reducing the size of the vesicles used to deliver the drug had a minimal effect on parasite numbers in the spleen and bone marrow. It is proposed that because of the resistance of spleen and bone marrow parasites to drug therapy, the BALB/c mouse infected with L. donovani provides an excellent model system for the study of drug delivery to these deeper tissue sites.
The effects of the selective κ-opioid agonist MR 2034 on the guinea-pig ileum
Authors: Coupar Ian M , Quinn Michael J
Published: April 2011

The effects of the selective κ-opioid agonist MR 2034 on the guinea-pig ileum were compared with those produced by the μ-agonist morphine. MR 2034 induced acute tolerance and inhibited electrically evoked contractions to the same extent as morphine. The slope of the concentration-effect curve to MR 2034 was not significantly different from that of morphine. However, MR 2034 and morphine may act at their respective receptors since naloxone was 6.57 times more effective at inhibiting responses to morphine than MR 2034. MR 2034, like morphine, induced acute dependence as revealed by naloxone-induced contractions of tissues that had been incubated with MR 2034 for 5 h. The functional properties of κ-opoid receptors are the same as μ-receptors in the guinea-pig ileum.
Influence of Relative Humidity on the Adhesive Properties of a Model Interactive System
Authors: Kulvanich Poj , Stewart P J
Published: April 2011

The influence of relative humidity on the adhesive properties of model drug-carrier interactive systems was investigated using the centrifuge method. The degree of adhesion was quantified by determining the S50 from the adhesion profile. High ambient humidity (greater than 40% r.h.) decreased the degree of interaction of three sulphonamide powders with model hydroxypropyl methylcellulose phthalate-coated glass bead carriers during blending. All drug-carrier interactive systems displayed decreases in the degree of adhesion during storage. The extent and rate of the decreases increased with relative humidity and was interactive system-dependent. Preconditioning the powders to varying moisture contents produced contrasting results during blending, with one system showing a decrease in adhesion as the relative humidity increased, while the other’s interactive capability increased. This increase was attributed to the enhancement of charging sites on the drug’s powders surface by the adsorbed moisture.
Influence of 5-Tridecylpyrazole-3-carboxylic Acid, a New Hypolipidaemic Agent, on Cholesteryl Ester Formation in Rabbit Intestinal Mucosa
Authors: Seki Kunio , Horie Shuichi , Watanabe Takafumi , Suga Tetuya
Published: April 2011

The comparative effects of 5-tridecylpyrazole-3-carboxylic acid (TDPC), β-sitosterol and melinamide on the esterification of cholesterol (CH) have been investigated in rabbit intestinal microsomes and cytosol in-vitro. The three agents did not show an effect on cholesteryl ester formation by cholesterol esterase (CEase). TDPC and β-sitosterol did not affect cholesteryl oleate formation from oleoyl CoA by microsomal acyl CoA: cholesterol acyltransferase (ACAT), whereas melinamide significantly inhibited cholesteryl oleate formation. TDPC significantly inhibited the incorporation of oleic acid into cholesteryl oleate, which is associated with acyl CoA synthetase (ACS) plus ACAT in mucosal microsomes, at a concentration of 20–100 μM. On the other hand, 5-tridecylpyrazole-3-carbinol (TDPC-OH) a congener of TDPC, and β-sitosterol did not show any effect. From these results, it is demonstrated that carboxylic moiety of TDPC is necessary to inhibit ACS in-vitro. According to the kinetic analytical results, it is suggested that TDPC acts as a competitive inhibitor of ACS. These results suggest that the inhibitory effect of TDPC on cholesteryl ester formation may be mediated by an inhibition of ACS activity. It is apparent from the data presented that there are substantial differences between TDPC, β-sitosterol and melinamide with respect to their action on cholesteryl ester formation in rabbit intestinal mucosa.
The Biphasic Effects of Centrally and Peripherally Administered Caffeine on Ethanol-induced Motor Incoordination in Mice
Authors: Dar M Saeed
Published: April 2011

The possible biphasic effect of caffeine on acute ethanol-induced motor incoordination by rotorod evaluation was investigated in mice. Caffeine in various doses was administered intracerebro-ventricularly (i.e.v.) to mice implanted with permanent indwelling stainless steel guide cannulae and intraperitoneally (i.p.) to non-cannulated animals. A motor incoordinating test dose of ethanol, 2 g kg−1, was given i.p. in both cases. Caffeine < 25 μg administered i.e.v., dose-dependently attenuated while 75 μg i.c.v. potentiated ethanol (i.p.)-induced motor incoordination. Similarly, caffeine < 20 mg kg−1 given i.p., dose-dependently attenuated while 62.5 mg kg−1 potentiated ethanol (i.p.)-induced motor incoordination. The data obtained demonstrated that caffeine given either i.c.v. or i.p. exerted biphasic effects on ethanol-induced motor incoordination. The data also suggested that caffeine antagonized ethanol-induced motor incoordination when administered in appropriately low concentrations. At these low concentrations (< 25 μg i.c.v.; < 20 mg kg−1 i.p.) caffeine is well known to display high affinity for adenosine binding sites. Therefore, the present investigation lends further support to our earlier suggestion that adenosine may be involved in the motor impairing effect of ethanol.
Effects of an extract of feverfew on endothelial cell integrity and on cAMP in rabbit perfused aorta
Authors: Voyno-Yasenetskaya T A , Loesche W , Groenewegen W A , Heptinstall S , Repin V S , Till U
Published: April 2011

Extracts of feverfew inhibit platelet aggregation and secretion of granular contents from platelets and other cells. They also modify the interaction of platelets with collagen substrates: feverfew extracts inhibit both platelet spreading and formation of thrombus-like platelet aggregates on the collagen surface. We have now investigated the effect of an extract of feverfew on the vessel wall using rabbit aortas that were perfused with a physiological salt solution in-situ. Addition of feverfew extract to the perfusion medium protected the endothelial cell monolayer from perfusion-induced injury and led to a reversible increase in the cAMP content of aorta segments. The results indicate that feverfew may have a vasoprotective effect in addition to its effects on platelets.
Comparison of the In-vitro Receptor Selectivity of Substituted Benzamide Drugs for Brain Neurotransmitter Receptors
Authors: Chivers J K , Gommeren W , Leysen J E , Jenner P , Marsden C D
Published: April 2011

The in-vitro selectivity of a group of substituted benzamide drugs for brain neurotransmitter receptors was determined to assess the most appropriate drugs for use in human PET studies. All substituted benzamide drugs studied inhibited [3H]haloperidol and [3H]spiperone binding to rat striatal membranes. The most potent compounds were YM 09151-2, clebopride and raclopride. However, these substances also interacted in differing degrees with α-l, α-2, β-adrenergic, 5-HT-1, 5-HT-2, and opiate sites. Sulpiride, alizapride, SL 74205, TER 1546 and tiapride were specific for D-2 receptors, but these drugs were active only in the 10−7–10−6 M range. Raclopride, amisulpiride and sultopride showed a 100–1000 differentiation between action on dopamine sites compared with other neurotransmitter receptors. No such selectivity was observed for clebopride or YM 09151-2. Specific substituted benzamides such as alizapride, may be appropriate in high concentrations for defining the interaction of PET ligands with brain dopamine receptors. More potent, but selective, drugs such as raclopride and amisulpiride, may be effective in low concentrations as ligands for labelling dopamine receptor sites. However, the ability of these various substituted benzamide drugs to penetrate into brain and in-vivo to identify dopamine receptors in all brain areas must be assessed.
High speed photographic analysis of aerosols produced by metered dose inhalers
Authors: Dhand R , Malik S K , Balakrishnan M , Verma S R
Published: April 2011

The design of pressurized metered dose inhalers (MDI) used to assess asthma is variable. We have examined the aerosol spray flumes generated by four commercially available MDI products using high speed video photography. For this purpose a moulded jacket was designed which could hold the inhaler in an immovable position during actuation. Fresh inhalers were fitted in the jacket after thorough shaking and three successive actuations 30 s apart were filmed with a high speed video camera (200 frames s−1). The aerosol, ejected at high velocity into calm room air, was seen to have a ‘jet’ phase followed by a ‘cloud’ phase as a result of particle dispersion. Filming was continued till the flume could no longer be visualized on the TV monitor. High speed photography was used to record flumes seen on the video monitor, to enable characterization of flume appearance, dimensions and mean velocity.
Excitatory P1-purinoceptors on pre- and post-ganglionic cholinergic nerve terminals in the chick oesophagus
Authors: Mishra S K , Raviprakash V
Published: April 2011

The mechanism of action of ATP and the purinoceptors involved have been investigated on the chick oesophagus. The susceptibility of the excitatory responses to ATP/adenosine to tetrodotoxin indicates that their action is neurally mediated. Blockade of ATP/adenosine responses by atropine suggests the involvement of endogenous acetylcholine. ATP action depends on breakdown to AMP/adenosine, since theophylline blocks ATP/adenosine responses. The inhibition of ATP responses by pentolinium implies the involvement of preganglionic fibres.
Enhancement of capsaicin-induced contraction of guinea-pig tracheal smooth muscle by vanadate
Authors: Nayler Ross A
Published: April 2011

Contractions of guinea-pig isolated tracheal smooth muscle by submaximal capsaicin (0.1 μM) were enhanced by 43% (P < 0.01) after vanadate (10 μM for 10 min) preincubation. Contractile responses to acetylcholine (0.1–100 μM), histamine (1–100 μM) or substance P (0.01–1 μM) were, in contrast, not affected by prior vanadate exposure. It is suggested that tachykinin release from capsaicin-sensitive afferent nerve endings within the airways was enhanced by vanadate while airway smooth muscle reactivity remained unchanged.
Chronic antidepressant treatment increases the apomorphine-induced elevation of plasma corticosterone in rats
Authors: Kourkoubas Anthony , Pitoulis Spyros , Spyraki Christina
Published: April 2011

Plasma corticosterone concentrations in response to subcutaneous administration of apomorphine (25 and 200 μg kg−1) have been assessed in rats treated acutely (2 days) or repeatedly (15 days) with saline, clomipramine, electroshock and clomipramine + electroshock. Chronic, but not acute, antidepressant treatment decreased the corticosterone level which remained unchanged in control and in rats acutely treated with apomorphine. Chronic antidepressant treatment significantly increased the corticosterone response to apomorphine. Neuroendocrine evidence is provided for an increased responsiveness of dopamine receptors which are thought to mediate the apomorphine effect on corticosterone secretion following chronic antidepressant treatment.
Hydroxylation of Debrisoquine Using Perfused Liver Isolated from Sprague Dawley and DA Rats: Comparison With In-vivo Results
Authors: Vincent-Viry M , Deshayes S , Mothe O , Siest G , Galteau M M
Published: April 2011

The hydroxylation of debrisoquine was investigated in Sprague-Dawley (SD) and Dark-Agouti (DA) rats. Female and male rats were phenotyped in-vivo with debrisoquine six times during their growth. The ratios debrisoquine/4-hydroxydebrisoquine of the female DA rats increased until the 15th week and then decreased; but the values of the metabolic ratios never exceeded 2. Female DA rats cannot be considered as genetically deficient for hydroxylation of debrisoquine in regard to the metabolic ratio, but the percentage of debrisoquine excretion is up to ten fold higher than that in the other strains. Therefore SD and DA rat livers were perfused for 2 h when the clearance of debrisoquine was significantly lower in the female DA group than in the other groups. 4-Hydroxydebrisoquine in the perfusate increased with time, but the amount after 120 min was 12 fold lower in the female DA rat group than in the female SD rat group. The results of the male DA group fell between. This study confirms that female DA rats present a lower debrisoquine 4-hydroxylating capacity than other rats but shows that urinary metabolic ratio is not sufficient to assess the deficiency of debrisoquine hydroxylation.
Effect of Chlorpromazine on the Permeability of β-Lactam Antibiotics Across Rat Intestinal Brush Border Membrane Vesicles
Authors: Iseki Ken , Sugawara Mitsuru , Saitoh Hiroshi , Miyazaki Katsumi , Arita Takaichi
Published: April 2011

The effect of chlorpromazine on the membrane permeability of β-lactam antibiotics (benzylpenicillin, ampicillin, cephradine and cephalexin) and actively transported substances (glycylglycine and D-glucose) has been studied using rat intestinal brush border membrane vesicles. Except for cephalexin, the initial uptakes at 25°C of these antibiotics were significantly enhanced in the presence of chlorpromazine. In contrast, the transport of glycylglycine and D-glucose was significantly inhibited. These results suggest that the two groups, drugs and actively transported substances, have a different permeation process. The effect of chlorpromazine concentration on membrane lipid fluidity, as assessed by the fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH) and 1-anilino-8-naphthalene sulphonate (ANS), was also examined. The fluorescence polarization of ANS decreased with increasing concentration of chlorpromazine, while that of DPH increased suggesting an increase of membrane surface fluidity might affect the permeation of β-lactam antibiotics and actively transported substances in a different manner.
Studies In The Guinea-pig With ICI 185,282: A Thromboxane A2 Receptor Antagonist
Authors: Birch J , Brown E , Calnan C , Jessup C L , Jessup R , Wayne M
Published: April 2011

The effects of ICI 185,282 (5(Z)-7-([2,4,5-cis]-4-O-hydroxyphenyl-2-trifluoromethyl-1,3-dioxan-5-yl)heptenoic acid) have been studied on guinea-pig platelets and pulmonary smooth muscle in-vitro and in-vivo. When tested on guinea-pig lung parenchyma in-vitro, ICI 185,282 (1 × 10−7 M) produced a significant shift in U-46619 response curves (concentration ratio of 13.3); the antagonist (1 × 10−5 M) did not modify histamine responses. When tested on guinea-pig trachea in-vitro ICI 185,282 (1 × 10−7 M) caused significant inhibition of U-46619 and PGD2 responses (concentration ratios of 8.3 and 14.1, respectively); the antagonist (1 × 10−5 M) proved less effective against contractions of PGF2α, LTD4 and histamine (concentration ratios of 7.0, 1.5 and 1.6). When added to guinea-pig platelet rich plasma in-vitro, ICI 185,282 (× 10−6, 1 × 10−5 M) caused concentration-dependent parallel shifts to the right of U-46619 aggregation curves, yielding concentration ratios of 13.6 and 141.9, respectively. In-vitro, addition of ICI 185,282 (× 10−5 M) to indomethacin-treated pulmonary smooth muscle did not modify resting tone, neither did it induce aggregation or swelling in platelet-rich plasma preparations. When administered orally to guinea-pigs ICI 185,282 (0.1, 0.5 mg kg−1) caused a significant inhibition of U-46619-induced platelet aggregation ex-vivo which persisted ≥8 h. In-vivo, a single oral dose of ICI 185,282 (1 mg kg−1) inhibited bronchospasm induced by U-46619, PGD2, PGF2α, arachidonic acid, LTD4 and PAF; responses to histamine were unaffected. When dosed intravenously to lightly anaesthetized spontaneously breathing guinea-pigs ICI 185,282 (25 mg kg−1) failed to modify Cdyn and Raw. We conclude that ICI 185,282 is a potent, selective, orally active antagonist, which expresses activity at platelet and pulmonary TXA2 receptors.
The local modulation of vascular permeability by endothelial cell derived products
Authors: Chander C L , Moore A R , Dfsa F M , Howat D , Willoughby D A
Published: April 2011

Endothelin has been shown to suppress increased vascular permeability in the rat at doses of 0.01 pmol. The agonists used were nitric oxide and nitroprusside, which have the same activity as endothelial-derived relaxing factor. Histamine, 5-hydroxytryptamine, platelet activating factor and carrageenan were the other agonists used. It is proposed that endothelin and EDRF act as local hormones produced by endothelial cells to control local vascular permeability.
Rate and Extent of Absorption of Clonidine from a Transdermal Therapeutic System
Authors: Toon S , Hopkins K J , Aarons L , Rowland M
Published: April 2011

The in-vivo performance of a clonidine transdermal therapeutic system (TTS 3·5 cm2, 2·5 mg) was assessed in 12 healthy normal volunteers. Particular attention was paid to the rate and extent of absorption of clonidine from the TTS dosage form by reference to a 2 h i.v. infusion of clonidine. The absolute bioavailability of clonidine from the TTS dosage form was found to be approximately 60% with clonidine being released from the TTS at a relatively reproducible and consistent rate of 4·32 μg h−1 over a 7-day period.
In-vivo Effects of (E)-2-(3′,4′-dimethoxyphenyl)-3-fluoroallylamine (MDL 72145) on Amine Oxidase Activities in the Rat. Selective Inhibition of Semicarbazide-sensitive Amine Oxidase in Vascular and Brown Adipose Tissues
Authors: Elliott Jonathan , Callingham Brian A , Barrand Margery A
Published: April 2011

One hour after MDL 72145 ((E)-2-(3′,4′-dimethoxyphenyl)-3-fluoroallylamine) (2·5 mg kg−1) was given by intraperitoneal injection, the semicarbazide-sensitive amine oxidase (SSAO) activity of rat aorta and brown adipose tissue measured in-vitro was reduced by more than 95% of its control value, whereas the monoamine oxidase (MAO-A) activity remained virtually unaffected. The action of this drug on amine oxidases in the liver at this dose was less selective. The in-vitro effect of MDL 72145 on the soluble enzyme diamine oxidase from rat intestine was 100 fold less potent than that of semicarbazide but about equipotent with semicarbazide on sheep plasma amine oxidase. Overall MDL 72145 was selectively more active against membrane bound SSAO enzymes that deaminate primary monoamines. Although MDL 72145 does inhibit MAO-B activity these results suggest that this compound may be used to study the effect of selective inhibition of SSAO activity on the pharmacological responses of appropriate preparations invitro.
The Effect of Diphenylamine-2-carboxylate on C1− Channel Conductance and on Excitability Characteristics of Rat Skeletal Muscle
Authors: Camerino Diana Conte , de Luca Annamaria , Mambrini Mercede
Published: April 2011

The effect of diphenylamine-2-carboxylate (DPC), a blocker of the C1− conductive pathway in C1− transporting epithelia, has been evaluated in-vitro on the electrophysiological variables of rat extensor digitorum longus muscle fibres. DPC (5–240 μM) caused a dose-related increase of membrane resistance which was attributed entirely to a fall in C1− channel conductance (IC50, 120 μM), since potassium conductance was not affected by the treatment. DPC also modified fibre excitability. A significant dose-dependent increase was observed in the latency of the action potential and in the excitability of the membrane. DPC was less potent on striated fibres than anthracene-9-carboxylic acid, another specific blocker of C1− channel conductance. Moreover DPC was less potent on skeletal muscle than on C1− transporting epithelia. Morphological differences in the C1− channels or of the drug binding sites may account for the differences between tissues.