bluuebunny/crossref_metadata_2025 huggingface dataset:
Modification of electrical field stimulation-induced contractions in the guinea-pig ileum by metoclopramide and ICS 205–930 depends on the integrity of the mucosa
Authors: Costall B , Gunning S J , Naylor R J , Tattersall F D
Published: April 2011

Contractions induced by electrical field stimulation of guinea-pig ileum longitudinal muscle strips were enhanced by metoclopramide and ICS 205–930 at concentrations similar to those required to antagonize at 5-hydroxytryptamine ‘M’ receptors. The enhancement of contraction was observed in intact ileum strips but was not recorded in the longitudinal muscle myenteric plexus preparation or from the ileum with the mucosal layer removed. It is concluded that an intact mucosal layer is required for metoclopramide and ICS 205–930 to enhance electrical field stimulation-induced contractions of the guinea-pig ileum.
Rapid drug haptenization procedure: application to gentamicin and quinidine
Authors: Regan Ciaran M
Published: April 2011

A rapid and simple drug conjugation procedure which utilizes the heterobifunctional reagent N-hydroxysuccinimidyl 6-(4′-azido-2′-nitrophenylamino)hexanoate is described. With this protocol two drugs of diverse structure and solubility have been successfully haptenized. Rabbits immunized with these conjugates yielded drug-specific antibodies as judged by a solid phase radioimmunoassay. Furthermore, using this technique, no cross-reactivity could be detected. Such haptens also elicited an immune response in mice thus further extending their potential for the production of drug specific monoclonal antibodies.
Tissue cholinesterase inhibition by propranolol and related drugs
Authors: Alkondon M , Ray A , Sen P
Published: April 2011

The effect of (±)-propranolol and some related drugs have been investigated on the cholinesterase (ChE) enzyme activity of heart and brain tissues of the rat. Brain homogenates hydrolysed more methacholine than benzoylcholine and the reverse was true for the heart tissue. In-vitro, (±)-, (+)- and (−)-propranolol, as well as its quaternary analogue, UM-272, all significantly inhibited heart and brain ChE. Timolol and sotalol, however, were less potent. In-vivo, (±)-propranolol (30 μmol kg−1) significantly inhibited brain ChE activity in rats when compared with saline controls. It is inferred that propranolol inhibits brain and heart ChE enzyme in a non-stereoselective manner and that this cholinomimetic action could be involved in the mediation of some of its therapeutic effects.
Effect of adrenergic drugs on the isolated colon of Rhesus cynomolgus
Authors: Grivegnée A R , Fontaine J
Published: April 2011

The effects of adrenaline, noradrenaline, isoprenaline and dopamine were studied on the longitudinal muscle of the ascending and descending colon of the rhesus monkey. All these drugs induced a relaxation of the preparation, dopamine being the less active agonist. The responses seem to be the result of β2-adrenoceptor stimulation since their inhibition by practolol (β1) is weaker than their inhibition by propranolol (β1 and β2 dopaminergic). There is no evidence for the presence of dopaminergic receptors in this preparation.
Amethocaine-induced inhibition of mitochondrial monoamine oxidase activity
Authors: Haque S J , Poddar M K
Published: April 2011

Amethocaine (tetracaine) (1–10 μM) produces a concentration-dependent in-vitro inhibition of mitochondrial membrane-bound MAO activity towards tyramine (18–84% in brain and 19–84% in liver) and 5-hydroxytryptamine (5-HT) (23–94% in brain and 20–100% in liver). At relatively higher concentrations (25–300 μM) of amethocaine, benzylamine oxidation is inhibited in brain (24–91%) and liver (29–100%). The extent of MAO inhibition is appreciably reduced when preincubation time of the enzyme with a low concentration (7.5 μM) of amethocaine is increased from zero to 45 min. This inhibition is reversible. The Km of MAO for tyramine is increased in brain (106–473%) and liver (121–352%) in the presence of amethocaine (2–7.5 μM) accompanied by a decrease in Vmax (21–51% in brain and 18–57% in liver). Similarly the Km of MAO for 5-HT is increased to the extent of 79–336% in brain and 51–225% in liver and the corresponding Vmax is decreased by 35–55% and 39–74%, respectively, in the presence of 2–5 μM amethocaine. At relatively higher concentrations (25–100 μM), amethocaine increases the Km of MAO for benzylamine in brain (25–101%) and liver (26–85%) and decreases the Vmax by 28–64% and 32–63% in the respective tissues. Thus these results suggest that amethocaine preferentially inhibits MAO-A and the nature of inhibition is reversible and of mixed type.
Antiarrhythmic effect of amperozide, a novel psychotropic compound with class III antiarrhythmic properties, on digoxin-induced arrhythmias in the guinea-pig
Authors: Höglund Peter , Eriksson Margareta , Christensson Erik G
Published: April 2011

Amperozide is a novel psychotropic compound with specific effect in limbic brain areas. Preliminary findings have also indicated an antiarrhythmic effect in-vitro. Injections of saline, amperozide, melperone, thioridazine, bretylium or lignocaine, were given i.p. to anaesthetized guinea-pigs, which 10 min later were given digoxin s.c. to induce arrhythmia. In a series of control experiments none of these compounds caused arrhythmia in combination with the vehicle of digoxin. The time to arrhythmia was significantly prolonged after treatment with amperozide, melperone and bretylium compared with saline, but there were no differences between the treatments. The digoxin concentrations in plasma at death varied considerably within the groups and no statistical significance was found.
Particulate contamination in plastic ampoules
Authors: Oppenheim Richard C , Gillies I Ross
Published: April 2011

Plastic ampoules of Water for Injections, JP, and Injection Sodium Chloride, JP, were investigated to determine their particle load. Four batches were studied. The ampoules were twist-opened as they would be in the clinical setting and the total particle load, both inherent and that created in opening, was determined by reading the contents with a HIAC 420 particle counter with a CMB 60 sensor. The total particle content was found to be minimal, easily complying with world L. V.P. standards and the S. V.P. standard of the USP XXI. The number of particles found in these opened plastic ampoules was significantly lower than that found in clinically snap-opened glass ampoules and also slightly lower than that found in laboratory heat-opened glass ampoules. Whilst the plastic ampoule has a restricted application because it is not suitable for all drugs, it is concluded that when they are used as the immediate container for Water for Injections and Injection Sodium Chloride they are highly effective in reducing the particulate contamination generated in opening.
Characterization of flufylline, fluprofylline, ritanserin, butanserin and R 56413 with respect to in-vivo α1-, α2- and 5-HT2-receptor antagonism and in-vitro affinity for α1-, α2- and 5-HT2-receptors: comparison with ketanserin
Authors: Korstanje C , Sprenkels R , Doods H N , Hugtenburg J G , Boddeke E , Batink H D , Thoolen M J M C , Van Zwieten P A
Published: April 2011

The experimental drugs butanserin (R 53393), ritanserin (R 55667), R 56413, flufylline (Sgd 195/78) and fluprofylline (Sgd 144/80) were evaluated with respect to their antagonism at postjunctional α1- and α2-adrenoceptors and 5-HT2-receptors in pithed rats. Moreoever, affinity for [3H]mianserin, [3H]prazosin and [3H]yohimbine binding sites was assessed using rat brain preparations. In all experiments ketanserin was taken as a reference compound. It is concluded that of the compounds investigated butanserin is the most potent and selective α1-adrenoceptor antagonist, whereas ritanserin was found to be a potent and selective 5-HT2-antagonist. Of the other compounds, fluprofylline was a very selective though not very potent α1-adrenoceptor antagonist. The other compounds were less active and less selective in this respect.
Buspirone decreases the activity of 5-hydroxytryptamine-containing dorsal raphe neurons in-vitro
Authors: Trulson Michael E , Arasteh Kamyar
Published: April 2011

Buspirone, a non-benzodiazepine anxiolytic agent, produced a dose-dependent decrease in the activity of 5-HT-containing dorsal raphe neurons recorded from mouse brain slices. The response was not changed in a low calcium/high magnesium incubation medium, indicating that the observed effects were the result of a direct action of buspirone on raphe neurons. These data are discussed within the context of the anxiolytic effects of buspirone.
Comparative lipophilicities of substrates of monoamine oxidase
Authors: Katayama Masako , Yamamoto Masato , Kobayashi Shinichi , Oguchi Katsuji , Yasuhara Hajime
Published: April 2011

Oil/water partition coefficients of various substrates of monoamine oxidase (MAO) and kinetic parameters of MAO-A and -B of rat liver at two pH values, pH 7 and pH 9, were investigated. Octanol, heptane or benzene were chosen for the oil phases. The deamination of the biogenic amines 5-hydroxytryptamine (5-HT), tyramine, 2-phenethylamine (PEA) and benzylamine was studied at pH 7 and pH 9. Results indicated all four substrates were very hydrophilic, and the oil/water partition coefficients of benzylamine and PEA were higher than those of 5-HT and tyramine. The changes in Km and Vmax values at pH 7 and pH 9 indicated that the affinities of MAO-A towards 5-HT and tyramine slightly increased at pH 9 and those of MAO-B towards tyramine and benzylamine also increased at pH 9, while uncharged amines at pH 9 amounted to about a hundred times of those at pH 7. It is concluded that the mitochondrial MAO bound to the membrane may metabolize charged molecules as well as uncharged counterparts.
α1-Adrenoceptor function in the rat hippocampus as assessed by noradrenaline-stimulated inositol phospholipid breakdown after destruction of noradrenergic neurons by neonatal 6-hydroxydopamine treatment
Authors: Fowler Christopher J , Fagervall Ingrid , Minor Bruce G , Ross Svante B
Published: April 2011

Neonatal 6-hydroxydopamine treatment of male Sprague-Dawley rats resulted in a large depletion of noradrenaline 84–87 days later, as demonstrated by an 82% reduction in the intra-synaptosomal deamination of [14C]noradrenaline within noradrenergic synaptosomes with only marginal effects upon the extrasynaptosomal deamination. The hippocampal stimulation of inositol phospholipid breakdown by noradrenaline was, however, unaffected by the neonatal 6-hydroxydopamine treatment.
In-vitro release of [14C]glutamate from dentate gyrus is modulated by GABA
Authors: Spencer P , Lynch M A , Bliss T V P
Published: April 2011

The effect of GABA (10−3 and 10−4 M) on the release of preloaded [14C]glutamate from slices of rat dentate gyrus, in response to K+ stimulation, was studied in Ca2+-free and normal Krebs solutions. Release in Ca2+-free solution was significantly enhanced, but there was no change in release in normal Krebs solution. These results imply that Ca2+-dependent (presumably neuronal) release of glutamate from the dentate gyrus is depressed by GABA, while non-neuronal Ca2+-independent release is enhanced.
Bulbocapnine is not a selective DA1 receptor antagonist
Authors: Kohli Jai D , Glock Dana , Goldberg Leon I
Published: April 2011

Antagonist activity of bulbocapnine on DA1 versus DA2 dopamine receptors was studied simultaneously in a dog under pentobarbitone anaesthesia and without phenoxy-benzamine pretreatment. Fenoldopam (SK&F 82526) injected into the renal artery was the DA1 agonist and dipropyl dopamine or piribedil injected into the femoral artery were the DA2 agonists. Both at 0.5 and 1 mg kg−1 doses intravenous bulbocapnine caused nearly equal inhibition of DA1 and DA2 dopamine receptor-mediated responses. Our results show that under these experimental conditions bulbocapnine is not a selective DA1 dopamine antagonist.
The role of adenosine in cerebral vascular regulation during reductions in perfusion pressure
Authors: Phillis John W , DeLong Robert E
Published: April 2011

The adenosine antagonist caffeine was used to test the hypothesis that endogenous adenosine contributes to the regulation of cerebral blood flow during acute reductions in mean arterial blood pressure. Caffeine, administered intraperitoneally in 20 and 40 mg kg−1 doses, failed to alter the autoregulatory flow responses to marked reductions in arterial blood pressure, showing that adenosine is not essential for cerebrovascular regulation during severe hypotension.
Inhibition of hepatic microsomal monooxygenase activity by cinchocaine: mechanistic studies and effects of ionization
Authors: Murray Michael
Published: April 2011

The quinoline-based local anaesthetic cinchocaine (dibucaine) was found to be a mixed-type inhibitor of microsomal aminopyrine N-demethylase and 7-ethoxycoumarin O-deethylase activities from control and phenobarbitone-induced rat liver in-vitro. Cinchocaine also elicited a characteristic type I optical difference spectrum in oxidized liver microsomes (Ks = 24 μm; ΔAmax = 3.4 × 10−3 absorbance units (nmol cytochrome P450)−1) but did not appear to bind to the reduced form of the cytochrome. Additional studies indicated that cinchocaine competitively inhibited the type I spectral binding of substrate (aminopyrine) to ferric cytochrome P450. Studies of monooxygenase inhibition by cinchocaine over a relatively narrow pH range (6.5–8.5) indicated that, as might be expected, the un-ionized form of the drug is associated with inhibitory potency superior to that of the ionized form. Thus 40% inhibition of aminopyrine N-demethylase activity was observed with 100 μm cinchocaine at pH 8.0 and 8.5 (24% and 50% un-ionized drug, respectively), whereas only 16% inhibition was observed at pH 6.5(1% un-ionized drug). These findings suggest that the inhibitory action of cinchocaine is mediated exclusively via an interaction with ferric cytochrome P450 and that the extent of ionization is a determinant of mixed function oxidase inhibition.
Effects of morphine and clonidine on sulphobromophthalein disposition in mice
Authors: Ben-Zvi Zvi , Hurwitz Aryeh
Published: April 2011

Levels of sulphobromophthalein (BSP) in plasma and liver were elevated by the opiate, morphine, and by the α2-adrenoceptor agonist, clonidine. Neither morphine, 1 mg kg−1, nor clonidine, 0.01 mg kg−1, affected BSP levels significantly. When given together at these doses, they caused BSP levels in plasma and liver to be raised. At 20 mg kg−1, the effect of morphine on BSP levels was maximal, as was that of clonidine, 1.0 mg kg−1. However, the effect of these drugs given together on plasma BSP exceeded the maximal effect of either alone. Yohimbine, an α2-adrenoceptor antagonist, did not affect BSP levels, nor did the opiate antagonist, naloxone. Each of these antagonists reversed the hepatobiliary effects of its respective agonist, as shown by return of BSP levels to those of saline-treated mice. Yohimbine did not reverse morphine, nor did naloxone reverse clonidine. The additive effects of morphine and clonidine and the specificities of their respective antagonists strongly suggest the involvement of discrete receptors mediating their essentially identical hepatobiliary effects.
Calculations of pH for complex mixtures of acids, bases and ampholytes
Authors: Cutler David
Published: April 2011

A general method for calculating the pH of complex mixtures of acids, bases and ampholytes is derived. Application of the method is illustrated with examples.
Chromatographic separation of thioridazine sulphoxide and N-oxide diastereoisomers: identification as metabolites in the rat
Authors: Watkins Geraldine M , Whelpton Robin , Buckley Dennis G , Curry Stephen H
Published: April 2011

(±)-Thioridazine and (±)-desmethylthioridazine have been oxidized to produce a number of chiral sulphoxide and amine oxide compounds. Diastereoisomeric isomers were separated by thin-layer and high performance liquid chromatography. Thioridazine-5-sulphoxide, N-desmethylthioridazine-5-sulphoxide and thioridazine-N-oxide diastereoisomers were found to be thioridazine metabolites following dosing in rats or after in-vitro incubation with rat liver homogenate.
Brittle fracture propensity measurements on ‘tablet-sized’ cylindrical compacts
Authors: Roberts R J , Rowe R C
Published: April 2011

The brittle fracture propensity test which was originally designed for large, square compacts with a central hole has been modified and extended to compacts of ‘tablet-sized’ dimensions. This allows a brittle fracture propensity (BFP) index to be measured at strain rates and conditions approaching those normally used in tableting. The BFP indices for microcrystalline cellulose, Tablettose and heavy magnesium carbonate were evaluated at punch velocities of 3.33 and 200 mm s−1 and found to be in good agreement with the results of previous workers.
The disposition of pyrimethamine in the rat isolated perfused liver: the effect of suramin
Authors: Coleman M D , Adjepon-Yamoah K
Published: April 2011

The pharmacokinetics of pyrimethamine (0.5 mg) were determined in the rat isolated perfused liver in the presence of suramin (17.75 mg). The clearance, half life, area under the curve, and volume of distribution of pyrimethamine were unaffected by the concurrent administration of suramin, as was the hepatic sub-cellular disposition of the drug. This report is of relevance to the future concurrent administration of suramin and pyrimethamine in West Africa.
Hypherphagia caused by muscimol injection in the nucleus raphe dorsalis of rats: its control by 5-hydroxytryptamine in the nucleus accumbens
Authors: Bendotti C , Garattini S , Samanin R
Published: April 2011

Muscimol injection in the nucleus raphe dorsalis caused intense eating by rats with access to food. A dose-related reduction of muscimol's effect was found after bilateral injections of 5-hydroxytryptamine (5-HT) in the nucleus accumbens (dose range 2.2–8.8 μg in 2 μl) but no effect was observed when an even higher dose (17.6 μg) of 5-HT was injected in the caudate putamen. Eating by food-deprived rats was not changed by any dose of 5-HT injected either into the nucleus accumbens or the caudate putamen. (+)-Norfenfluramine, 20 μg, injected in the nucleus accumbens also reduced muscimol-induced eating but had no effect on the food intake of starved rats. The results suggest an important role of 5-HT in the nucleus accumbens in the control of certain types of hyperphagia in rats.
Haem arginate: a new stable haem compound
Authors: Tenhunen R , Tokola O , Lindén I-B
Published: April 2011

Intravenous administration of haem in acute hepatic porphyrias inhibits the induction of β-aminolaevulinic acid synthase, reduces the formation of potentially harmful metabolites of porphyrin synthesis and corrects the haem deficiency. Typically, haem therapy has been given in the form of haematin—haem dissolved in alkali. Such haematin solutions are, however, extremely unstable. Thus, the rapid decomposition of this therapeutic agent may have been responsible for the ineffectiveness of treatment in some clinical states and adverse reactions may have been caused by haematin degradation products. There is, therefore, a need for a stable, effective and well-tolerated haem preparation. We have prepared certain highly soluble haem compounds of which haem arginate has proved to be the most promising. Pure haemin was isolated from HIV and hepatitis B negative human blood. The haem derivatives prepared were screened as substrates for haem oxygenase. Haem arginate and haem lysinate were found to be as good substrates as methaemalbumin. Stock solutions of haem arginate were stable for 2 years at +6 °C. After dilution with sterile isotonic saline the haem arginate infusion was clearly more stable than haematin solutions made in the laboratory or prepared by dissolving commercial lyophilized haematin. The antiporphyrogenic effect of haem arginate (even after storage for two years) in 2-allyl-2-isopropylacet-amide-induced experimental porphyria of rats was equal to that of freshly prepared haematin. The acute oral toxicity of haem arginate was low compared with the parenterally administered drug, indicating poor oral bioavailability. The acute toxic effects after high intravenous or intraperitoneal doses were directed to the liver. Conventional haematin caused thrombophlebitic reactions at the site of infusion in all rabbits, but haem arginate did not cause any thrombophlebitis even after repeated infusions. The dose of haem arginate used in clinical trials, 0ṁ2 mg of haem kg−1 min−1 during 15 min (= total dose 3 mg kg−1 diluted in 100 mL isotonic saline), did not cause any clinically significant changes in the numerous haemostatic parameters measured in patients, and ten times higher infusion rates or total doses were needed to cause a decrease in the blood pressure of rats. Haem arginate has proven to have many advantages over conventional haematin solutions.
The effect of prostaglandins on gastric parietal and non-parietal secretion in the anaesthetized rat
Authors: Bunce K T
Published: April 2011

The effects of prostaglandin E2 (PGE2), 16,16-dimethyl prostaglandin E2 (dmPGE2) and prostaglandin F2α (PGF2α) on gastric secretion have been examined in the anaesthetized rat. The prostaglandins stimulated the secretion of a non-parietal juice which was rich in Na+ and Cl- with smaller amounts of K+ and HCO3-. Doses of the prostaglandins that stimulated gastric non-parietal secretion also inhibited histamine stimulated gastric acid secretion, and thus the same rank order of potency was obtained for the prostaglandins on the two secretory mechanisms, viz. dmPGE2 > PGE2 > PGF2α. During the secretion of endogenous gastric acid the secretagogue effect of the prostaglandins on non-parietal secretion was diminished, and this effect appeared to be due to the presence of intraluminal acid since it was mimicked by application of exogenous HCl to the gastric mucosal surface. Thus, the present results show that prostaglandins affect both the parietal and non-parietal secretions in the rat stomach and that these mechanisms show some interdependence.
Biodegradable microspheres: polyacryl starch microparticles as a delivery system for the antileishmanial drug, sodium stibogluconate
Authors: Baillie A J , Coombs G H , Dolan T F , Hunter C A , Laakso T , Sjöholm I , Stjärnkvist P
Published: April 2011

Liver parasite burdens of Leishmania donovani in the mouse have been determined after treatment with intravenous administration of sodium stibogluconate in the free or carrier form. The carrier form, in which the drug was covalently bound to polyacryl starch microparticles, was up to 100 x more effective than the free form in this murine model of visceral leishmaniasis. Empty microparticles had no effect on liver parasite burdens and the enhanced in-vivo antileishmanial activity of the carrier form of the drug was apparently due to passive drug delivery to the infected liver.
Metabolic N-oxidation of metronidazole
Authors: Essien E E , Ogonor J I , Coker H A B , Bamisile M M
Published: April 2011

Metronidazole when treated at the N-3 nitrogen with a mixture of hydrogen peroxide and acetic acid, or liver homogenate preparations, yields the N-3 oxide as identified by thin-layer chromatographic analysis on silica gel G, RF 0ṁ62 in ethanol-chloroform-ammonia (50:49:1), by chemical reduction with sulphur dioxide, and by ultra-violet spectrophotometry and nuclear magnetic resonance spectroscopy. Incubation of metronidazole at 37°C with rat liver 10 000g supernatant fortified with cofactors gave a product with identical chromatographic and UV spectral data suggesting that metronidazole like other tertiary amine drugs undergoes microsomal N-oxidation.
Rhein: an anthraquinone that modulates superoxide anion production from human neutrophils
Authors: Mian M , Brunelleschi S , Tarli S , Rubino A , Benetti D , Fantozzi R , Zilletti L
Published: April 2011

Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid), the active metabolite of diacetylrhein, which has been reported as an effective antirheumatic drug in man, inhibited superoxide anion production from human neutrophils challenged with N-formylmethionyl-leucyl-phenylalanine (FMLP: IC50, 2 times 10−5  M) and A23186 (IC50, 10−5M), but not with phorbol myristate acetate. In the same concentration range (10−6-10−3M), the drug did not affect oxy-radical production by a cell-free hypoxanthine-xanthine oxidase system and exerted weak inhibitory effects on FMLP-evoked lysosomal enzyme release. Rhein inhibitory effects on neutrophil functioning may contribute to the overall therapeutic activity of the parent drug, diacetylrhein.
Distribution and urinary excretion of the desethylmetabolites of chloroquine in the rat
Authors: Salako L A , Ajayi Funmilayo O
Published: April 2011

The tissue distribution of desethylchloroquine and bis-desethylchloroquine has been studied in rats after single intraperitoneal administration of the drugs at a dose of 10 mg kg−1. Concentrations of the chloroquine metabolites in the liver, heart, lungs, kidney and spleen were 34 to 250 times higher than their plasma concentrations 24 h after the drugs had been injected. Urinary excretion of the drugs was studied in rats after single intravenous administration of 2ṁ5, 5 or 10 mg kg−1 doses. The total estimated urinary excretion of desethylchloroquine and bisdesethylchloroquine was 25 and 64% respectively of the administered dose, with the maximum urinary excretion occurring on the first day. The results show that the desethylmetabolites of chloroquine are concentrated in the tissues in the same manner as the parent compound.
The angle of internal flow as an indicator of filling and drug release properties of capsule formulations
Authors: Newton J M , Bader F
Published: April 2011

The cohesiveness of size fractions of acetylsalicylic acid and lactose alone and in various combinations has been determined by estimation of the rate of decrease in volume as a function of tamping under standard conditions. The cohesiveness was quantified in terms of empirically derived characteristic, the angle of internal flow ϕ. The value of ϕ was found to decrease with the particle size of acetylsalicylic acid, but not lactose, and was found to be dependent on the relative proportion and particle sizes of acetylsalicylic acid and lactose when blends of powder were studied. The value of the time for 50% of the drug content to be released from a hard gelatin capsule in an in-vitro dissolution test, T50, was found to decrease with decreasing values of ϕ for capsules containing acetylsalicylic acid alone. For capsules containing powder blends there was no consistent relationship between the value of T50 and ϕ.
An investigation of the mechanism involved in the cholinergic action of meptazinol
Authors: Hetherington M S , Hughes I E , Lees A
Published: April 2011

In concentrations above 20 μM, (±)-meptazinol produced a contraction of the guinea-pig isolated ileum and this effect was antagonized by atropine (0.01 to 0.3 μM) in a manner which was not competitive. Cooling the preparation to 15 °C blocked the contractile action of meptazinol and of dimethylphenylpiperazinium (DMPP) but did not affect the action of carbachol. Twitch responses of the rat phrenic nerve-diaphragm preparation induced by indirect electrical stimulation in the presence of naloxone (20 nM) were potentiated by meptazinol (1 to 40 μM) which also reversed a partial blockade of the twitch induced by tubocurarine. Neither of these effects was seen in tissues which had been pretreated with the cholinesterase inhibitor BW284C51 (0.2 μM) though tetraethylammonium iodide (40 μM) was still able to enhance the responses to stimulation. In the presence of naloxone (20 nM) electrically induced responses of the rat isolated rectum were abolished by cinchocaine (10 μM), partially blocked by atropine (0.1 to 0.4 μM) and potentiated by meptazinol (1 to 30 μM). The latter action was not seen when meptazinol was administered in the presence of BW284C51. It is concluded that the cholinergic action of meptazinol in these tissues is due to an indirect effect, probably involving inhibition of cholinesterase and that no evidence was seen of any ability to increase the release of acetylcholine itself.
The effects of pH, calcium and chloride ions on the binding of tolmetin to human serum albumin: circular dichroic, dialysis and fluorometric measurements
Authors: Matsuyama Kenji , Sen Asok C , Perrin John H
Published: April 2011

The binding of the non-steroidal anti-inflammatory drug, tolmetin (1-methyl-5-p-toluoylpyrrole-2-acetic acid) to human serum albumin (HSA) has been shown by circular dichroism, fluorescence and equilibrium dialysis to be dependent on the N-B conformational change of the albumin. The influence of calcium and chloride ions on the interaction was also investigated using the same techniques. Experiments suggested that calcium ions increased the binding constant of tolmetin to HSA whereas chloride ions decreased it. The displacement study showed that tolmetin caused a significant increase in the affinity of diazepam to HSA whereas it decreased the binding of warfarin to HSA. Tolmetin seems to cause an allosteric change in the diazepam binding site in spite of it sharing a primary site with warfarin.
Comparison of changes in locomotor activity with striatal homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations following the bilateral intranigral injection of dopamine agonist drugs in rats
Authors: Kelly Eamonn , Jenner Peter , Marsden C David
Published: April 2011

Bilateral injection of apomorphine (2.5 μg) into the substantia nigra zona reticulata of rats reduced both locomotor activity and striatal HVA and DOPAC concentrations. Bilateral injection of dopamine (10 μg) did not affect locomotor activity whereas a higher dose of dopamine (50 μg) enhanced locomotor activity. Striatal HVA and DOPAC concentrations were unchanged following injection of dopamine. Bilateral injection of (±)-3PPP (0.1 or 2.5 μg) into the zona reticulata of the substantia nigra did not alter locomotor activity while a higher dose (10 μg) enhanced locomotion. Injection of (±)-3PPP (0.1–10 μg) into the zona reticulata was without effect on striatal HVA or DOPAC concentrations. The bilateral manipulation of nigral dopaminergic neurotransmission alters motor activity and nigrostriatal dopamine turnover in conscious rats. However, the changes in motor activity are not necessarily related to altered nigrostriatal activity, suggesting the involvement of dopamine receptors located at non-dopaminergic sites within the substantia nigra.
The effect of meptazinol on the guinea-pig sphincter of Oddi in-vitro
Authors: Wade V , Pleuvry B J , Modla C Y , Bradley P
Published: April 2011

Meptazinol causes a dose-dependent contraction of the guinea-pig sphincter of Oddi in-vitro. This was antagonized by atropine in concentrations which blocked the contractile response to acetylcholine but not that to KCl. Naloxone was unable to block the response of the tissue to meptazinol, and other opioid drugs had inconsistent effects. Although meptazinol has significant anticholinesterase activity on this preparation, comparison with neostigmine suggests that this is irrelevant to its contractile action.
Detrimental effect of propylene glycol on natural killer cell and neutrophil function
Authors: Denning David W , Webster A David B
Published: April 2011

Propylene glycol (PG) in a concentration of 0.5–1.0% inhibits natural cytotoxicity and neutrophil chemiluminescence. This is the first reported effect of PG on defence mechanisms in man. PG is frequently used as a vehicle in high concentrations by the pharmaceutical industry and it would be wise to consider its potential immunosuppressive effects in the evaluation of drug formulations.
Correlation between n-octanol/water partition coefficient and liquid chromatographic retention for caffeine and its metabolites, and some structure-pharmacokinetic considerations
Authors: Gaspari F , Bonati M
Published: April 2011

A method to establish the correlation between the reverse phase high performance liquid chromatographic retention of caffeine and its metabolites and their n-octanol/water partition coefficients is described. The log (P) values were always below zero, ranging from −0.02 to −2.03. The capacity factor quadratically back-extrapolated to 100% water eluent (k'w) was used as the index of lipophilicity. The compounds examined gave a good correlation (r > 0.99) with log (k'w) if considered in separate series, depending on the substituent position. For a structure-pharmacokinetic relationship study, correlations were found between the partition coefficient and some pharmacokinetic parameters, suggesting that for drugs that are widely metabolized, any predictions of their disposition from physicochemical characteristics are hazardous.
Albumin microspheres for intra-articular drug delivery: investigation of their retention in normal and arthritic knee joints of rabbits
Authors: Ratcliffe J H , Hunneyball I M , Wilson C G , Smith A , Davis S S
Published: April 2011

The retention of 131I-labelled albumin microspheres and microsphere-entrapped [131I]rose bengal was investigated in normal and experimentally arthritic knee joints of rabbits. Albumin microspheres were cleared slowly from the joint cavity and no significant difference was observed between normal and inflamed joints. Entrapment of rose bengal within albumin microspheres was found to delay the clearance of the drug from the joint when compared with a solution of rose bengal. In addition, the retention time for entrapped rose bengal was dependent on the degree of inflammation present.
Central muscarinic activation elicits compulsive drinking behaviour in the rat
Authors: Schiavone A , Prudentino A , Giachetti A
Published: April 2011

Injection of bethanechol into the lateral cerebral ventricle of the rat induces a marked increase in drinking, within 30 min from administration. The response is dose-related, maximal water intake (6.1 ± 0.55 mL; mean ± s.e.) occurring at 10 μg of bethanechol. Peripheral administration of the agonist (up to 3 mg kg−1 i.p.) fails to elicit drinking. Among several specific antagonists only anti-muscarinic drugs produced a significant inhibition of the response, suggesting that the compulsive drinking behaviour in the rat is caused by activation of central muscarinic receptors. The drinking behaviour emerges as a reliable test to assess central muscarinic activity of both agonists and antagonists.
1-(ℴo-Methoxyphenyl)piperazine is a metabolite of drugs bearing a methoxyphenylpiperazine side-chain
Authors: Benfenati E , Caccia S , Vedova F Della
Published: April 2011

Drugs bearing an o-methoxyphenylpiperazine (oOCH3PP) moiety in the side-chain of their molecule may form oOCH3PP during biotransformation in-vivo in the rat. This has been verified by combined gas chromatography-mass spectrometry of urine from rats given orally a series of relatively new o-methoxyphenylpiperazine-substituted derivatives. The metabolite is reported to be biochemically and pharmacologically active and therefore its formation may have pharmacological significance, at least for derivatives undergoing extensive cleavage of the arylpiperazine side-chain.
Plasma protein binding—lipophilicity relationships: interspecies comparison of some organic acids
Authors: LÁZNÍČEK M , KVĚTINA J , MAZÁK J , KRCH V
Published: April 2011

Relationships between plasma protein binding of 11 organic acids (benzoic and phenylacetic acid derivatives) and their lipophilicity were studied in man, rabbits, rats and mice. For description, the relationship fu = 1/(1 + aDb) was developed, where fu is the fraction of the unbound drug in plasma, D is the partition coefficient octanol/water and a and b are parameters. While the value of the parameter a is widely different in interspecies comparison, the value of the parameter b is very close in all species studied and is approximately equal to 1. The model used allows the simple calculation of the extent of plasma binding of structurally similar drugs from their lipophilicity, or conversion of the extent of plasma binding from one species to another.
Fate of haem after parenteral administration of haem arginate to rabbits
Authors: LINDÉN I-B , TOKOLA O , KARLSSON M , TENHUNEN R
Published: April 2011

Rabbits were injected either intravenously or intramuscularly with [14C]haem arginate and [59Fe]haem arginate (haem 5 mg kg−1). The main part (80%) of AUCINF of labelled haem was associated with the β-phase, T½ being about 6 h. Only 1% of the haem dose had been taken up by the red blood cells. In contrast, the iron moiety from the haem molecule was effectively utilized. Thirty days post-injection of [59Fe]haem arginate, 40% of the dose after intravenous injection and 60% after intramuscular injection was circulating with the red cells. Radioactivity was shown to concentrate in the liver, where haem is mainly metabolized and eliminated. An accumulation of haem in the adrenals was also evident. Haem itself did not concentrate in the bone marrow, and a negligible amount of radioactivity was recovered from brain, implying a poor penetration of the blood brain barrier.
Adrenergic receptor subtype activation by (+)-, (−)- and (±)-norephedrine in the pithed rat
Authors: MOYA-HUFF FERNANDO A , MAHER TIMOTHY J
Published: April 2011

The ability of (±)-norephedrine (phenylpropanolamine) and its component isomers, (+)- and (-)-norephedrine, to activate adrenergic receptor subtypes in the cardiovascular system of the urethane/chloralose-anaesthetized pithed rat has been investigated. At all adrenoceptor subtypes, (-)-norephedrine was the most potent agonist followed by (±)- then (+)-norephedrine. The greatest activity was observed at the α1-receptor, with little activity observed at either β1 or β2-adrenoceptors. Reserpinization shifted the (-)- norephedrine dose-response curve slighty to the right, indicating that only a minor portion of its activity is due to the release of stored endogenous catecholamines. These results suggest that most of the cardiovascular activity of the compounds is through the direct activation of α1-adrenoceptors.
Evaluation of permeability enhancement of hydrophilic compounds and macromolecular compounds by bile salts through rabbit corneas in-vitro
Authors: Morimoto Kazuhiro , Nakai Tohru , Morisaka Katsuaki
Published: April 2011

The effect of bile salts, sodium taurocholate (TC-Na) and sodium taurodeoxycholate (TDC-Na), on the permeability of hydrophilic compounds and macromolecular compounds through the rabbit cornea in-vitro was examined. 6-Carboxyfluorescein and glutathione were used as low molecular weight hydrophilic model compounds and FITC-dextran (mol. wt 4000) and insulin were used as relatively macromolecular model compounds. TC-Na (2 and 10 mM) marginally increased the corneal permeabilities to hydrophilic compounds and macromolecular compounds. TDC-Na (2 and 10 mM) markedly increased the corneal permeabilities of these compounds.
The effect of phenylpentenyl-khatamines on the release of radioactivity from rat striatal tissue prelabelled with [3H]dopamine
Authors: Kalix P , Geisshüsler S , Brenneisen R
Published: April 2011

The CNS-stimulating properties of leaves of the khat shrub (Catha edulis, Celastraceae) are presumed to be due mainly to (-)-cathinone, a phenylpropylamine alkaloid that has been shown to have an amphetamine-like releasing effect at physiological catecholamine storage sites. Recently, several phenylpentenylamine alkaloids have been identified in khat leaves, and these have been evaluated, in-vitro, in the present study for their ability to induce release of radioactivity from [3H]dopamine-prelabelled rat striatal tissue. It was found that the phenylpentenylamines have a weak releasing effect, and are therefore considered unlikely to play an important role in the stimulating properties of khat leaves.
Effect of lapachol, a naphthaquinone isolated from Tectona grandis, on experimental peptic ulcer and gastric secretion
Authors: Goel R K , Pathak N K R , Biswas M , Pandey V B , Sanyal A K
Published: April 2011

Lapachol, a naphthaquinone isolated from the roots of Tectona grandis given at a dose of 5 mg kg−1 p.o. twice daily for 3 days was found to have an anti-ulcerogenic effect on subsequently induced experimental gastric and duodenal ulcers in rats and guinea-pigs. Its action appears to be associated with an effect on the protein content of gastric juice, and it reversed aspirin-induced changes in peptic activity, protein and sialic acid.
The anticoagulant activity of some selected warfarin analogues
Authors: Obaseki Andrew O , Coker Herbert B
Published: April 2011

The anticoagulant activities of 6-, 7-, 8-, 4′-hydroxy, 6-chloro- and 6-bromowarfarin were determined in rabbits after intraperitoneal administration of 16.2 μmol kg−1 over 96 h. Substitution on the 4-hydroxycoumarin moiety resulted in reduction of the anticoagulant activity. 6-Chlorowarfarin was more potent than 6-bromowarfarin suggesting that the molecular size of 4-hydroxycoumarin moiety may be crucial for biological activity.
The effect of particle size and concentration on the adhesive characteristics of a model drug-carrier interactive system
Authors: Kulvanich Poj , Stewart P J
Published: April 2011

The effect of concentration and particle size on the adhesive tendency of drug particles in a model interactive system was investigated using a centrifuge technique. The model interactive system consisted of drug powders adhered to coated glass carrier beads. Adhesion profiles of per cent of drug remaining on the carrier versus the square of the speed of rotation were a logarithmic normal function. Increase in the adherent particle size and concentration decreased the adhesive tendency of all drug powders studied. Particle collisions during detachment and the formation of multiparticulate layers even before the monolayer saturation of the carrier surface were responsible for the reduced adhesive stability of the drugs on the carrier as the particle loading increased.
Experimental investigation of adhesion between powders and surfaces
Authors: Booth S W , Newton J M
Published: April 2011

The adhesion between two pharmaceutical powders (poly (ethylene glycol) 4000 and Sta-Rx 1500) and various metal and polymer substrates has been investigated. The powders were either deposited on the substrates with negligible force or forced on by spinning in a centrifuge. The force required to remove the particles was then evaluated by spinning the substrate-powder samples in a centrifuge and counting the remaining powder after rotation at various spéeds. The median adhesive force between the powders and various substrates was similar in the case of particles deposited with negligible force, with the exception of adhesion to PTFE, which was about one-third of the force. After the powders had been forced on to the substrate surface the median adhesive force increased. This increase was approximately five-fold for the Sta-Rx 1500 and up to thirty-fold for the PEG 4000. Differences in the adhesion between each powder and the various substrates were now evident with, for example, Sta-Rx 1500 adhering to stainless steel with a force of 1510 times 10−9 N, but to Dural with a force of 2380 times 10−9 N.
Antimicrobial activity of n-alkyltrimethylammonium bromides: influence of specific growth rate and nutrient limitation
Authors: Wright Naomi E , Gilbert Peter
Published: April 2011

The antimicrobial activity of an homologous series of n-alkyltrimethylammonium bromides has been assessed towards Escherichia coli grown at a variety of specific growth rates and under various conditions of nutrient limitation. For each individual set of growth conditions activity was parabolically related to the n-alkyl chain length of the compounds and thus to compound lipophilicity (log P). The compound that showed optimal activity and thereby optimal lipophilicity (log P***o) changed according to growth rate and nutrient limitation. Such changes are related to variations in the gross cell envelope composition of the cultures (phospholipid, lipopolysaccharide, neutral lipids, proteins). The data therefore support the hypothesis that changes in growth rate and nutrient limitation alter the overall lipophilicity of the cell envelope and thereby the optimal value of log P for compounds to traverse it. Additionally, the data suggest that for the compounds examined, the acidic: neutral phospholipid ratios of the cell envelope, also influence the permeation of it.
Cardiovascular responses in rats with chronic renal failure
Authors: Yates M S , Askey Elizabeth A , Bowmer C J
Published: April 2011

Cardiovascular responses were determined in rats with chronic renal failure (CRF) produced by five sixths nephrectomy and in sham-operated rats. The conscious systolic blood pressure of rats with CRF was significantly higher than the pressure in controls although, after anaesthesia, there were no significant differences in the mean arterial pressure between the two groups of rats. The pressor responses to noradrenaline in rats with CRF were not significantly different from those recorded in sham-operated controls. The bradycardia elicited by electrical stimulation of the vagus nerve was significantly diminished in rats with CRF. However, indomethacin treatment (1 mg kg−1 s.c. twice daily for 2 days) abolished the differences in response to vagal stimulation. Changes in heart rate in response to electrical stimulation of the cervical sympathetic nerve and to bolus i.v. injections of isoprenaline and carbachol were similar in rats with CRF and controls. The most notable disturbance of cardiovascular function in rats with CRF is the diminished cardiac chronotropic response to vagal stimulation which appears to be mediated by a presynaptic action of prostaglandins.
Comparison of the effects of nabumetone with indomethacin on rat gastric mucosal 6-keto-PGF1α production and on bile salt-induced changes in gastric mucosal function
Authors: Melarange R , Rashbrook L C
Published: April 2011

The effect of nabumetone on rat gastric mucosal cyclooxygenase activity ex-vivo and in-vitro has been compared with that of indomethacin. Nabumetone was less potent and less active in inhibiting the production of gastric mucosal 6-keto-PGF1α compared with indomethacin either ex-vivo or in-vitro. Anti-inflammatory doses of nabumetone failed to enhance bile salt-induced gastric erosion or mucosal permeability to dextran whereas indomethacin significantly enhanced gastric erosion and increased dextran permeability. These results suggest that nabumetone fails to promote gastric damage or increase permeability because of minimal effects on gastric mucosal cyclooxygenase.
Hypothermic effect of GABA in conscious stressed rats: its modification by cholinergic agonists and antagonists
Authors: Miñano F J , Sancibrian M , Serrano J S
Published: April 2011

γ-Aminobutyric acid (GABA) intraperitoneally injected (i.p.) produced a dose-dependent hypothermia in restrained rats. GABA-induced hypothermia (1000 mg kg−1) was antagonized by pretreatment with atropine (2ṁ5 and 10 mg kg−1 i.p.), hyoscine butylbromide (2ṁ5 mg kg−1 i.p.), hexamethonium (0ṁ75 mg kg−1 i.p.) or physostigmine (0ṁ2 mg kg−1 s.c). Hexamethonium (7ṁ5 mg kg−1 i.p.) did not influence the hypothermia induced by GABA. The antagonism by physostigmine of GABA-induced hypothermia was attenuated by pretreatment of the rats with either α-methyl-p-tyrosine (200 mg kg−1 i.p.) or hexamethonium (0ṁ7mg kg−1 i.p.), but it was potentiated by either atropine (5 mg kg−1 i.p.) or hexamethonium (0ṁ75 mg kg−1 i.p.). The data indicate that GABA-induced hypothermia may be partly mediated by acetylcholine release. Muscarinic receptors may play an important role in the effect of GABA. The results support the hypothesis of nicotinic presynaptic receptors modulating noradrenergic nerve endings that play a part in the hypothermic response of GABA.