bluuebunny/crossref_metadata_2025 huggingface dataset:
Some emulsifying and suspending properties of a polysaccharide gum derived from Mucuna flagillepes, Papilionaceae
Authors: UDEALA O K , UWAGA U N
Published: April 2011

The emulsifying and suspending properties of a new polysaccharide gum derived from an edible bean, Mucuna flagillepes have been investigated. The stability of the emulsion prepared with the gum was compared with that of emulsions prepared with acacia or tragacanth. Sherman's equations for concentrated emulsions were applied to determine the rate of coalescence k, and changes in mean cube globule diameter. Suspensions of sulphdimidine or zinc oxide prepared with tragacanth gum were compared with those prepared with mucuna gum. The final sedimentation height, Hu for each suspension was predicted using a biexponential relationship in the sedimentation pattern. The indication is that mucuna gum can be usefully employed as both an emulsifying and a suspending agent.
The effect of punch tip geometry on powder movement during the tableting process
Authors: SIXSMITH DAVID , MCCLUSKEY DAVID
Published: April 2011

Axial and radial powder movements during the tableting process have been studied using punches with various tip geometries. Radial powder movement has been shown to occur. Alteration of punch tip geometry did affect both axial and radial powder movement, the extent being dependent on the relative curvature of the punch tip. Addition of lubricant decreased relative axial movement but had little effect on radial movement.
The effect of compression on the capillary microstructure of tablets
Authors: CARLI F , COLOMBO I , SIMIONI L , BIANCHINI R
Published: April 2011

The effect of compaction pressure on the capillary characteristics of compacts of a crystalline drug and of a pure polymer was studied by means of penetration and porosimetry measurements. Not only the constant but also the exponent m of the general penetration volume-time relationship V = Kmtm proved to be strongly dependent on the pressure: as the compaction pressure is increased, the value of m tends to decrease. The capillary penetration data also showed the development of a marked heterogeneity in the structure of the polymer compacts at the lower compaction pressures: at these pressures the surface layers showed a much lower penetrability than the inner core of the compacts, whereas at the higher pressures the structure of the compacts was homogeneous. Furthermore, on the basis of a generally used equation describing the powder consolidation process, it was possible to relate the most relevant variation of the kinetics of capillary penetration into the drug compacts to the deformation of the particles. It is concluded that the capillary penetration measurements can give useful information in the understanding of the behaviour of pharmaceutical powders under compression.
Human brain monoamine oxidase: one molecular entity-multiple binding sites?
Authors: SCHURR AVITAL , HO BENG T , SCHOOLAR JOSEPH C
Published: April 2011

Monoamine oxidase (MAO) of human brain cortex was partially characterized by using different substrates and inhibitors. Two Km values were calculated for each of the three substrates tested, i.e., phenethylamine (PEA), benzylamine (BA) and 5-hydroxtryptamine (5-HT). Clorgyline and 5-HT, both known as MAO-A occupants, were able to abolish the second (high) Km deamination of PEA. 5-HT, while non-competitively inhibiting the deamination of low BA concentrations, competitively inhibited the deamination of high concentrations of this type B substrate. The kinetics of 5-HT deamination showed positive cooperation which indicates the involvement of subunits in the enzyme structure. The ability of some phospholipids to change the enzyme behaviour was considered as indication that these molecules might play a role in determining the ratio between the so-called A and B types of MAO, and in the regulation of the enzyme's activity.
Stability of bovine insulin
Authors: FISHER BARRY V , PORTER PATRICIA B
Published: April 2011

A stability experiment on purified crystalline bovine insulin showed that it deteriorates at normal refrigeration temperature (5°C) and that storage at −20°C is necessary to ensure stability. Purified insulin degrades by two mechanisms: deamidation and polymerization. Immunochemical potency determinations alone are insufficient to determine the stability of insulin as they may be little affected by the chemical changes which occur on storage. The activation energy for the polymerization of insulin was found to be 66 kJ mol−1 and for deamidation 45 kJ mol−1. It is recommended that crystalline bovine insulin be stored at −20°C.
Non-ionic surfactants and gastric mucosal transport of paraquat
Authors: WALTERS K A , DUGARD P H , FLORENCE A T
Published: April 2011

The influence of a range of polyoxyethylated non-ionic surfactants upon the transport of [14C]-paraquat dichloride across rabbit isolated gastric mucosa was investigated. Paraquat was shown to cross the mucosal epithelium by passive diffusion. Certain members of the surfactant series enhanced transmucosal paraquat transfer at low surfactant concentration (e.g. 0·001%) but the occurrence and magnitude of this effect was not dependent in a simple manner upon surfactant structure or physicochemical properties. At micellar concentrations the increase in paraquat transport was greatest with those surfactants possessing both ethylene oxide chains of 10–20 units and alkyl chains longer than C7-C9. The most effective absorption promoter was found to be Brij 36T (C12E10). At micellar surfactant concentrations, the enhancement of paraquat transfer appeared, from histological evidence, to be related to the ability of the surfactants to solubilize membrane components and disrupt epithelial cells.
The pharmacokinetics of a new benzamide drug, clebopride, in the rat and the dog
Authors: SEGURA J , GARCÍA I , BORJA L , TARRÚS E , BAKKE O M
Published: April 2011

After intravenous, intramuscular and oral administration of clebopride in the rat and the dog its apparent volume of distribution is high (1·6–3·2 1 kg−1) and it has a longer biological half-life than metoclopramide in both species. High clearance values and concentrations of metabolites in plasma after oral administration indicate that the drug is subjected to an extensive first pass metabolism in the rat. Thus, clebopride administered orally gives relatively low concentrations in the systemic circulation in rats even though it is rapidly absorbed. The metabolic processes appear to become saturated at high doses which is reflected in dose-dependent kinetics. Linear kinetics were observed in the dog, although enterohepatic recycling could occur.
How β2-selective is the adrenoceptor antagonist drug, IPS 339?
Authors: O'DONNELL STELLA R , WALDUCK KARIN
Published: April 2011

Schild plots for the compound (t-butylamino-3-ol-2-propyl)oximino-9-fluorene (IPS 339) have been obtained on isolated intrinsic tone trachea and atria (rate) of guinea-pigs. α-Adrenoceptors and uptakes were inhibited. The Schild plots for IPS 339 on trachea (fenoterol as agonist) and on atria (noradrenaline as agonist) were not superimposed suggesting that IPS 339 was β2-selective. The slopes of the Schild plots obtained on intrinsic tone tracheal preparations (isoprenaline or fenoterol as agonist), although greater than 1·0, were not significantly different from that on atria (noradrenaline as agonist). From the average separation of these Schild plots on trachea and atria IPS 339 was assessed to be only 3·3 times more active on β2- than on β1-adrenoceptors. The experiments in the literature which showed a high β2-selectivity for IPS 339 (155 fold) were carried out on carbachol-contracted tracheal preparations (isoprenaline as agonist) and the Schild plot obtained had a very low slope which was quite different from that on atria. Therefore, the results illustrate how the quantitative estimate of the selectivity of a β-adrenoceptor antagonist can be misleading when Schild plots with different slopes are compared.
A hypertensive response to baclofen in the nucleus tractus solitarii in rats
Authors: PERSSON B
Published: April 2011

The hypertension and tachycardia after intraperitoneal administration of baclofen, 5 mg kg−1, to conscious rats was prevented by a midcollicular decerebration but not by a brain transection rostral to the hypothalamus. In conscious rats, local application of baclofen (50 ng) into the region of the nucleus tractus solitarii (NTS) caused a consistent pressor response while injections into the hypothalamus, n. fastiguus, nn. amygdala, nn. dorsalis raphe or n. locus coreuleus did not. The cardiovascular effects of NTS injections of baclofen in anaesthetized animals were variable. The reflex heart rate reduction to noradrenaline (0·5 μg i.v.) was prevented by administration of baclofen i.v. as well as locally into the NTS. It is concluded that baclofen causes elevation of blood pressure in the NTS, and that this structure is a possible locus of action for systemically administered baclofen in producing hypertension.
Withdrawal syndrome after continuous infusion of clonidine in the normotensive rat
Authors: THOOLEN M J M C , TIMMERMANS P B M W M , VAN ZWIETEN P A
Published: April 2011

The effects on heart rate and arterial pressure of continuous subcutaneous infusion of clonidine (500 μg kg−1 day−1) via an ALZET miniosmopump and sudden termination of this treatment were studied in conscious normotensive rats. No consistent decreases of heart rate and blood pressure were observed during the clonidine infusion. Within a few hours following removal of the minipumps, a pronounced and long-lasting tachycardia developed. Mean arterial pressure did not exceed control level consistently, but transient blood pressure ‘upswings' were observed. The withdrawal phenomena were accompanied by a small, significant rise in plasma noradrenaline content. During the clonidine-infusion period piloerection and sedation were prominent. The present study indicates, that the occurrence of the withdrawal phenomena following cessation of clonidine treatment is not dependent upon a decrease of blood pressure and heart rate preceding clonidine withdrawal. Furthermore, the model presented may be suitable for the study of withdrawal phenomena of other antihypertensive drugs.
Cardioregulatory properties of indoramin in the rat
Authors: ALGATE D R , RASHID S , WATERFALL J F
Published: April 2011

The antihypertensive action of the competitive α-adrenoceptor antagonist indoramin is not accompanied by reflex tachycardia in animals or man. The possibility that the established local anaesthetic property of indoramin is involved in its cardioinhibitory action has been investigated. Indoramin evoked a dose-dependent bradycardia in anaesthetized/pithed rats. The decrease in heart rate was slightly greater than that evoked in anaesthetized intact animals suggesting that indoramin had a direct action on the heart. Reflex tachycardia was simulated in pithed rats by increasing the frequency of cardiac nerve stimulation from 0·3 to 1 Hz. Indoramin and the local anaesthetic agents, lignocaine and procaine, reduced the positive chronotropic response without markedly altering the basal rate. The response curves were parallel. In contrast, phentolamine decreased the positive chronotropic response, but only at high doses which were associated with a marked decrease in the basal rate. Thymoxamine and prazosin had no significant effects on the chronotropic response. These experiments suggest that the cardioregulatory action of indoramin is attributable to its local anaesthetic property and this action further distinguishes it from the other α-adrenoceptor antagonists tested.
Free fraction change with differing volume ratios in equilibrium dialysis: cases of non-linear drug-protein binding
Authors: BEHM HARRIET L , WAGNER JOHN G
Published: April 2011

When equilibrium dialysis is used to measure drug-protein binding, an increase in the volume ratio (buffer solution/protein solution) causes a decrease in the total drug concentration at equilibrium. When binding is non-linear, this decrease in total drug concentration also causes a decrease in the free fraction. By use of the same volume ratio (3:1) binding curves were obtained for the binding of prednisolone to plasma proteins, and for the binding of salicylic acid and tolmetin to human serum albumin (HSA). When the volume ratio was changed, the observed free fractions were appreciably different from those expected by taking into account only the changes in the total equilibrium drug concentration. There is evidence that this phenomenon is the result of competition for binding sites between the drug and an impurity in the HSA. The effects are not the result of the presence of free fatty acids.
The effect of stress and indomethacin, carbenoxolone, salbutamol, metiamide, zolimidine and CF19415 on rat gastric mucus
Authors: GREEN A P , LANDER J E , TURNER D H
Published: April 2011

A method for measuring mucus adherent to the gastric mucosa using the dye alcian blue has been evaluated. Mucus was reduced by cold-restraint stress, reserpine and pyloric ligation, but not by 18 h fasting or indomethacin. The fasting mucus level was increased by carbenoxalone, but not by salbutamol or metiamide, and zolimidine only prevented the reduction in mucus induced by stress. A novel compound, 2-α-methoxyiminopyrazine acetonitrile (CF 19415), at 100 mg kg−1 orally increased alcian blue binding in fasted rats and in a cold restraint test, 100 mg kg−1 orally inhibited gastric damage and stimulated mucus secretion.
Inhibitory effect of two steroids on the accumulation of [3H]metaraminol by rat tissues in vivo
Authors: DAVILA D , IVANOV ROZA , DAVILA TATJANA
Published: April 2011

The present experiments were designed to investigate the effect of methylprednisolone and dexamethasone on tritiated metaraminol uptake in the whole animal. Rats received i.p. injections of methylprednisolone (5, 10 and 20 mg kg−1) or dexamethasone (1, 2 and 4 mg kg−1) on each of 3 consecutive days. Under light ether anaesthesia 5 min before death the rats received radioactive metaraminol (3 μg kg−1) via the femoral vein. Samples of various organs were removed and prepared for scintillation counting. The highest radioactivity was observed in the lungs and heart, followed by the kidney medulla, aorta, kidney cortex and submaxillary gland. Both steroids significantly inhibited uptake of metaraminol in the tissues examined. Dexamethasone seems to be more potent than methylprednisolone. It is concluded that these steroids may modify the uptake mechanism responsible for inactivation of the sympathomimetic neurotransmitter.
A polymeric film responding in diffusion properties to environmental pH stimuli: a model for a self-regulating drug delivery system
Authors: ALHAIQUE F , MARCHETTI M , RICCIERI F M , SANTUCCI E
Published: April 2011

A new polymeric film, ethylene-vinyl-NN-diethylglycinate random copolymer, has been studied to evaluate possible applications of such a material to produce controlled release dosage forms. Protonation of the substituted amino groups took place to different extents according to environmental pH conditions. The polymeric film proved to be permeable only to uncharged species, the rate of diffusion of which increased with the increasing charge of the membrane. This effect might be related to strong polymer-proton interactions affecting structure and transport properties of the film and enhancing the solvation process. The charged form of a number of barbituric acid derivatives did not diffuse through the membrane. The uncharged forms permeated the polymeric sheeting at rates consistent with their partition coefficients and which increased with the increasing charge of the polymer.
Kainic acid lesions of striatum and decortication reduce specific [3H]sulpiride binding in rats, so D-2 receptors exist post-synaptically on corticostriate afferents and striatal neurons
Authors: THEODOROU A , REAVILL C , JENNER P , MARSDEN C D
Published: April 2011

Unilateral kainic acid lesions of rat striatum reduced specific striatal [3H]spiperone and [3H]sulpiride binding sites (Bmax) by 52 and 67% respectively compared with the intact side. The dissociation constant (KD) for [3H]spiperone binding was unchanged but that for [3H]]sulpiride binding was reduced. Specific striatal [3H]spiperone and [3H]sulpiride binding was reduced by 22 and 37% respectively in unilateral decorticate animals, but there was no change in KD. Unilateral 6-hydroxydopamine lesions of the medial forebrain bundle caused no change in striatal [3H]spiperone binding sites or KD value, but produced a 27% increase in [3H]sulpiride binding sites with no change in KD. These data support the hypothesis of D-2 receptors located on cortico-striate glutamate fibres, but also indicate the presence of both D-1 and D-2 receptors on the cell bodies of striatal neurons.
Whole brain tyrosine hydroxylase activity during the development of deoxycorticosterone acetate-1% sodium chloride-induced hypertension in rats
Authors: JACKSON NIGEL , GULLIVER PETER A , DEAN HARVEY G
Published: April 2011

Water was chosen as the optimal medium for the extraction of tyrosine hydroxylase (TH) from rat brain. Determination of TH activity in crude homogenates failed to exhibit a linear relationship between enzyme concentration and measured activity, however, when a supernatant was used, a linear relationship existed. At a time when TH activity is maximally increased in the locus coeruleus after reserpine treatment (Reis et al 1975; Zigmond 1979) (2.5 mg kg−1 day−1 for 3 days, kill 24 h after last dose) we could detect no alterations in whole brain TH, however if treatment continued for 4 days and animals were killed 72 h after the last dose it was possible to detect increases in TH activity in various brain regions. These results suggest that local changes in brain TH activity are not revealed in measurements made on whole brain. The early rise in blood pressure, following the administration of deoxycorticosterone acetate (doca) and 1% NaCl to male Wistar rats, was accompanied by bradycardia. Whole brain TH activity was determined in these hypertensive animals 6–21 days after the commencement of treatment and the results failed to confirm the reported elevation of TH activity (Rylett et al 1976). The results are discussed with reference to the TH assay employed.
The neuromuscular and autonomic blocking effects of azasteroids containing choline or acetylcholine fragments
Authors: MARSHALL I G , HARVEY A L , SINGH H , BHARDWAJ T R , PAUL D
Published: April 2011

Nine analogues of the azasteroid muscle relaxant chandonium have been tested for neuromuscular blocking activity, ganglion blocking activity, inhibitory effects on cardiac muscarinic receptors, and for effects on noradrenergic transmission. Experiments were performed in anaesthetized cats and in isolated preparations. The two bisquaternary compounds HS-626 and HS-627, choline and acetylcholine-like analogues of chandonium respectively, were approximately equipotent with chandonium as neuromuscular blocking agents in the cat, but HS-672 possessed slightly more vagal blocking action. No evidence was obtained for ganglion block. The monoquaternary analogues, HS-408 and HS-465 and two 4-aza-androstanes, (HS-522 and HS-523) were more than 100 times less active than the bisquaternary compounds as neuromuscular blocking agents, and produced vagal blockade and ganglion blockade at sub-neuromuscular blocking doses. pA2 determinations in the chick biventer cervicis muscle, the guinea-pig atria and guinea-pig ileum showed that the bisquaternary compounds chandonium, HS-626 and HS-627 were much more potent in blocking cardiac than intestinal muscarinic receptors and that HS-626 possessed the widest margin between concentrations blocking the nicotinic receptors at the neuromuscular junction and the cardiac muscarinic receptors. Evidence for the three bisquaternary compounds blocking neuronal noradrenaline reuptake was obtained only at very high concentrations. HS-626 possessed a slightly more desirable spectrum of activities than chandonium, but the degree of improvement over the parent compound is insufficient to merit extensive clinical testing.
Determination of interparticulate forces in ordered powder mixes
Authors: STANIFORTH J N , REES J E , LAI F K , HERSEY J A
Published: April 2011

The theory of interparticle bond formation is considered with particular reference to ordered powder mixing. A technique is described for measuring the interparticle adhesion forces between drug and excipient particles bound in ordered units. The method uses a specially constructed ultracentrifuge rotor tube insert such that fine adherent particles can be separated from coarser carrier particles in ordered mixes. The ordered units are held behind a screen in the rotor tube insert and when the forces generated by ultracentrifugation become greater than the interparticle adhesion forces the ordered units break down into their component particles. Adhesion profiles were obtained for four different ordered mixes containing drug and excipient powders by plotting force of adhesion against the cumulative percentage of fine drug particles adhering to the carrier particle surface. The adhesion profile is influenced by the quantity of drug powder adhering to the excipient carrier particle surface. Above a critical drug content, each ordered mix shows a ‘composite' adhesion profile consisting of two distinct curves linked by a lag period. The initial curve, preceding the lag period, appears to correspond to loss of large amounts of weakly bound drug particles; after the lag period only relatively strongly adhered particles are removed and this phase occurs more gradually. The critical drug concentration is related to the surface properties of the excipient and drug particles which determine the strength of adhesion forces within an ordered unit.
Influence of coating and core modifications on the in vitro release of methylene blue from ethylcellulose microcapsules produced by pan coating procedure
Authors: BROPHY M REGINA , DEASY P B
Published: April 2011

Core pellets containing methylene blue, a highly water-soluble drug, lactose and polyvinylpyrrolidone (PVP) were produced and coated by pan technology with ethylcellulose 7 cp. Scanning electron microscopy revealed that larger microcapsules were aggregates of smaller microcapsules which remained intact during the dissolution testing. The coating appeared porous with rough and smooth areas. Polymer disc studies confirmed a lack of swelling of the ethylcellulose used when in contact with the dissolution medium. Modifications of the coating applied included addition of hydroxypropylmethylcellulose (a cofilm former), diethyl phthalate, di-n-butylphthalate and castor oil (plasticizers), talc (an extender and anti-tack agent) and paraffin wax and hydrogenated castor oil (waxy sealants) to the coating solution. Most products had released 50% drug after about 20 min dissolution treatment although the inclusion of the waxy sealants in the coating markedly retarded release during the first 60 min. In contrast, the inclusion of hydrogenated castor oil or polyethylene powder in the core, retarded dissolution of the drug over 3 h but tended to produce a coarser product. Other modifications of the core were addition of hydroxypropylmethylcellulose, carnauba wax-beeswax (1:1) and carnauba wax, with little retardation of drug release. The mechanism of drug release from the microcapsules was complex involving mainly diffusion.
Acetylcholine release from the myenteric plexus of guinea-pig ileum by prostaglandin E1
Authors: YAGASAKI O , TAKAI M , YANAGIYA I
Published: April 2011

Release of acetylcholine (ACh) by prostaglandin E1 from the nerve terminals of the guinea-pig longitudinal muscle strip was studied in order to reveal the effect of PGE1 on myenteric plexus activity. The ACh released was collected in the presence of physostigmine (2·1 μg ml−1) and choline (0·1 μg ml−1) at 38° C. Five to 100 ng ml−1 PGE1 enhanced the release dose-dependently. The effect was maintained during the presence of PGE1 in the organ bath, while rapid tachyphylaxis was observed with the ACh-releasing action of nicotine. Tetrodotoxin or morphine almost completely inhibited the effect of PGE1 on ACh release. Hexamethonium, in a concentration which completely blocked the effect of nicotine, partially inhibited the effect of PGE1. In the late phase of nicotine action, the tissue was still sensitive to PGE1 despite the continued exposure to nicotine. These data suggest the presence in the myenteric plexus of PG receptors which can increase ACh release.
Influence of 1,8-dihydroxyanthraquinone and loperamide on the paracellular permeability across colonic mucosa
Authors: VERHAEREN E H C , DREESSEN M J , LEMLI J A
Published: April 2011

Administration of 1,8-dihydroxyanthraquinone (DHA) markedly increases the permeability of guinea-pig colonic mucosa. In 1 h 25% of the administered dose of99m Tc-EDTA complex leaks through the mucosa. Orally administered loperamide blocks the99m Tc-EDTA transfer after DHA administration. Loperamide injected in situ in the ligated colon segment shows the same blocking properties of the transfer rate of the complex. These findings suggest that the opposing action on fluid transport of the laxative DHA and the antidiarrhoeal loperamide could be due to these drugs affecting the permeability of the colonic mucosa. The minimal dose of loperamide, able to restore normal permeability, was as low as 0·01 mg kg−1.
Influence of deaminated metabolites on the relaxing effect of dopamine on dog saphenous vein
Authors: TEIXEIRA F , MACEDO T R A
Published: April 2011

The relaxing effect of dopamine was studied on the dog isolated saphenous vein contracted by prostaglandin F2α after α-adrenoceptor blockade by phentolamine. This effect is partially inhibited by propranolol and haloperidol suggesting that dopamine has two types of receptors in this vessel: β- and dopaminergic receptors. However, the results obtained after treatment with drugs that interfere with deamination of catecholamines or after denervating the venous tissue led us to conclude that the agonist substance is not dopamine, but probably one of its deaminated metabolites or a secondary condensation product, namely tetrahydropapaveroline. Adrenaline has also been used to compare the behaviour of the two amines when interference in the deamination process is produced. The dissimilar results obtained with adrenaline are in good agreement with the hypothesis.
Theoretical considerations of the influence of polymer film coatings on the mechanical strength of tablets
Authors: STANLEY P , ROWE R C , NEWTON J M
Published: April 2011

A theoretical analysis of the influence of polymer film coatings on the mechanical strength of tablets has been undertaken. Making some basic assumptions, the theory predicts that neither the thickness of the substrate nor that of the coating has any influence on which fractures first, this being solely determined by the ratio of the tensile fracture strength to the Young's modulus for the two materials. Such a finding suggests that in practice for film-coated tablets the substrate will usually fracture before the coating. Simple measurements of maximum failure loads are of little value in assessing the influence of film coating on the mechanical strength of tablets.
Comparison of the in vitro dissolution behaviour of various indomethacin formulations with their in vivo bioavailability
Authors: ROWE J S , CARLESS J E
Published: April 2011

The effects of the core to colloid wall ratio and particle size of the core on the in vitro release of indomethacin microcapsules prepared by the gelatin-acacia complex coacervation process have been examined. All formulations showed a zero order release pattern after an initial burst phase. The release rate increased with increasing core to coat ratios and decreasing particle size of core material. In vivo plasma level studies showed no difference in bioavailability between different microcapsule formulations or a conventional indomethacin capsule. In vitro release studies on a commercially available sustained release formulation of indomethacin (Indocid R) were slower than any of the microcapsule formulations and exhibited a √t dependence indicating a diffusion controlled process from a matrix formulation. In vivo studies show this formulation to have a longer, smoother plasma concentration than the microcapsule formulation, and to avoid high initial peak values of drug. Thus from the in vitro studies a sustained release effect was not unexpected but the in vitro differences between the microcapsule products were not paralleled by the in vivo behaviour. These results illustrate some of the problems in extrapolation of in vitro dissolution data to the in vivo situation.
Enhancement of the intestinal absorption of ergot peptide alkaloids in the rat by micellar solutions of polyoxyethylene-24-cholesteryl ether
Authors: FRANZ J M , VONDERSCHER J P
Published: April 2011

The incomplete intestinal absorption of hydrogenated ergot peptide alkaloids as measured in bile duct cannulated rats is much increased when the ergot compounds are administered as micellar solutions together with POE-24-cholesteryl ether. In vitro diffusion experiments with isolated intestinal mucus show that the ergot peptide alkaloids are strongly retained by the mucus layer. It is suggested that the diffusion of the ergot compounds across the mucus barrier is facilitated by micellar entrapment of the drug.
Histamine receptors in the guinea-pig duodenum
Authors: BERTACCINI G , ZAPPIA L
Published: April 2011

Guinea-pig duodenum contracted by histamine or by acetylcholine was relaxed dose-dependently by a series of H2-receptor selective agonists namely dimaprit, impromidine, clonidine and tolazoline. This relaxation was not neurally mediated since it was not modified by tetrodotoxin nor was it exerted through sympathetic receptors because it was not modified by pretreatment with propranolol or phentolamine. Apparently it was connected with the H2-receptor stimulation more than to peculiarities of the single compounds. However a series of H2-blockers (metiamide, cimetidine, ranitidine or oxmetidine) were unable to counteract the effect of the H2-agonists or the relaxant effect of histamine in the presence of chlorpheniramine. This peculiar situation seems to indicate the existence of anomalous H2-receptors, susceptible to the action of the agonists but not to that of the antagonists.
Effect of slugging pressure on the properties of granules and tablets prepared from potassium phenethicillin
Authors: KHAN K A , MUSIKABHUMMA P
Published: April 2011

The mechanism of preparing compacts by precompression has been investigated. The influence of slugging pressure on the bulk and tapped density, particle size distribution and the surface area of precompressed granules has been examined. The slugged granules have been tableted and the effect of compaction force on the weight uniformity, friability, crushing strength, disintegration time, dissolution rate and internal surface area of the tablets has been studied. The results show that the granules obtained from 15·9 mm slugs manufactured at low compaction forces (e.g. 49 MNm−2) had a lower bulk density, higher friability and larger surface area than those made at higher compaction pressures (e.g. 196 MNm−2). The lighter granules compacted into stronger tablets over a range of compaction forces and the effect was attributed to greater intergranular bonding caused by increased plastic flow.
The effect of DSP-4 (N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine) on monoamine oxidase activities in tissues of the rat
Authors: LYLES GEOFFREY A , CALLINGHAM BRIAN A
Published: April 2011

The in vitro inhibition of monoamine oxidase (MAO) in rat liver, and of the clorgyline-resistant amine oxidase (CRAO) in rat heart and aorta, by DSP-4 (N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine) has been studied. Inhibition of each enzyme activity was independent of prolonged preincubation, was reversed by dialysis, and also Ackermann-Potter plots were consistent with reversible inhibition. Simple linear competitive inhibition of MAO-A and MAO-B was observed, with Ki values of 6 × 10−6 and 8 × 10−5 m, respectively. CRAO was inhibited in a mixed, non-competitive manner (Ki of 3·2 × 10−5 and 7·8 × 10−6 m in heart and aorta, respectively) which conformed to a kinetic model in which the binding of DSP-4 to CRAO increased the affinity of substrate binding, but prevented product formation. The possible significance of these results for the in vivo actions of the drug is discussed.
Some biochemical aspects of the potential benefit of associating MD780515 with tricyclic antidepressants
Authors: DOSTERT P , BENEDETTI M STROLIN , SONTAG N
Published: April 2011

In the rat, suitable oral doses of tricyclic antidepressants (amitriptyline 20 mg kg−1, imipramine, desipramine 2·5 mg kg−1) are able to antagonize the increase of cardiac levels of intravenous tyramine after a pharmacologically active dose (3·5 mg kg−1 orally) of a reversible and specific type A MAO inhibitor, MD780515 (3-[4-(3-cyanophenyl-methoxy)phenyl]-5-(methoxymethyl)-2-oxazolidinone). MD780515, in oral doses up to 35 mg kg−1, does not alter the liver microsomal drug metabolizing enzymes in the rat. Therefore, when given with tricyclic antidepressants, it should not interfere with their metabolism.
Cultured neonate rat myocytes as a model for the study of myocardial ischaemic necrosis
Authors: HIGGINS TREVOR J C , BAILEY PETER J , ALLSOPP DAVID , IMHOF DERYL A
Published: April 2011

The preparation of cultures of neonate rat heart muscle cells is described. These cultures, when subjected to anoxia, show enzyme release that can be directly related to the uptake of a vital dye such as trypan blue. Enzyme release is a valid method of estimating cell necrosis in this model. The survival of anoxic cultures is closely associated with glycolytic activity. Glycolysis rate falls and enzyme release increases as the medium glucose concentration is reduced. If glycolysis is inhibited by either 2-deoxyglucose or L-lactate, enzyme release under anoxic conditions is enhanced. Enzyme release correlates inversely with glycolytic activity and the intracellular ATP content of the cultures. Addition of ATP to anoxic cultures partially ameliorates the effect of the anoxia on enzyme release. Elevation of the calcium content of the culture medium exacerbates the damage caused to cardiac myocytes by anoxic insult. This effect can be obtunded by calcium-antagonist drugs such as verapamil or nifedipine and can be explained in terms of a reduction in utilization of intracellular ATP by the anoxic myocytes. These observations indicate that cultured myocytes may represent a useful model of hypoxic injury against which novel pharmacological agents, that may reduce hypoxic or ischaemic injury in vivo, could be evaluated.
Pharmacological reactivity of granulation tissue
Authors: GARCÍA-VALDECASAS J C , GARCÍA-VALDECASAS F , PERA C
Published: April 2011

The contractile system of the myofibroblast has well defined characteristics. The findings suggest the presence of 5-hydroxytryptaminergic as well as α and β-adreno-receptors, although both appear to be immature. It does not have cholinergic or histaminergic receptors. The contractile system is inhibited by cytochalasin B and is not sensitive to colchicine. The contractile machinery is suggested to be the microfilament system, as it occurs in the contractile apparatus of primitive cells. This is in accordance with the role of myofibroblasts in granulation tissue neoformation.
Noradrenergic component in the vasoconstriction induced by 5-hydroxytryptamine in goat cerebral arteries
Authors: MARIN J , SALAICES M , GÓMEZ B , LLUCH S
Published: April 2011

5-Hydroxytryptamine (5-HT) elicited dose-dependent increases in tension in the middle cerebral artery of the goat, which were significantly antagonized by lysergic acid diethylamide (LSD, 10−8 M) and methysergide (10−7 M). In the presence of phentolamine (10−6 M), the dose-response curve to 5-HT was shifted to the right, the pA2 value for this antagonism was 6·52. Pretreatment of goats with reserpine (0·02 mg kg−1 day−1 for three days) or removal of both superior cervical ganglia 15 days before the experiment brought about a significant decrease in the vasoconstriction induced by doses of 5-HT higher than 10−7 M. The remaining contraction produced by 5-HT in arterial segments from reserpinized or gangliectomized goats was further reduced in the presence of LSD. In addition, high concentrations of 5-HT induced tritium release from goat pial arteries preloaded with (−)-[3H]noradrenaline, 2 × 10−7 M) which was significantly decreased in vessels from gangliectomized or reserpinized goats. These results in goat cerebral arteries indicate that in the contraction evoked by 5-HT there are two components. The first appears with low concentrations (up to 10−7 M) in which 5-HT acts directly on 5-HT receptors. The second occurs at high doses (>10−7 M) in which 5-HT also acts indirectly on α-adrenoceptors by release of noradrenaline from noradrenergic nerve endings.
Altered ocular absorption and disposition of sodium cromoglycate upon ion-pair and complex coacervate formation with dodecylbenzyldimethylammonium chloride
Authors: WILSON C G , TOMLINSON E , DAVIS S S , OLEJNIK O
Published: April 2011

Ion-pair formation between the dianionic drug sodium cromoglycate and dodecylbenzyldimethylammonium chloride has been found to alter the extent and rate of corneal penetration of both large ions upon their coadministration. Additionally, using a complex coacervate of the two large ions as the applied dose form (in which the complex is in equilibrium with the ion pairs), a change in the overall disposition of both large ions to the various components of the eye is observed.
Differential blockade of pre- and postsynaptic α-adrenoceptors by the 2-R and 2-S enantiomers of WB4101
Authors: MOTTRAM DAVID R
Published: April 2011

Agonists and antagonists of the α-adrenoceptor have been shown to possess different degrees of potency at the pre- and postsynaptic levels. The present investigation was undertaken to see whether the two optical isomers of WB4101 likewise exhibit differential blockade at the two receptor sites. This was achieved by measuring the potencies of 2-R and 2-S WB4101 against noradrenaline-induced contractions of the rat isolated vas deferens and against clonidine-induced inhibition of the twitch response in field stimulated rat vas deferens. Results showed that though the enantiomers exhibited widely differing potency, as indicated by calculations of pA2 values, at the postsynaptic level, they possessed almost identical potency presynaptically. In addition, 2-aminomethyl-1, 4-benzodioxan itself both exhibited reasonable presynaptic α-adrenoceptor blocking activity, whilst being devoid of activity postsynaptically. The values for slope on the Schild plots for 2-R and 2-S WB4101 indicated that they produced classical competitive antagonism at the postsynaptic receptor but at the presynaptic level the values for slope were indicative of a non-competitive type of blockade. Results are discussed in terms of recent suggestions of that agonists and antagonists of the α-adrenoceptor may not share a common mechanism or site of action at the presynaptic level.
Age-related changes in the chronotropic effect and the enzymic decarboxylation of L-threo-3,4-dihydroxyphenylserine in the rat heart
Authors: ARAKI HIROMASA , FUJIWARA HIROSHI , TANAKA CHIKAKO
Published: April 2011

The cardiac effect of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) and the enzymatic decarboxylation of the drug by L-aromatic amino acid decarboxylase (AADC) were studied in atria isolated from rats ranging in age from newborn to adults and the findings compared with the cardiac effect of noradrenaline (NA). L-threo-DOPS produced dose-dependent, slow-onset and positive chronotropic effects in atria from rats of different ages. Its effect was inhibited in atria from benserazide-treated rats, suggesting that the effects are due to NA formed from L-threo-DOPS by enzymic decarboxylation rather than to the compound itself. Chronotropic sensitivity to L-threo-DOPS was highest in the newborn and decreased with age during the first 3 weeks of life. The development of cardiac response to it correlated well with the development of enzymic decarboxylation of the drug but did not correlate with the developments of chronotropic sensitivity to NA and of NA concentrations in the heart. These findings suggest that in newborn rats, L-threo-DOPS is effectively converted by AADC to NA which in turn acts on β-receptors in the pacemaker cell membrane.
In vitro dissolution of dapsone
Authors: SWARBRICK JAMES , MA DIANA
Published: April 2011

Log normal samples of dapsone (DDS) were prepared in which the geometric mean diameter ranged from 20 to 50 μm while the geometric standard deviation was in the range 1·62 to 1·88. Using a simple in vitro flow-through dissolution cell at 37°C, the data obtained were found to fit the Hixson-Crowell cube root dissolution law up to a critical time, Tc, where a distinct break occurred. Such a biphasic phenomenon has been predicted by other workers and is related to the time at which the smallest particles present have undergone dissolution. The initial slopes of the cube root dissolution plots were shown to be directly related to the reciprocal of the geometric mean diameter.
Distribution of daunorubicin, a potent in vitro trypanocide which lacks in vivo activity, in the blood of trypanosome-infected mice
Authors: BROWN J E , BROWN J R , WILLIAMSON J
Published: April 2011

Daunorubicin is a highly potent trypanocide in vitro but lacks significant in vivo activity. Distribution of the drug in the blood components and in trypanosomes from mice infected with Trypanosoma rhodesiense was therefore examined. Drug is accumulated in the trypanosomes in a similar manner to, but to a greater extent than, its accumulation in platelets; it is, however, taken up by erythrocytes to a much smaller extent. Drug concentrations in trypanosomes, platelets and erythrocytes declined with its decline in plasma whereas in white blood cells the drug was retained at a constant level. Daunorubicin concentrations in plasma were several orders of magnitude higher than the in vitro trypanocidal concentration. Fluorescence microscopy showed that although daunorubicin reaches the trypanosome nucleus, its concentration decreases rapidly so that adequate levels of drug may not be sustained in the bloodstream form of the organism for a sufficient length of time to give a trypanocidal effect in vivo.
Prenylamine and the myocardial response to ischaemia and reperfusion: effects of acute and chronic treatment
Authors: MANNING ALLAN S , SHATTOCK MICHAEL J , HEARSE DAVID J
Published: April 2011

The ability of prenylamine gluconate (Segontin) to influence the extent of myocardial ischaemic injury was investigated in the isolated ‘working’ rat heart preparation. The drug was administered either acutely alone (4 μM litre−1 in the perfusion medium) or chronically plus acutely in which case animals were pre-treated (10 mg kg−1 day−1 orally) for 10 days and the drug was then also added (4 μM litre−1) to the perfusate. Acute administration alone resulted in a small reduction in spontaneous functional performance of the aerobic isolated heart in comparison with gluconate treated controls. It also increased the percentage of hearts able to recover functional activity after a period of severe ischaemia and decreased ischaemia induced injury as assessed by enzyme leakage. In contrast to the acute results the combination of chronic and acute administration of prenylamine did not significantly alter spontaneous cardiac function. Although a small increase in the number of hearts that recovered function was apparent, there was a concomitant decrease in post-ischaemic functional performance with no reduction of ischaemia induced enzyme leakage.
The permeability of enteric coatings and the dissolution rates of coated tablets
Authors: PORTER S C , RIDGWAY K
Published: April 2011

The effect of an increasing concentration of plasticizer and pigment on the permeability to both water vapour and simulated gastric juice of cellulose acetate phthalate and polyvinyl acetate phthalate has been evaluated. There were significant differences between the permeability coefficients of each polymer, particularly with regard to water vapour. The presence of additives within the film coatings had a greater effect on the properties of cellulose acetate phthalate than those of polyvinyl acetate phthalate. Suitable formulations of each polymer were used to enteric coat 325 mg aspirin tablets, which were subsequently subjected to both the Disintegration Test for Enteric Coated Tablets B.P. and a dissolution procedure to monitor the release of drug in simulated gastric juice and simulated intestinal fluid. Both polymers demonstrated their suitability for producing enteric coatings. However, polyvinyl acetate phthalate yielded a faster release of aspirin in simulated intestinal fluid than did cellulose acetate phthalate.
Effect of (+)- or (−)-enantiomers of fenfluramine or norfenfluramine on nutrient selection by rats
Authors: HIRSCH JOSEPH A , GOLDBERG SCOT , WURTMAN RICHARD J
Published: April 2011

The effects of the (+)- and (−)-enantiomers of fenfluramine and norfenfluramine on food choice and total food consumption by rats, have been examined. Animals were trained to select their food during an 8-h daily interval from two isocaloric-isocarbohydrate (40%) diets differing in protein contents (5 or 45% casein). Low doses of (+>-fenfluramine (1.25 or 1.65 mg kg−1) selectively reduced consumption of the 5%-protein diet during the hour after administration, thereby also reducing carbohydrate intake by a greater proportion than protein intake. Higher doses (2.5 or 4.0 mg kg−1) diminished consumption of both test diets to an equivalent extent. (+>-Norfenfluramine, although anorectic, did not modify the relative consumptions of carbohydrate and protein at any dose tested. These observations affirm that nutrient selection as well as total food consumption can be altered by drugs affecting particular neurotransmitters.
On the ability of domperidone to selectively inhibit catecholamine-induced relaxation of circular smooth muscle of guinea-pig stomach
Authors: SAHYOUN H A , COSTALL B , NAYLOR R J
Published: April 2011

The effects of noradrenaline and dopamine, and their interactions with α- and β-adrenoceptor antagonists and with domperidone, were studied on circular smooth muscle strips taken from the cardia, fundus, body and antrum of the guinea-pig stomach. Noradrenaline and dopamine caused relaxations of all tissues which were generally susceptible to antagonism by either propranolol or phentolamine in concentrations shown to antagonize the relaxations caused by isoprenaline or phenylephrine respectively. In addition, dopamine, in concentrations subthreshold for relaxation, caused contraction of the muscle strips which increased in intensity from the cardia to the antral region: these contractions were antagonized by phentolamine and yohimbine but were insensitive to prazosin: prazosin selectively inhibited the phenylephrine relaxations. With the exception of a modest reduction in the responses of the cardia to dopamine, all tissue responses to noradrenaline and dopamine were resistant to reserpine. Domperidone and haloperidol were found to selectively inhibit the phenylephrine- noradrenaline- and dopamine-induced relaxations of the stomach strips and to enhance the contractile component of dopamine's action: this ability of domperidone to facilitate a dopamine induced contraction, which was most marked in the body and antral regions, was prevented by phentolamine. It is thus concluded that domperidone antagonizes noradrenaline- and dopamine-induced relaxations at one adrenoceptor site having characteristics conistent with an α1-adrenoceptor type whilst failing to antagonize at a further dopamine-sensitive adrenoceptor site involved in contraction of circular smooth muscle of the stomach and having characteristics consistent with an α2-adrenoceptor.