bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of some benzodiazepines on peripheral neuromuscular function in the rat in-vitro hemidiaphragm preparation
Authors: Driessen J J , Vree T B , Booij L H D J , Van Der Pol F M , Crul J F
Published: April 2011

The effect of equimolar cumulative concentrations of 11 different benzodiazepines on the indirectly evoked twitch contraction was investigated in the rat in-vitro phrenic nervehemidiaphragm preparation. Depending on the pattern of the concentration-response curves two groups of benzodiazepines can be distinguished: (i) a first group with a biphasic action, e.g. potentiation of twitch tension in low concentrations and depression of twitch tension in high concentrations, and (ii) a second group with primary depression of twitch tension with increasing concentrations. All of the tested compounds ultimately caused a 100% depression of twitch tension at concentrations ranging from 0·175 to 0·35 mmol litre−1. Although this peripheral effect of benzodiazepines on neuromuscular function is not the main site of action of these compounds, there are enough arguments to state that it is not a simple toxic effect. There is some evidence from this study that the peripheral component of the benzodiazepine effect on muscle relaxation may involve a multi- rather than one single receptor system.
Xylan–-a possible filler and disintegrant for tablets
Authors: Juslin M , Paronen P
Published: April 2011

Xylan, a novel possible adjuvant for tablets was tested and compared with modified starch, Sta-Rx 1500, for weight variation, strength and disintegration of tablets. There was no remarkable difference in weight variation between the tablets of the corresponding compositions. The tablets containing xylan were stronger and disintegrated more rapidly than those containing modified starch.
Effects of freezing on human skin permeability
Authors: Harrison S M , Barry B W , Dugard P H
Published: April 2011

The percutaneous absorption of water was measured in-vitro at 30 °C for pale caucasian abdominal skin which had been stored at −20 °C for up to 466 days and compared with fresh skin. Prolonged freezing of the skin did not affect the absorption of water which had a mean permeability coefficient of 1·71 ± 0·62 times 10−3 cm h−1 (180 diffusion experiments with 39 skin specimens). No significant difference was found between the absorption of water through human skin which was fresh or had been frozen. The mean permeability coefficient for skin which had not been frozen was 1·30 ± 0·55 times 10−3 cm h−1 for 6 skin specimens.
Acetylcholine-induced inhibition of responses to field stimulation in rabbit pulmonary artery is unaffected by endothelium removal
Authors: Loiacono R E , Story D F
Published: April 2011

Acetylcholine (0·01–10 μmol litre−1) relaxed normal rings (endothelium-retained) of rabbit pulmonary artery precontracted with clonidine (10 μmol litre−1) while preparations with the endothelium removed responded with contraction only. Removal of the endothelium had no effect on contractions of the preparation to clonidine or field stimulation of the adventitial nerves (2 Hz, 10 s). Furthermore, the inhibitory effect of acetylcholine (0·3 and 1·0 μmol litre−1) on contractions induced by field stimulation was not influenced by the vascular endothelium.
The effect of levamisole on gastric ulcers induced in the rat by anti−inflammatory and necrotizing agents
Authors: Evangelista S , Maggi C A , Meli A
Published: April 2011

Levamisole, in doses similar to those required to observe immunostimulation in animals, antagonized dose−dependently, in rats, gastric ulcers produced by necrotizing agents (HCl and ethanol) and NSAIDs (indomethacin and piroxicam) without affecting the anti−inflammatory properties of these latter drugs.
Preliminary study of the disposition in man of acebutolol and its metabolite, diacetolol, using a new stereoselective hplc method
Authors: Sankey M G , Gulaid A , Kaye C M
Published: April 2011

A new stereospecific hplc method that is capable of simultaneously quantitating the S-(-)- and R−(+)−enantiomers of acebutolol and its major metabolite, diacetolol, in plasma and urine, is described. When applied to the assay of biological fluids collected during single and chronic oral dosing with acebutolol (Sectral), this procedure failed to reveal any important stereoselectivity in the disposition of either acebutolol or diacetolol in man. This may occur because acebutolol is metabolized by hydrolysis and N-acetylation, whereas the other β−blockers which exhibit some degree of stereoselective disposition (e.g. metoprolol and propranolol) are primarily metabolized by oxidation.
A contribution, from a possible local anaesthetic action, to the effects of yohimbine on evoked noradrenaline overflow
Authors: Goodall Jacqueline , Hagan R M , Hughes I E
Published: April 2011

Both yohimbine (0·1 to 10 μm) and phentolamine (10 μm) increased the tritium overflow evoked by electrical stimulation (2·5 Hz, 1 ms, 15 V, for 90 s every 20 min) of mouse isolated vas deferens previously incubated with (–)−[3H]noradrenaline. At their maximally effective concentrations, phentolamine (10 μm) produced an effect that was sustained over the 2 h of the experiment while the effect of yohimbine (6 μm) decreased by about 60% over the first 40 min and was then sustained at a lower level. At higher concentrations of yohimbine, the increase in evoked tritium overflow was less marked and at the highest concentration tested (30 μm) evoked overflow was reduced below the levels seen before exposure to the drug. It is concluded that at concentrations maximally effective in inhibiting the presynaptic α−adrenoceptor−mediated mechanism controlling transmitter release, the known local anaesthetic effect of yohimbine may contribute to the overall effect on evoked transmitter overflow.
The use of phenothiazines to enhance the rectal absorption of water―soluble compounds
Authors: Fix Joseph A , Leppert Paula S , Porter Patricia A , Alexander Jose
Published: April 2011

The ability of phenothiazines to enhance the rectal absorption of sodium cefoxitin and gentamicin sulphate from aqueous formulations was examined in rats. In the absence of absorption―promoting adjuvants, sodium cefoxitin and gentamicin sulphate bioavailabilities from the rectal compartment were less than 5% of the corresponding intravenous administration. In aqueous microenemas containing 20 mg ml−1 phenothiazine, sodium cefoxitin bioavailability increased to 16–62%, while gentamicin sulphate bioavailability increased to 74–146%. The absorption―promoting potential of chlorpromazine and perphenazine was concentration―dependent, with significant increases in gentamicin sulphate absorption occurring with 1 mg ml−1 chlorpromazine or 2·5 mg ml−1 perphenazine. Maximal gentamicin sulphate bioavailability and serum concentrations were achieved with 10 mg ml−1 chlorpromazine or 20 mg ml−1 perphenazine. The findings indicate that the phenothiazines, which are well absorbed rectally, also significantly enhance the rectal absorption of watersoluble, poorly absorbed compounds.
Formation of encapsulated hydrophilic polymer beads by combined techniques of bead polymerization and phase separation
Authors: Suryakusuma H , Jun H W
Published: April 2011

A novel and rapid procedure for the preparation of hydrophilic polymer beads coated with ethyl cellulose has been developed. The coated polymer beads were prepared by combining techniques of bead polymerization and phase separation into a single step procedure. The final product has a size range of 200–1000 μm and consists of the core copolymer of 2-hydroxyethyl methacrylate—acrylamide and the barrier membrane of ethyl cellulose. Examination of beads in which amaranth dye was used as a model of active ingredient showed the dye to be uniformly distributed throughout the polymer matrix. Microscopic examination indicated that ethyl cellulose coated the core matrix. The effects of ethyl cellulose concentration, degree of agitation and molar ratio of monomers on the size of coated beads were investigated.
The preparation and characterization of ferrous sulphate hydrates
Authors: Mitchell A G
Published: April 2011

Ferrous sulphate BP, FeSO4, 7H2O, dehydrates to form FeSO4, 4H2O when the relative humidity (RH) is less than 65%, or on heating at 40 °C. The tetrahydrate was also prepared by recrystallization at 60 °C from aqeuous solutions of the sulphate. Commercial dried ferrous sulphate BP is FeSO4, H2O but the method of preparation given in the BP produces FeSO4, 4H2O which is the stable form at RH < 65% (25 °C). A crystalline monohydrate was prepared either by heating the tetrahydrate on a boiling water bath to constant weight or heating the heptahydrate under vacuum at 60 °C in the presence of water vapour evolved from the water of crystallization. An X-ray amorphous form of FeSO4, H2O was made by heating the heptahydrate at 100 °C under vacuum with the removal of water vapour. Crystalline FeSO4, H2O rehydrates to the heptahydrate when RH > 65% but the amorphous form recrystallizes as the stable tetrahydrate at RH > 0 and <65%. The various hydrates were characterized by DSC and X-ray diffraction. A simple procedure is described for obtaining data to construct a RH-composition phase diagram. The method combines measurement of any weight changes of each hydrate after storage at various controlled humidities together with a direct measurement of RH over the hydrate pairs. The thermal dehydration pathways are reported together with the RH-composition phase diagrams.
Mianserin: is the intraperitoneal route of administration the best?
Authors: Sugrue Michael F
Published: April 2011

A 1 h pretreatment with s.c. mianserin (0·5 mg kg−1) markedly blunted the oedema of the rat paw induced by the subplantar injection of 5-HT (5 μg). In contrast, i.p. mianserin (same dose) failed to modify 5-HT-induced oedema. However, pretreatment with SKF-525-A (40 mg kg−1) resulted in a profound potentiation of the action of i.p. mianserin, the effect of the combination of SKF-525-A and i.p. mianserin rivalling that of s.c. mianserin. It is concluded that i.p. mianserin is metabolized by the rat liver to compounds which possess a reduced propensity to block peripheral 5-HT receptors and that the i.p. route of administration is not to be recommended when mianserin is being studied as a 5-HT receptor antagonist in the rat.
An evaluation of the relative importance of formulation and process variables using factorial design
Authors: Sanderson I M , Kennerley J W , Parr G D
Published: April 2011

A factorial design method for assessing the relative importance of various formulation and process factors and their interactions in model paracetamol tablets is described. The design was a 2 times 2 × 2 times 3 type using mixing time, starch concentration, drug particle size and compaction pressure respectively. The starch concentration was the most significant factor in affecting the dissolution rate but the larger drug particle size also gave a significant increase in drug release rate. Interactions between starch concentration and drug size and between these and mixing time were also observed. The most significant factor affecting the tensile fracture stress of the tablets was the mixing time, followed in order by the drug particle size, starch concentration and compaction pressure.
Convergent flow analysis in the extrusion of wet powder masses
Authors: Harrison P J , Newton J M , Rowe R C
Published: April 2011

The angle of convergent flow which occurs when a wet powder mass is extruded through a die has been assessed by the inclusion of dyes in the mass before extrusion. The angles obtained are dependent on the powder components and their proportion, the moisture level, and the ratio of the dead space to the area of open die. The method allows assessment of the type and ease of flow which occurs during extrusion.
Structure-activity in the carrageenans: iota-carrageenan and experimental oedemagenic activity
Authors: Anderson W , Harthill J E , Zeitlin I J
Published: April 2011

The oedemagenic activities of several iota-carrageenans from Eucheuma spinosum have been compared using the rat hindpaw model. From the parent ι-carrageenan of weight average molecular weight 541 100 an acid-degraded ι-carrageenan (M̄w = 20 300) was obtained which on fractionation yielded five ι-carrageenans M̄w ranging from 73 700 to 4 600. The oedemagenic activity of ι-carrageenan resided in the fraction of M̄w = 73 700, the parent undegraded high molecular weight ι-carrageenan being no more active and fractions of lower molecular weight being inactive. Fractionation was based on differential solubilities of the barium salts of the fractions in water and aqueous ethanol and was probably determined by aspects of primary structure in addition to molecular weight.
Anti-inflammatory and anti-ulcer properties of hypolaetin-8-glucoside, a novel plant flavonoid
Authors: Villar A , Gasco M A , Alcaraz M J
Published: April 2011

The anti-inflammatory, analgesic and anti-ulcer activities of a novel flavonoid, hypolaetin-8-glucoside, obtained from Sideritis mugronensis, have been tested in the rat. The flavonoid was more potent than phenylbutazone in suppressing the acute phase of adjuvant-carrageenan-induced inflammation, but had less effect in the prolonged inflammatory phase. However, unlike phenylbutazone, it did not cause gastric erosions. Both compounds were equiactive in inhibiting the development of carrageenan-induced abscesses, whereas phenylbutazone had greater analgesic activity in tests on pressure pain threshold. The flavonoid and cimetidine both prevented the formation of cold-restraint induced gastric lesions, but cimetidine was more potent. These results show that hypolaetin-8-glucoside combines both anti-inflammatory and anti-ulcer properties and suggest that it may offer useful alternatives to anti-inflammatory drugs of the aspirin type.
The energetics of the interaction of piroxicam with plasma albumin
Authors: Oyekan A O , Thomas W O A
Published: April 2011

The thermodynamics of the binding of piroxicam to human and bovine plasma albumins revealed the reactions to be spontaneous and exothermic with bond strengths indicating the involvement of hydrogen and hydrophobic bonds. The association constants (K) decreased as temperature increased for both human serum albumin (HSA) and bovine serum albumin (BSA); and at all the temperatures in this study, K values obtained for BSA were higher (except at 36 °C) but not the bound fraction of piroxicam (β) and the quantity of binding (V). Scatchard plots of the data indicated at least two classes of binding sites.
Inhibition of lipid absorption by non-ionic hydrophobic surfactant Pluronic L-81, and its benzoyl esters
Authors: Bochenek Wieslaw J , Slowinska Regina , Kapuscinska Barbara , Mrukowicz Miroslaw
Published: April 2011

The benzoyl ester of Pluronic L-81 (BEP) has been purified on an aluminium oxide column and fractionated on the basis of its mobility characteristics into three fractions, BEP I, II and III. Absorption studies were made with rats fed by Ravage a lipid preparation containing [14C]triolein and [3H]lcholesterol (control animals) and one of the fractions or Pluronic L-81, or crude BEP. After 4 h the amount of lipid absorbed and transported was calculated as the difference between the dose fed and the amount of lipid recovered from the gastric and intestinal luminal contents and intestinal mucosa. Pluronic L-81 was the most effective in inhibiting absorption of triolein but it did not inhibit absorption of cholesterol. BEP-II was almost as effective in inhibiting the absorption of triolein and also inhibited absorption of cholesterol. Crude BEP was less effective and BEP-I and III had only limited activity. Inhibition of triolein absorption by Pluronic L-81 may be partly related to its delaying action on gastric emptying. As purified BEP preparations had practically no effect on gastric emptying, their inhibiting activity involved intestinal mechanisms of lipid absorption.
Behavioural and biochemical effects in C57BL/6J mice after a prolonged treatment with the δ-opiate antagonist ICI 154129
Authors: Volterra A , Brunello N , Cagiano R , Cuomo V , Racagni G
Published: April 2011

A long term treatment with the δ-selective opiate antagonist NN-bisallyl-Tyr-Gly-Gly-ψ-(CH2S)-Phe-Leu-OH (ICI 154129) produces an increase in the number of δ-opiate binding sites, whereas the same treatment with the non selective opiate antagonist naloxone results in an enhancement of both μ- and δ-binding sites. This biochemical effect in naloxone-pretreated mice is paralleled by a more pronounced increase in locomotor activity induced by a challenge dose of morphine. In contrast, no difference in the effect of morphine was seen in ICI 154129-pretreated mice with respect to control. These data suggest that the locomotor response to morphine in C57 mice is not mediated through δ-opiate receptors.
Norzimelidine, a metabolite of a highly selective 5-hydroxytryptamine uptake inhibitor, can inhibit the uptake of noradrenaline in-vivo
Authors: Pawlowski Leszek , Mazela Halina
Published: April 2011

Zimelidine and norzimelidine were tested for their ability to counteract reserpine (2·5 mg kg−1). or apomorphine (1–16 mg kg−1)-induced hypothermia and to potentiate TRH (40 mg kg−1)-induced hyperthermia in mice. Norzimelidine produced positive results in all three tests, behaving like a weak NA uptake inhibitor. Zimelidine was practically inactive. We conclude that the weak inhibitory effect of norzimelidine on the uptake of NA (in-vitro experiments) may be of importance for its pharmacological action and for the clinical action of zimelidine.
The effect of sinusoidal vibration on the uniformity of packing of powder beds
Authors: Woodhead P J , Newton J M
Published: April 2011

Sinusoidal vibration, at a number of defined sets of conditions, has been applied to packings of certain particle size fractions of lactose. The distribution of local porosity within these vibrated packings was determined using a gamma-ray attenuation technique, and could be compared with porosity data for samples not subjected to vibration. It was found that the application of vibration in a vertical mode markedly increased the uniformity of packing; horizontal vibration was less effective in this respect. The relationship between local porosity and position with a packing, observed in most non-vibrated samples, was generally absent from vibrated packings.
Representation and quantitation of the binding interaction between prednisone, prednisolone and corticosteroid binding globulin
Authors: Unadkat Jashvant D , Rowland Malcolm
Published: April 2011

The interaction between prednisone and prednisolone (0–500 ng ml−1) for binding sites on corticosteroid binding globulin (CBG) in rabbit plasma has been investigated. The fraction unbound of each steroid rose markedly with increasing concentration at low concentrations (250 ng ml−1), tending to a plateau (0·29 prednisone, 0·15 prednisolone) at the higher concentrations (250–500 ng ml−1), indicating both saturation of CBG and the importance of binding to albumin in higher concentrations. A method is proposed of representing graphically the prednisone–prednisolone–protein interaction in three dimensions.
Indirect inhibition of vitamin K epoxide reduction by salicylate
Authors: Hildebrandt E , Suttie J W
Published: April 2011

Salicylate antagonizes the vitamin K-dependent biosynthesis of clotting factors in the rat and produces an elevation of the ratio of vitamin K epoxide to vitamin K in the liver. Vitamin K epoxide is reduced to vitamin K by a vitamin K epoxide reductase, and 1 mm salicylate was required to cause a 50% inhibition of the dithiothreitol-dependent in-vitro reduction of vitamin K epoxide by this enzyme. This enzyme was, however, inhibited 50% by as little as 70–80 μm salicylate when reducing equivalents for the reaction were furnished by endogenous cytosolic reductants. This effect on the cytosolic reductant supply was shown to be unrelated to a previously demonstrated inhibition of DT-diaphorase by salicylate. The concentrations of salicylate at which significant inhibitory effects are exerted in-vitro (50–100 μm) are below the 200 μm levels observed in the livers of rats given an anticoagulating dose of salicylate.
Age-related changes in benzylamine oxidase activity in rat tissues
Authors: Danh Hung Cao , Benedetti Margherita Strolin , Dostert Philippe , Mousset Arlette
Published: April 2011

Brain, liver, heart, lung, kidney and duodenum benzylamine oxidase (BZAO) activities were measured from young and old rats. Protein content was found to decrease in liver (-17%), kidney (-20%) and duodenum (-17%) but remained unchanged in brain, heart and lung of old rats compared with that of young rats. A significant decrease (-41%) of BZAO activity was found in lung whereas a significant increase of enzyme activity was found in brain (+49%) and kidney (+25%) and no change was found in heart and duodenum of old rats. BZAO was not detected in either young or old rat liver. Kinetic analysis for lung BZAO activity of old rats showed that Vmax was decreased but Km was unchanged in comparison with that of young rats. Since, as we have shown previously, MAO-A and -B activity in lung of old rats was also found to be decreased, the decrease of lung BZAO activity with increasing age merits further investigation, lung playing an important role in removing amines from the circulation.
Cmc of mixtures of chlorpromazine hydrochloride and polysorbate 80 determined by pH measurements
Authors: Paiement J
Published: April 2011

The cmc of mixtures of chlorpromazine hydrochloride and polysorbate 80 was determined by pH titration. The values thus obtained coincided with those determined by the surface tension method. The mixtures studied could be divided into two groups according to the shape of their pH concentration curves. For mixtures containing less than 0·8 mole fraction chlorpromazine, the curves suggest that some interaction occurs in the premicellar concentration range. For mixtures containing more than 0·8 mole fraction chlorpromazine, the curves suggest that the micellar process occurs in more than one step.
The involvement of opiate receptors in the effects of trimebutine on intestinal motility in the conscious dog
Authors: Fioramonti J , Fargeas M J , Bueno L
Published: April 2011

The effects of intravenous (i.v.) vs intracerebroventricular (i.c.v.) administration of trimebutine on the motility of the small intestine and colon of fasted dogs were assessed using chronic electromyography. Trimebutine, injected intravenously, stimulated small intestinal motility, by inducing a propagated phase of regular spike activity, and inhibited colonic motility for some 4 h. These effects were not reproduced by i.c.v. administration which disrupted the cyclic motor profile of the small intestine for about 2·5 h and did not modify colonic motility. The stimulation of the small intestine motility induced by i.v. administration of the drug was blocked by previous i.v. but not by i.c.v. administration of naloxone. It was concluded that in the dog, the effects of trimebutine on the small intestine but not on the colon, involve peripheral opiate receptors.
Increased number of brain benzodiazepine receptors after in-vivo administration of estazolam to rats
Authors: Mennini T , Gobbi M , Garattini S
Published: April 2011

Estazolam significantly increased the Kd of [3H]flunitrazepam in-vitro, like other benzodiazepines (BDZs) acting competitively at the receptor site. At variance with other BDZs, estazolam significantly raised the Bmax for [3H]flunitrazepam, at concentrations lower than its Ki for BDZ receptors. This effect may be responsible for the observed increase in [3H]diazepam binding after in-vivo administration of estazolam to rats.
On the role of the baseline firing rate in determining the responsiveness of cingulate cortical neurons to iontophoretically applied substance P and acetylcholine
Authors: Jones Roland S G , Olpe Hans-Rudolf
Published: April 2011

The relationship between baseline firing rate and the magnitude of excitatory responses to iontophoretically applied substance P (SP) and acetylcholine (ACh) was determined for neurons in the anterior cingulate cortex of the rat. Whereas the size of responses to ACh was positively correlated with the level of ongoing neuronal activity, no correlation, either positive or negative, could be demonstrated for responses to SP. It seems unlikely that the excitatory effects of SP in this brain area result from release of endogenous ACh.
Chronic treatment with electroconvulsive shock prevents the salbutamol-induced hypoactivity in rats
Authors: Przegaliński E , Siwanowicz J , Bigajska K , Baran L
Published: April 2011

Several lines of evidence (binding studies, reduced responsiveness of brain adenylate cyclase to noradrenergic stimulation) indicate that chronic treatment with electroconvulsive shock (ECS) induces down-regulation of central β-adrenoceptors. The effect of acute and chronic (10 days) treatment with ECS on salbutamol-induced suppression of exploratory activity in rats has been examined. This effect was prevented by chronic but not by acute treatment with ECS. Chronic treatment with ECS did not affect exploratory activity. The salbutamol-induced hypoactivity is mediated through central β-adrenoceptors (antagonistic effect of (-)-propranolol but not (+)-propranolol or practolol), so the results may be regarded as functional evidence at the behavioural level for the down-regulation of β-adrenoceptors produced by chronic treatment with ECS.
Relative absorption of tryptophan ethyl ester amide derivatives with various fatty acid chains in the dog
Authors: Tse Francis L S , Christiano Juliet R , Talbot Kenrick C
Published: April 2011

Sandoz compound 57–118 is a mixture of tryptophan ethyl ester amide derivatives (analogues I–V) possessing one of five fatty acid chains which differ in chain length, configuration, or the degree of unsaturation. The relative absorption of each of the five analogues was investigated in the dog following single oral doses of the homologous mixture containing one 14C labelled analogue. It was shown that the extent of absorption of analogue I and its trans-homer, II, both with a mono-unsaturated fatty acid chain, were similar. An additional double bond in the fatty acid moiety (analogue III) facilitated gastrointestinal absorption. On the other hand, saturated fatty acid chains appeared to render the molecule less efficiently absorbed; the extent of absorption being dependent on the chain length. Thus, analogue V with 16 carbon atoms on the fatty acid chain was better absorbed than IV with 18.
Plasma concentrations of clobazam and its N-desmethyl metabolite; protection against pentetrazol-induced convulsions in mice
Authors: Haigh J R M , Gent J P , Calvert R
Published: April 2011

The anticonvulsant effects of acute administration of clobazam and its principal metabolite N-desmethyl-clobazam were studied in mice. Pentetrazol, given by slow intravenous infusion 1 or 2 h after the anticonvulsant dose, was used as the convulsant stimulus. Log dose response relationships for both clobazam and N-desmethylclobazam appeared linear, but there was no correlation between plasma concentrations of clobazam and protection. However, correlation between plasma concentrations of N-desmethylclobazam and protection was significant in both cases.
The hydroxy-hexanydronaphthoxazines: a new group of very potent and selective dopamine agonists
Authors: Horn A S , Hazelhoff B , Dijkstra D , de Vries J B , Mulder T B A , Timmermans P , Wynberg H
Published: April 2011

Replacement of the pyrrole ring system in the dopaminergic oxaergolines (e.g. RU 29717) by a phenolic OH group leads to the hydroxy-hexahydronaphthoxazines, a new group of potent dopamine agonists which exhibit increased selectivity due to their lower affinity for adrenergic and 5-HT receptors.
The effect of different oils on the absorption of probucol in the rat
Authors: Palin K J , Wilson C G
Published: April 2011

The effect of oily vehicles on the gastrointestinal absorption of the hypocholesterolaemic agent probucol has been investigated in the rat. The plasma concentration was determined following its administration in arachis oil (peanut oil), Miglyol 812 (fractionated coconut oil) and liquid paraffin. The total absorption of the drug, calculated as the area under the plasma concentration time curve, was significantly greater for the arachis oil formulation than with the other vehicles. The drug was selectively absorbed via the lymphatic system, lymph drug concentrations being highest following co-administration of arachis oil.
Radioimmunoassay of benzoylecgonine in samples of forensic interest
Authors: Robinson Katherine , Smith R N
Published: April 2011

A simple and economical radioimmunoassay for benzoylecgonine in blood or urine is described. Haemolysis, decomposition, common anticoagulants and sodium fluoride do not affect the results. A commercially available antiserum is used at a dilution of 1:600. The tracer is radioiodinated p-hydroxybenzoylecgonine. It is prepared by reacting p-acetoxybenzoic anhydride with methyl ecgonine followed by mild hydrolysis and radioiodination by the Iodo-gen method. The product is purified on a disposable silica cartridge and has a specific activity of about 30 TBq mmol−1. Polyethylene glycol is used to separate the bound and free fractions in the assay. The range of the dose-response curve is 0–400 ng ml−1 benzoylecgonine. The assay is largely specific for benzoylecgonine. Cocaine, ecgonine, methylecgonine and cinnamoyl cocaine have slight or negligible cross-reactivities. The inter-assay coefficient of variation is 7·5% and the recovery of benzoylecgonine from ‘spiked’ blood is 103%. The ‘cut-off’ is 20 ng ml−1 benzoylecgonine for both blood and urine. Radioimmunoassay and high-performance liquid chromatography results agree well.
Studies into the mode of action of non-steroidal anti-inflammatory drugs using a model of facsimile synovium
Authors: Sedgwick A D , Sin Y M , Mackay A R , Al-Duaij A , Willoughby D A
Published: April 2011

The effect of non-steroidal anti-inflammatory drugs on inflammation produced in the 6-day old air pouch by carrageenan or calcium pyrophosphate crystals has been examined. The system is a very reproducible way of studying the cellular and vascular components of inflammation. Non-steroidal drugs have different profiles of activity when tested on the inflammation produced with the two irritants. In general, however, the tested compounds showed similar activity on individual models.
AD-1590, a potent antagonist of lipopolysaccharide-induced fever in rabbits
Authors: Nakamura Hideo , Yokoyama Yuichi , Seto Yasuhiro , Kadokawa Toshiaki , Shimizu Masanao
Published: April 2011

The antipyretic activity of AD-1590 (2-[8-methyl-10,11-oxodibenz[b,f]oxepin-2-yl]propionic acid), a non-steroidal anti-inflammatory drug with a novel chemical structure, was investigated in rabbits with lipopolysaccharide (LPS)-induced fever and monkeys with leucocytic pyrogen-induced fever. AD-1590 produced a dose-related inhibition of the LPS-fever at oral doses of 0·1 mg kg−1 or more (ED50 = 0·089 mg kg−1). Its potency was 10–12, 20–35, 100–170, 400–540, >1500 and >2000 times that of ketoprofen, diclofenac sodium, indomethacin, ibuprofen, mefenamic acid and aspirin, respectively. The fever caused by leucocytic pyrogen was significantly inhibited by intravenous administration of 0·1–0·2 mg kg−1 of AD-1590. AD-1590 (10 mg kg−1 oral or i.v.) did not affect body temperature in afebrile rabbits or monkeys. These results suggest that AD-1590 shows a potent antipyretic activity in the rabbit and monkey and is a potent antagonist of LPS-fever.
A 1H nmr study of the amide-bond conformational equilibrium in pirenzepine
Authors: Feeney J , Pascual C
Published: April 2011

The hindered rotation about the exocyclic amide bond of pirenzepine has been studied using 1H nuclear magnetic resonance spectroscopy. The ratios of the two slowly interconverting conformations (1:1·76 at 2 °C and 1:2·37 at 30 °C) and the rate of interconversion (1 ± 0·5 s−1 at 20 °C and 247 ± 20 s−1 at 80 °C with ΔG80 = 71 KJ mol−1) have been measured at various temperatures. The observed rapid rates of interconversion allow us to eliminate the rate of conformational selection of forms II and III as a major contributor to the slow phase of the binding kinetics observed when pirenzepine binds to muscarinic receptors from rat brain (Stockton, Birdsall, Hulme and Burgen, unpublished results).
Polymorphic behaviour of chloroquine diphosphate
Authors: Van Aerde Ph , Remon J P , De Rudder D , Van Severen R , Braeckman P
Published: April 2011

The crystalline structure of two different batches of chloroquine diphosphate was studied. Differential thermal analysis showed the existence of two polymorphic modifications in one of the batches, whilst spectral analysis did not reveal any differences. This discrepancy is attributed to the fact that the second modification is formed during the transition phase when analysed by differential thermal analysis. This recrystallization process is initiated by the presence of seed material. The ratio of transition heat of both modifications is dependent on particle size and heating rate during analysis.
Cardiovascular responses in spontaneously hypertensive rats with acute renal failure
Authors: Yates M S , Bowmer C J , Brown G M
Published: April 2011

Cardiovascular status and reactivity have been investigated in spontaneously hypertensive rats (SHR) with glycerol-induced acute renal failure. SHR with acute renal failure had significantly lower mean arterial blood pressures and heart rates. The pressor responses to noradrenaline and the chronotropic responses to right cervical sympathetic and vagal nerve stimulation were diminished in uraemic SHR compared to control SHR. The cardiovascular depression observed in SHR with acute renal failure was similar to that previously noted in normotensive rats with acute renal impairment.
Inhibition of prostaglandin synthesis in rabbit kidney medulla slices by antioxidants
Authors: Fujimoto Yohko , Tanioka Hidetoshi , Toibana Eiko , Yamamoto Taku , Fujita Tadashi
Published: April 2011

The inhibitory effects of NN’-diphenyl-p-phenylenediamine (DPPD), sodium diethyldithiocarbamate (SDDC) and 2,6-di-t-butylphenol (DTBP) on the generation of medullary prostaglandin E have been compared. DPPD (1 μm) and SDDC (1 mm) failed to inhibit arachidonic acid-induced stimulation of prostaglandin E synthesis, while DTBP (1 mm) inhibited it. This suggests that DPPD and SDDC inhibit prostaglandin formation by affecting a phospholipase pathway, and the inhibition of prostaglandin generation by DTBP occurs at the cyclooxygenase step.
Effects of lipoxygenase inhibitors in arachidonate-induced sudden death
Authors: Roth David M , Feduska Richard , Lefer Allan M , Smith J Bryan
Published: April 2011

Both BW 755c, a cyclo-oxygenase and lipoxygenase inhibitor, and nordihydroguaiaretic acid (NDGA), a selective lipoxygenase inhibitor, were tested for their protection against arachidonate-induced sudden death in rabbits. 100% survival was seen with BW 755c (1 mg kg−1), while NDGA showed 0 and 17% survival (2 mg kg−1 and 4 mg kg−1). BW 755c prevented 12-fold increases in plasma thromboxane B2 concentrations and the formation of pulmonary artery thrombi normally seen with arachidonate-induced sudden death, while NDGA showed no such protective effect. Radioimmunoassay of rabbit plasma for leukotrienes (LTC4, LTD4 and LTE4) indicated that they do not accumulate in blood in the model and BW 755c had no effect, suggesting that the deleterious effects seen are caused by cyclo-oxygenase pathway metabolites such as thromboxane A2, but not by lipoxygenase pathway products such as leukotrienes.
Contractile effect of 1-O-hexadecyl-2-O-acetyl-sn-glycero-3-phosphocholine on strips of isolated rat intestine
Authors: Tokumura A , Fukuzawa K , Tsukatani H
Published: April 2011

The contractile effects of AGEPC were examined on various regions of rat isolated intestine. The duodenum, jejunum and ileum showed only the tonic component of contraction to AGEPC at the low dose (<10−9 m) but at the high dose (10−7 m) biphasic contractions were induced, consisting of a phasic followed by a tonic component. In the colon, however, the AGEPC-induced maximum contraction was comparable in magnitude to that produced by acetylcholine; also the contraction profile was different from that elicited from the other regions of the intestine. Low doses of AGEPC caused a slow, sustained contraction and at high doses phasic and tonic components were not dissociated.
Influence of smoking on serum protein composition and the protein binding of drugs
Authors: Benedek I H , Blouin R A , McNamara P J
Published: April 2011

The influence of smoking on α1-acid glycoprotein (α1-AGP) and serum albumin concentrations and the protein binding of phenytoin and propranolol in healthy volunteers was investigated. α1-AGP concentrations were found to be statistically different (P < 0·05) in the smokers (mean = 84·3 mg dl−1) versus non-smokers (mean = 62·8 mg dl−1). There was a trend for lower serum albumin concentrations and lower fraction unbound of propranolol in the smokers. Smoking did not affect the protein binding of phenytoin.
The effect of punch velocity on the compaction of a variety of materials
Authors: Roberts R J , Rowe R C
Published: April 2011

The effect of punch velocity over the range 0 033–400 mms−1 on the compaction of a variety of materials has been studied using constants derived from the Heckel equation as criteria to describe their behaviour. For materials known to deform plastically, e.g. maize starch and polymeric materials, there was an increase in the yield pressure with punch velocity attributable to a change either from ductile to brittle behaviour or a reduction in the amount of plastic deformation due to the time dependent nature of plastic flow. For materials known to consolidate by fragmentation, e.g. magnesium and calcium carbonates, there was no change in yield pressure with increasing punch velocity. The data has been analysed in terms of the strain rate sensitivity of the materials calculated from their yield pressure at low and high punch velocities.
The effect of polycations on the activity of pepsin
Authors: Lawton J B , Mekras C I
Published: April 2011

A study has been made of the interaction of selected polycations with pepsin A (E.C. 3.4.23.1). Protamine, polybrene, spermine, spermidine and poly(L-lysine) all acted as inhibitors of the enzyme at low concentrations, but at higher concentrations of the polycations the inhibition was less pronounced. A more detailed study of the anomalous inhibition was made using protamine, polybrene and poly(L-lysine) and it was shown experimentally that, when used by themselves, each of these polycations acted as a weak proteolytic catalyst. The order of catalytic effectiveness was: protamine > polybrene » poly(L-lysine). Thus, it is now possible to explain why the observed inhibition of pepsin decreases when the concentration of the inhibiting polycation is increased.
The active principles of the branchlet and hook of Uncaria sinensis Oliv. examined with a 5-hydroxytryptamine receptor binding assay
Authors: Kanatani Hirotoshi , Kohda Hiroshi , Yamasaki Kazuo , Hotta Izumi , Nakata Yoshihiro , Segawa Tomio , Yamanaka Etsuji , Aimi Norio , Sakai Shin'ichiro
Published: April 2011

Of the alkaloids obtained from Uncaria sinensis Oliv., geissoschizine methyl ether, corynantheine and dihydrocorynantheine decreased specific [3H]5-HT binding to membrane preparations from rat brain and from in-vitro experiments on guinea-pig ileum, these alkaloids were found to be partial agonists for 5-HT receptors. Therefore, they might be useful in the treatment of diseases resulting from disorders of 5-HT metabolism.
Peripheral cardiovascular α- and β-adrenergic effects of some hypotensive and bradycardic arylalkyl imidazole derivatives in the rat
Authors: Savola J-M , Puurunen J , Ruskoaho H , Kärki N T
Published: April 2011

In pithed rats, a series of four alkyl bridge analogues of 4(5)-substituted arylalkyl imidazole induced α-adrenoceptor-mediated vasoconstriction and inhibition of electrically stimulated tachycardia. These effects were induced in the order of potency clonidine = MPV 207 > MPV 295 > MPV 304 > MPV 390, correlating with the length of the alkyl bridge between the phenyl and imidazole moieties. The peripheral postsynaptic actions of MPV 207 and MPV 304 were attenuated by prazosin (0.1 mg kg−1 i.v.) and yohimbine (1 mg kg−1 i.v.). The pressor responses induced by MPV 295 were antagonized only by yohimbine (0.3 and 1 mg kg−1 i.v.). The peripheral sympathoinhibitory action of these compounds was antagonized by yohimbine (1 mg kg−1 i.v.). In spontaneously beating rat atria, the MPV compounds showed neither agonistic nor antagonistic activity at cardiac postsynaptic α- and β-adrenoceptors. The results indicate that the hypotensive and bradycardic MPV compounds are agonists at peripheral cardiovascular α-adrenoceptors. The extension of the alkyl bridge between the phenyl and imidazole moieties reduces their activity at α-adrenoceptors. Finally, MPV 295 seems to be a selective agonist of peripheral α2-adrenoceptors in the cardiovascular system of the pithed rat.
Solute conformation of enkephalin-like pentapeptides in deuterated dimethylsulphoxide
Authors: Casy A F
Published: April 2011

NMR evidence of the temperature dependence of NH resonances and magnitudes of α-CH-NH couplings is advanced in support of preferred β-bend conformations for five enkephalin-like pentapeptides as solutes in DMSO-d6. The relevance of these and related conformational studies to the interactions of peptides of the enkephalin class with opioid receptors is questioned.
Comparative effects of sodium azide and aminophylline on the rat isolated uterus during muscle activation
Authors: Milovanović S R , Varagić V M
Published: April 2011

Sodium azide is a strong inhibitor of the tonic component of contraction produced by oxytocin, whereas aminophylline produces almost equal inhibition of all types of activation of the isolated rat uterus. Both substances inhibited the spontaneous rhythmic activity of the uterus. The effect of sodium azide is easily reversed by calcium. The results are taken to indicate a complex relation between calcium and substances which stimulate metabolism either of cGMP (sodium ***azide) or cAMP (aminophylline) in producing relaxation of the isolated rat uterus.
Gastrointestinal neurotensin receptors: lack of modulation by thyrotropin releasing hormone
Authors: Donoso M Veronica , Huidobro-Toro J Pablo
Published: April 2011

To examine whether thyrotropin releasing hormone (TRH) antagonized gastrointestinal neurotensin receptors in isolated segments of the rat fundus, duodenum and ileum, tissues were superfused, mounted and the isometric tension recorded. Picomoles of neurotensin caused concentration-dependent contractions of the fundus and relaxation of the smooth muscles of the small intestine. Preincubation with 1–10 μm TRH failed to antagonize the activity of neurotensin but potentiated neurotensin-induced relaxation of the ileum. Pretreatment of the tissues with 0.6 μm of neuropeptide fragment 1–11, also failed to block the neurotensin-induced effects but produced a significant potentiation of the relaxant action of neurotensin.
Dose-dependent absorption of disodium etidronate
Authors: Gural Richard P , Chungi Vinod S , Shrewsbury Robert P , Dittert Lewis W
Published: April 2011

The gastrointestinal absorption of disodium etidronate (as [14C]disodium etidronate) was investigated in the rat proximal jejunum in-situ. Studies using various initial concentrations of the drug suggested that etidronate absorption occurred by passive diffusion at initial concentrations below 0.08 M. At initial concentrations above 0.08 M, the rate of absorption was significantly greater than would be expected if passive diffusion was the only mechanism responsible for absorption. Etidronate absorption is not mediated by the carrier mechanism responsible for phosphate ion absorption.
The effect of the surface free energy of pharmaceutical tablets on liquid penetration
Authors: De Lourdes Costa Maria , Baszkin Adam
Published: April 2011

The surface free energies (γsv) of the integral and partial tablet formulations of an antiarrhythmic drug—cibenzoline succinate, have been assessed by contact angle measurements using high-viscosity polyols and Neumann's equation of state. Independent measurements of penetration for these liquids into the tablets yielded pore size values through the use of the Washburn equation. The role of different constituents of the formulations are analysed in terms of their influence upon the free surface energy of the tablets and penetration rates. The relation between (γsv) and penetration rates yields for a series of liquids two threshold values: (γsv)s ‘start’ and (γsv)r ‘rapid’, which define respectively the beginning of the measurable penetration and the rapid penetration.
Absorption characteristics of the lipophilic prodrug of mitomycin C from injected liposomes or an emulsion
Authors: Sasaki Hitoshi , Kakutani Toshiyuki , Hashida Mitsuru , Sezaki Hitoshi
Published: April 2011

Mitomycin C (MMC) is amphiphilic and so cannot be incorporated into lipoidal delivery systems. To develop a lipoidal delivery system, its prodrug, nonyloxycarbonyl MMC, was formulated in liposomes and in o/w emulsions and the usefulness of these formulations was evaluated. After injection into the rat thigh muscle, MMC was rapidly absorbed regardless of the dosage form. However, the prodrug was retained at the injection site for considerably longer when formulated in a lipid dispersion system. The accumulation of MMC at regional lymph nodes was also investigated and whereas free MMC arrived at and disappeared from the lymph nodes almost immediately after injection, the prodrug arrived at an early stage and its concentration decreased only gradually, remaining fairly high 2 h after injection. Liposomal lipids appeared to accumulate at the lymph nodes to a greater degree than o/w emulsions. It is suggested that the combination of lipidic carrier devices with lipophilic prodrugs may be a useful adjunct to cancer chemotherapy.
Effect of age on the hepatic clearance of propranolol in rats
Authors: Iwamoto Kikuo , Watanabe Jun , Araki Kaoru , Deguchi Naoko , Sugiyama Hisako
Published: April 2011

The effect of age on hepatic clearance of propranolol was investigated in male Wistar rats (3 to 104 weeks old). Pharmacokinetic analysis of the plasma propranolol data obtained after i.v. dosage (1.0 mg kg−1) indicated that both the elimination rate constant and the volume of distribution decreased with age between weeks 5 and 11, after when the distribution volume remained almost constant. The elimination rate constant was reduced consistently with age after 15 weeks. Total body clearance of the drug was reduced extensively with age between weeks 5 and 11 (94 to 43 ml min−1 kg−1) and decreased gradually thereafter. The plasma free fraction of propranolol also decreased with age, falling from more than 20% in 3 to 5 weeks-old rats to about 10% in rats of 52 to 104 weeks. In immature rats the renal clearance was approximately 5 to 12% of the total body clearance. Intrinsic hepatic clearance for unbound propranolol also decreased with age between weeks 7 and 24. As expected from the evidence that propranolol has a high extraction ratio, the extent of its hepatic clearance was significantly dependent on the liver blood flow. These data suggest that the age-dependent decrease in hepatic clearance of propranolol is largely due to a reduction of the elimination rate that might be accompanied by the age-dependent decrease in liver blood flow.