bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional distribution of an opioid mechanism in the guinea-pig isolated intestine
Authors: KROMER W , PRETZLAFF W , WOINOFF R
Published: April 2011

Opioid receptor blockade by naloxone enhanced peristalsis in isolated segments from the guinea-pig duodenum, jejunum and ileum, increasingly aborally. Thus, an increase in the influence of an intrinsic opioid mechanism may be responsible for the decrease in the level of peristaltic activity, observed aborally. However, the peristalsis of ileal segments which worked against their closed distal end was enhanced by naloxone to a similar degree as normal peristalsis.
On the pharmacological actions of a diuretic, fenquizone, with particular reference to its site of action
Authors: FERRANDO CHRISTINA , FOY J M , PRATT C N F W , PURVIS J R
Published: April 2011

The pharmacological actions of a diuretic drug, fenquizone have been investigated and its effects compared with well characterized diuretics in rats, mice and rabbits. Changes in sodium and potassium excretion and urine volume were similar in magnitude and duration to those of the thiazide diuretics over dose range 0·05–100 mg kg−1. Free water clearance in rabbits was decreased indicating an action at the cortical diluting site in the nephron and since free water reabsorption was relatively unaffected it appears unlikely to have actions at other sites. Calcium and phosphate excretion studies also suggested that the predominant effects are those occurring at the cortical diluting segment of the nephron. Additional parameters not affected by the drug were blood flow to the cortex and medulla of the kidney (and other major organs), plasma glucose concentration and plasma urate concentration.
Bifluranol, a novel fluorinated bibenzyl anti-androgen, its chemistry and disposition in different animal species
Authors: POPE D J , GILBERT A P , EASTER D J , CHAN R P , TURNER J C , GOTTFRIED S , PARKE D V
Published: April 2011

The synthesis of bifluranol, a new fluorinated bibenzyl anti-androgen, and of 3H-labelled bifluranol is described. The absorption, distribution and excretion of bifluranol has been studied in mouse, rat, ferret and dog; it is readily absorbed following oral administration, but blood concentrations of the drug are low due to hepatic uptake and biliary excretion. Enterohepatic re-circulation occurs, but the drug is excreted primarily in the faeces and only small amounts appear in urine. This pattern of disposition and excretion is similar to that reported elsewhere for the bibenzyl, hexoestrol, and for the stilbene, diethylstilboestrol.
The acetylenic monoamine oxidase inhibitors clorgyline, deprenyl, pargyline and J-508: their properties and applications
Authors: FOWLER C J , ORELAND L , CALLINGHAM B A
Published: April 2011

The article presents a short review of some of the properties of the acetylenic inhibitors of monoamine oxidase currently under investigation: clorgyline, (—)-deprenyl, pargyline and J-508. Their substrate-selective inactivation, mechanism of inhibition, titration and pharmacology with respect to monoamine oxidase are critically discussed.
Effects of diethyl ether anaesthesia on the pharmacokinetics of antipyrine and paracetamol in the rat
Authors: JOHANNESSEN W , GADEHOLT G , AARBAKKE J
Published: April 2011

The effects of two anaesthetic procedures: continuous administration of ether throughout the periods of drug infusion and blood sampling, and brief ether administration (5 min) before drug infusion were examined. Continuous ether reduced total clearance, β, and k10 for both drugs, and in addition Vc and Vβ for antipyrine. Brief ether anaesthesia had no effect on antipyrine kinetics, but caused a decrease in total clearance, k10 and Vβ of paracetamol. The rates of distribution and redistribution of the drugs were unchanged by ether. The data suggest that ether interferes with the hepatic conjugation of paracetamol and may interfere with the hepatic oxidation of antipyrine and therefore should not be used as an anaesthetic when the kinetics of drugs with short elimination half-lives are studied. It may be used for drugs with longer half-lives.
The cracking of film coatings on film-coated tablets—a theoretical approach with practical implications
Authors: ROWE R C
Published: April 2011

A theoretical approach of film cracking is presented using equations which allow for the calculation of both the internal stress in a film coating due to shrinkage of the film on evaporation of the solvent and the thermal stress due to differences in the thermal expansion of the film coating and tablet substrate during changes in temperature arising out of the coating processes. The practical implications of this approach in film formulation are discussed with particular reference to the choice of tablet core formulation, the grade of polymer used, the type and concentration of both plasticizers and pigments and the solvent system used in the coating process.
Inhibition of lymphocyte transformation by mepacrine and chloroquine
Authors: TRIST D G , WEATHERALL M
Published: April 2011

Mepacrine inhibited the uptake and the incorporation of leucine, thymidine and uridine into acid-insoluble material in human lymphocytes stimulated by phytohaemagglutinin (PHA) in vitro. The IC50 for each uptake was of the order of 2μM. Mepacrine was inhibitory if applied at any time up to 48 h after PHA. The inhibition differed from that produced by colchicine and prostaglandin E1. The dose-response curve was steep, nearly all incorporation being inhibited by 2 × IC50. Chloroquine also had a steep dose-response curve, was about one-fifth as potent as mepacrine and was maximally effective in the first 6 h after PHA.
Plasma protein binding of fentanyl
Authors: BOWER SUSANNE
Published: April 2011

Whole plasma of 15 normal volunteers bound 79·16% ± 0·16 s.e. (n = 45) of fentanyl, at a concentration of 0·6 ng ml−1. Measurement was by equilibrium dialysis at 37°C, pH 7·4. The largest contribution to binding appears to be due to serum albumin, since 45·52% ± 0·40 s.e. (n = 3) of fentanyl was bound to a solution of purified albumin at a concentration of 46 g litre−1 in buffer. Physiological concentrations of isolated very low density, low density and high density lipoprotein fractions in buffer bound 18·39% ± 0·65 s.e.; 39·14% ± 0·42 and 21·18% ± 0·51 (n = 15) respectively. A significant correlation was found between percent binding and serum albumin concentration (r = 0·745, P = 0·0022) and oestrogen and progestagen therapy (r = 0·766, P = 0·0014). There was no significant correlation with fasting serum cholesterol, triglyceride, age, sex or the concentration of total protein minus albumin. Binding to fibrinogen and α1-acid glycoprotein did not occur. Binding increased with increasing pH, temperature and ionic strength of the buffer. The results were compatible with hydrophobic bond formation between fentanyl and proteins. Fentanyl concentration did not affect the percent bound to whole plasma or the protein fractions over a range of 0·6 ng-10 mg ml−1. Dilution of plasma with buffer gave a linear relation of percent bound or free to log plasma dilution. The binding of fentanyl to pooled plasma of the normal subjects was not affected by a wide variety of anionic, cationic and uncharged drugs when these were tested at a concentration of 20 μg ml−1. At higher concentrations, aspirin, phenylbutazone and quinidine caused inhibition of fentanyl binding. A linear relation was found between percent bound and concentration of the inhibitory ligand. For aspirin, r = 0·873, P <0·01; for phenylbutazone, r = 0·81, P <0·05; and for quinidine, r = 0·982, P <0·01. Aspirin and phenylbutazone inhibited binding of fentanyl to albumin, while quinidine caused inhibition of binding to lipoproteins of all three densities, but not to albumin. Changes in the concentrations of the common ions of plasma (except H+), of free fatty acids and of creatinine did not affect fentanyl binding to whole plasma. 8 M urea reduced binding by 25% of the normal value.
Effects of cyclodextrins on chlorpromazine-induced haemolysis and central nervous system responses
Authors: UEKAMA K , IRIE T , SUNADA M , OTAGIRI M , IWASAKI K , OKANO Y , MIYATA T , KASÉ Y
Published: April 2011

Cyclodextrins (CyDs) protected the human erythrocytes from haemolysis induced with chlorpromazine (CPZ) in isotonic solution, depending upon the magnitude of the stability constant of CPZ-CyD complexes (β-> γ-> α-CyD). From the observations of CPZ uptake into erythrocytes and changes in surface activity of CPZ, the protective effects of CyDs in vitro appeared to be due to the decrease in effective haemolytic concentration of CPZ through inclusion complex formation rather than the direct interaction of CyDs with the erythrocyte membrane. The effect of β-CyD on some central nervous system (c.n.s.) actions of CPZ in rats was also investigated to see if there were any advantages in the use of β-CyD complexes given by injection. The results suggest that β-CyD does not alter the time-course or magnitude of the effects of CPZ on the c.n.s.
Rectal absorption of some glycosaminoglycan sulphates and heparin in rats
Authors: STANZANI L , MASCELLANI G , CORBELLI G P , BIANCHINI P
Published: April 2011

A standardized extract of glycosaminoglycan sulphates containing heparin, with a low affinity for antithrombin III, and a commercial heparin were administered to rats, by the rectal route. When the glycosaminoglycan sulphates were given in oil emulsion with sodium laurylsarcosinate as surfactant, 1 mg kg−1 and 3 mg kg−1 were sufficient for the clearing and anticoagulant activities respectively. The rectal absorption of glycosaminoglycans after dosing with a suitable ‘promoter' produced dose-dependent effects and their kinetics were comparable to those obtained after intramuscular administration. The oil emulsion improved the bioavailability of glycosaminoglycan sulphates at least 20 times.
Electrostatic charge interactions in ordered powder mixes
Authors: STANIFORTH J N , REES J E
Published: April 2011

A method is described for measuring the electrostatic charge generated in powders following contact with a plane substrate. The method uses a Faraday well connected to an electrometer and allows the specific charge of powders to be determined. Of the various drugs and excipients studied, most charged electronegatively following contact with glass surfaces, but became electropositive after contact with polyethylene surfaces. The charge interactions of drug and excipient powders modified the behaviour of ordered mixes formed in similar conditions to those of charge measurement. Powders with like charges formed less stable ordered mixes than those in which drug and excipient particles carried opposite charges. Following triboelectrification in an air cyclone constructed of brass, powders had charges at least 100 times greater than those formed after contact with glass surfaces. Optimization of the triboelectric charging conditions allowed ordered mixes to be prepared in which a maximum electronegative charge was applied to the excipient whilst the drug was given a maximum electropositive charge. Studies of segregation/stability showed that ordered mixes subjected to triboelectrification were less prone to segregation than uncharged powders.
Optical studies on the specific interaction of dipyridamole with α1-acid glycoprotein (orosomucoid)
Authors: EL-GAMEL SAFAA , WOLLERT The late UWE , MÜLLER WALTER E
Published: April 2011

The interaction of dipyridamole with α1-acid glycoprotein was investigated by circular dichroism and ultraviolet absorbance measurements as well as by equilibrium dialysis experiments. Dipyridamole is bound to the protein via one site of extremely high affinity and by at least one site of considerably lower affinity. Only the association of dipyridamole with the high affinity site produces typical extrinsic Cotton effects. As a result of experimental observations it is concluded that the high affinity site is located in a hydrophobic protein structure of the glycoprotein.
Three-ply walled w/o/w microcapsules formed by a multiple emulsion technique
Authors: WARBURTON NATALIE J MORRIS AND B
Published: April 2011

A new method of microencapsulation is described. Interfacial rheological studies had shown the formation of a rigid bipolymer film at the interface between an aqueous solution of a water-soluble polymer and a non-aqueous solution of an oil-soluble polymer. This led to the idea that small spherical bodies might be formed on making a w/o/w emulsion from these solutions. The present work has shown that ethyl cellulose/acacia microcapsules are formed when the organic solvent ethyl acetate is removed from the multiple emulsion drops. These microcapsules may be obtained as a free-flowing powder.
Effects of paraffin coatings on the shearing properties of lactose
Authors: IRONO CECILIA I , PILPEL N
Published: April 2011

An annular shear cell has been employed to measure the shearing properties of lactose powder coated with up to 104 mol g−1 of powder of a series of paraffin hydrocarbons. The angle of internal friction, Δ, of the coated powders was independent of their packing density. The shearing properties of the powders depended on the concentration, the viscosity and thickness of the coating material.
Prejunctional inhibition mediated via α2-adrenoceptors in excitatory transmission of canine small intestine
Authors: NAKAHATA NORIMICHI , NAKANISHI HIRONORI , SUZUKI TAKEHIKO
Published: April 2011

Noradrenaline(NA) inhibited the contractile responses of longitudinal and circular muscles of canine small intestine to field stimulation (20 Hz, 1 ms, supramaximal voltage for 5 s). The purpose of this study was to see if NA-induced inhibitory action is mediated via α1- or α2-receptors and whether the inhibitory action involved prostaglandins. In both muscle layers the α2-agonist, clonidine inhibited the contractile response to field stimulation more potently than did the α1-agonists phenylephrine or methoxamine. It is suggested that NA-mediated prejunctional inhibition is mediated via α2-receptors. Yohimbine, an α2-adrenoceptor blocking drug antagonized NA-induced prejunctional inhibition, while E-643, an α1-blocker, did not affect the inhibition. These results suggest that the inhibitory action of NA is mediated via α2-receptors in both muscle layers. Indomethacin, an inhibitor of prostaglandin synthesis, did not affect NA-induced prejunctional inhibition in circular muscle, while augmenting it in longitudinal muscle. It is thought that NA-induced prejunctional inhibition is not mediated via prostaglandin release.
Disulfiram-like effect of diethyl maleate on barbiturate-induced hypnosis and 5-hydroxytryptamine metabolism
Authors: MINEGISHI AKEMI , FUKUMORI RYUJI , SATOH TETSUO , KITAGAWA HARUO
Published: April 2011

Diethyl maleate (DEM, 600 mg kg−1 i.p.) significantly potentiated hexobarbitone hypnosis and lowered plasma hexobarbitone level on awakening. Sleeping time following intra-cerebroventricular (i.c.v.) injection of phenobarbitone was also prolonged by DEM treatment. When administered to DEM-treated rats, L-tryptophan (50 mg kg−1 i.p.) significantly potentiated hexobarbitone hypnosis, although alone it had no effect in control rats. DEM markedly diminished the activity of brain low-Km aldehyde dehydrogenase (AlDH) and the formation of 5-hydroxyindoleacetic acid from 5-hydroxytryptamine (5-HT) without affecting MAO activity in various areas of the brain. Conversely, the protein-bound radioactivity derived from i.c.v. [14C]-5-HT was increased by DEM treatment. These results showed that DEM is comparable with disulfiram, a brain AlDH inhibitor, in terms of its effect on 5-HT metabolism and barbiturate hypnosis.
A study of the effects of nabumetone (BRL 14777), a novel anti-inflammatory drug, on cell infiltration into sterile cotton pellets implanted in rats
Authors: FREEMAN P C , MANGAN F R , WATKINS D K
Published: April 2011

Nabumetone a new non-steroidal anti-inflammatory drug is active in reducing the DNA content of implanted cotton pellets in rats on various dosing regimens. The effect of nabumetone can be seen during the early and late phases of the cellular reaction to the implant implicating effects upon polymorphonuclear leucocytes and monocytes. The levels of two lysosomal enzymes are reduced in the exudate by the drug treatment.
Conformationally restricted dopamine congeners—a molecular mechanics-based study
Authors: Kocjan D , Hadži D
Published: April 2011

Potential energies of several systems containing the phenylethylamine fragment were computed by the QCFF/PI method and some of them also by the PCILO method. The systems considered are: octahydrobenzo [f]- and [g]-quinolines, aporphine, 1-phenyl-benzazepine, 4-phenyltetrahydroisoquinoline, 3-phenylpiperidine and 9-aminodihydrophenanthrene. No common set of torsion angles defining the stereostructure around the amine head is apparent if only the lowest energy conformations are considered. Leaving out the orientation of the N-CH3 group, and considering also some higher energy conformations, two groups of systems may be formed, A and B, the members of which are congruent amongst themselves in parameters defining the spatial relations of the amine site and the catechol ring, and in the orientation of the N+-H bond. The stereostructure of the rigid representatives of group A is postulated to be the one required by the brain and cardioaccelerator nerve receptor. A corresponding postulate for the vascular bed DA receptors cannot be made since systems forming group B, the derivatives of which are active both on brain and vascular bed receptors, have more conformation space and, moreover, they carry additional potential anchoring groups.
Acenocoumarol and its amino and acetamido metabolites. Comparative pharmacokinetics and pharmacodynamics in the rat
Authors: Thijssen H H W , Baars L G , Reijnders M J
Published: April 2011

The elimination, distribution and anticoagulant activity of racemic acenocoumarol, its amino (AM) and acetamido (AA) derivative were determined in male Wistar rats after subcutaneous injection of a single dose of 2 mg kg−1. The effect of daily administration of acenocoumarol on the prothrombin complex activity (PCA) was also investigated. A rapid onset of the hypothrombogenic effect was observed for all three derivatives with the half-life of decline of PCA=3˙6 h. The duration of the hypothrombogenic effect was short for the drug and its AA derivative and long for the AM compound (normalization at about 24 and 70 h, respectively), parallelling the half-life of elimination of the compounds of, 3˙3, 4, and 8 h respectively. Daily administration of acenocoumarol for 8 days showed no change in the kinetics of the anticoagulant effect. Elimination of the drug is solely by metabolism. Reduction of the 4′-nitro group was not a metabolic route of importance; the amount of its two derivatives cumulatively excreted in urine over 5 days accounted for 2–3% of the dose only. Elimination of AM derivative is mainly by acetylation to AA, the compound which itself is eliminated by renal excretion. The distribution of acenocoumarol between liver and plasma was determined. The liver to plasma ratio was higher than 1 beyond 10 min after administration. The elimination rate of the drug from liver was slower than from plasma giving an increase in liver to plasma ratio in time. Plasma protein binding was extensive, being the highest for the drug; 1˙81, 2˙84 and 3˙89% free for drug, AM, and AA derivative, respectively.
β2-Adrenoceptors in guinea-pig atria
Authors: Johansson Lars-Håkan , Persson Henry
Published: April 2011

The occurrence of β2-adrenoceptors in the isolated, spontaneously beating right atrium and the electrically driven left atrium of the guinea-pig was studied. Isoprenaline was used as reference compound and procaterol as selective β2-agonist. Cumulative concentration response (C/R) curves were obtained with the agonists. The C/R curve of procaterol was biphasic in both preparations. Compared with isoprenaline, procaterol was a partial agonist, with a mean maximum response of 0˙78 ± 0˙04 in the right atrium and 0˙29 ± 0˙05 in the left atrium. The β2-selective antagonist ICI 118,551, 10−7 mol litre−1, caused a small but significant shift of the C/R curve of isoprenaline to a higher concentration range in both preparations. The same concentration of the β2-blocker changed the shape of the C/R curve of procaterol from biphasic to monophasic by blocking the responses to low concentrations of procaterol. Practolol, a β1-selective antagonist, 10−6 mol litre−1, gave a highly significant shift of the C/R curve of isoprenaline to a higher concentration range in both preparations but had no effect on the responses to low concentrations of procaterol. The effect of practolol on the responses to high concentrations of procaterol is discussed. We conclude that the guinea-pig atria may contain β2-adrenoceptors mediating positive chronotropic and inotropic effects.
The pharmacokinetic assessment of sodium cromoglycate
Authors: Fuller R W , Collier J G
Published: April 2011

The plasma concentration of sodium cromoglycate (SCG) was measured in four healthy subjects by radioimmunoassay after a 4 mg intravenous dose and after inhaling from 20 mg capsules, and from 10 and 30 mg ml−1 nebulizer solutions. The mean absorption constant (K1) after inhalation was 0·43 h−1. The mean elimination constant from the plasma (Kelim) after intravenous administration was 11·5 h−1, and that after inhalation was similar. The apparent volume of distribution of SCG (Vdβ) was 0·2 litre kg−1 and the mean plasma clearance was 0·35 litre h−1kg−1. The amount of SCG absorbed after inhalation varied according to the method of inhalation and dose. After the inhalation of powder from 20 mg capsules, 1·30–3·96 mg reached the plasma, after inhalation of SCG produced by nebulizing a 10 mg ml−1 solution for 5 min at 10 psi using a Minineb nebulizer 0·19—0·31 mg reached the plasma and when the solution was increased to 30 mg ml−1 the figure was 0·33—0·45 mg.
An assessment of indomethacin-induced gastrointestinal mucosal damage in-vivo: enhancement of urinary recovery after oral administration of phenolsulfonphthalein in rats
Authors: Nakamura Junzo , Takada Shigeyuki , Ohtsuka Noboru , Heya Toshiro , Yamamoto Akira , Kimura Toshikiro , Sezaki Hitoshi
Published: April 2011

The permeability of phenolsulfonphthalein(phenol red), a poorly absorbed drug, was examined as an index of an assessment of gastrointestinal mucosal damage in-vivo. The urinary recovery after oral administration of phenol red was significantly increased in rats with indomethacin-induced ulcers. However, the urinary recovery of phenol red after its intravenous administration was not affected by the ulcers. Gastric absorption of phenol red from the stomach was examined by means of the in-situ loop technique. A significant increase in disappearance of phenol red from the luminal solution was observed in rats orally pretreated with indomethacin. These findings suggest that the increase in urinary recovery of phenol red is due to increased gastrointestinal absorption. This method may be utilized as a simple, useful and non-invasive screening test for an assessment of gastrointestinal mucosal damage in-vivo.
Stereoselectivity of catecholamines: differential effects of cocaine and desipramine on catecholamine-induced contractions of the rat isolated vas deferens
Authors: Park B K , Haynes B P , Sheridan S A , Nowell P T
Published: April 2011

The effect of uptake1 inhibitors, cocaine and desipramine, on the contractile response of the rat isolated vas deferens to the enantiomers of noradrenaline and adrenaline and to the corresponding deoxy-derivatives, dopamine and epinene, was investigated. Cocaine (10−6 M) significantly potentiated all six agonists; the effect was most marked for the laevo-isomers (-)-noradrenaline and (-)-adrenaline. Desipramine (10−7 M) also potentiated (-)-noradrenaline, (+)-noradrenaline, (-)-adrenaline, (+)-adrenaline and epinene but, in contrast, antagonized dopamine. This selective antagonism of dopamine by desipramine was also observed for the separated epididymal and prostatic ends of the rat vas deferens.
On the substrate specificities of the two forms of monoamine oxidase
Authors: Fowler Christopher J , Tipton Keith F
Published: April 2011

By use of the selective irreversible inhibitors clorgyline and selegiline [(-)-deprenyl], it is possible to determine the Km and Vmax values of the two forms of monoamine oxidase towards a variety of substrates. The validity of this procedure is demonstrated for the deamination of dopamine by rat liver monoamine oxidase -A and -B, and the specificities of the two forms are analysed in terms of their kinetic parameters towards different substrates.
Evidence for the intrusion of polyoxyethylene into the hydrocarbon core of non-ionic surfactant micelles
Authors: Elworthy P H , Patel M S
Published: April 2011

The intrinsic viscosities, [η], of non-ionic surfactants of structure, CH3[CH2]m-1[OCH2OCH2]1·25mOH, were measured in water at 298 K. [η] increased linearly with hydrocarbon chain length from m = 3 to m = 15, and between m = 17 and m = 31. There was a discontinuity between m = 15 and m = 17, which was attributed to intrusion of some polyoxyethylene into part of the hydrocarbon core for surfactants in which m > 15. This effect gave a micellar hydration which was lower than expected for the higher members of the series. Other factors relevant to the intrusion of polyoxyethylene into hydrocarbon are discussed.
Benzodiazepine receptor antagonists reverse the effect of diazepam on plasma corticosterone in stressed rats
Authors: Bizzi A , Ricci M R , Veneroni E , Amato M , Garattini S
Published: April 2011

The aim of this work has been to investigate the mechanism by which diazepam counteracts the plasma corticosterone rise induced by stress in rats. This effect is reversed by pretreatment with RO151788 and CGS8216. This observation suggests that the effect is mediated by benzodiazepine-specific receptors in brain.
Simultaneous measurement of gastric emptying of the soluble and insoluble components of a formulation using a dual isotope, gamma scintigraphic technique
Authors: Kaus Lydia , Sharma H , Fell J T
Published: April 2011

The gastric emptying of a soluble and an insoluble component of a capsule formulation has been monitored by gamma scintigraphy using a dual isotope technique. There was no significant difference between the emptying rates for the two components or between fasting and non-fasting conditions (P > 001).
The action of R51619 on transport processes in the rat small intestine
Authors: Hardcastle Jacqueline , Hardcastle P T , Kelleher Debra K
Published: April 2011

R51619, an agent reported to release endogenous acetylcholine, increased the potential difference and short-circuit current across non-stripped, but not stripped sheets of rat mid-intestine. The response was abolished by both hexamethonium and atropine. R51619 stimulated fluid accumulation by intestinal loops in-vivo suggesting its predominant effect is to stimulate anion secretion. These results are consistent with R51619 releasing endogenous acetylcholine within the myenteric plexus to activate postganglionic cholinergic fibres which stimulate intestinal secretion via muscarinic cholinoreceptors.
Development of a sensitive radioreceptor assay for oxyphenonium in plasma and urine
Authors: Ensing K , Kluivingh F , Gerding T K , De Zeeuw R A
Published: April 2011

A radioreceptor assay (RRA) for oxyphenonium has been developed. It is based on competition between [3H]dexetimide and oxyphenonium for binding to muscarinic receptors from calf striata. The RRA is optimized towards incubation medium and to extraction by ion pair formation with sodium picrate. At least 4 times 10−10 m of oxyphenonium is necessary to permit a reliable assay. This corresponds to a detection limit of drug of 2 ng ml−1 urine. After extraction, drug at 100 pg ml−1 of plasma can be estimated using 4 ml samples. The method is applicable to monitoring the drug and to the determination of its pharmacokinetics after therapeutic dosing. Urine levels can also be monitored.
Mechanism of the indirect adrenergic effect of histamine in cat cerebral arteries
Authors: Balfagón Gloria , Galván Rosa , Marco Emilio J
Published: April 2011

KCl (50 mm), tyramine (10−7 m), and histamine (10−4 m) induced an increase in tritium release from cat cerebral arteries preincubated with [3H]noradrenaline, this increase being due in part to noradrenaline. When calcium was absent from the superfusion medium, only tyramine (10−7 m) enhanced the tritium outflow. Colchicine (10−3 m) partially inhibited the increase in radioactivity brought about by 10−4 m histamine. KCl (50 mm) also evoked release of radioactivity from cerebral arteries preloaded with [3H]histamine; this release was unafffected by reserpine pretreatment or removal of both superior cervical sympathetic ganglia. Neither tyramine (10−7 m) nor compound 48/80 (300 μg ml−1) altered the spontaneous tritium outflow from cerebral blood vessels preincubated with [3H]histamine. These results suggest that histamine is not accumulated by sympathetic nerve endings and elicits its noradrenaline-releasing effect by means of an exocytotic process.
Relationship between sine random vibrations, resonance and drug content uniformity
Authors: Staniforth John N
Published: April 2011

The effect of sine random vibrations on the segregation tendency of 3 ordered powder mixes was studied. Ordered mixes containing either Emdex, Dipac or recrystallized lactose carrier particles mixed with 0·5% fine-particle potassium chloride were prepared. It was found that the coefficients of variation of drug content in samples removed from the ordered mixes following random vibration were, in general, lower than those derived from vibration at equivalent single frequencies. Ordered mixes vibrated at low centre-frequencies were found to be most prone to slight demixing and under these conditions, a vibration bandwidth of 30 Hz produced more de-mixing than a 10 Hz bandwidth. Most ordered mixes were considered to be segregation free following random vibration.
The influence of α1- and α2-adrenoceptor agonists on cardiac output in rats and cats
Authors: Kalkman Hans O , Thoolen Martin J M C , Timmermans Pieter B M W M , Van Zwieten Pieter A
Published: April 2011

In pithed rats, but not in pithed cats, the α2-/dopamine agonist B-HT 920 (10–300 μg kg−1) increased cardiac output. The increase was inhibited by yohimbine (1 mg kg−1), but not by sulpiride (0·3 mg kg−1) and nifedipine (1 mg kg−1). Both in pithed rats and cats, the α1−adrenoceptor agonist methoxamine (30–300 μg kg−1 and 30–1000 μg kg−1, respectively) increased cardiac output. This increase (rats) was inhibited by prazosin (0·1 mg kg−1). The results indicate the existence of functional venous α2−adrenoceptors in pithed rats, and their absence in pithed cats. Furthermore, α2−adrenoceptor−mediated venoconstriction appears independent of extracellular calcium.
The effect of garlic extracts on contractions of rat gastric fundus and human platelet aggregation
Authors: Gaffen J D , Tavares I A , Bennett A
Published: April 2011

Garlic has been extracted and separated chromatographically into various fractions which show different degrees of activity as inhibitors of platelet aggregation and smooth muscle. The most potent smooth muscle inhibitor fraction had little activity on platelet aggregation, but μg ml−1 concentrations greatly reduced the contractions of rat gastric fundus to prostaglandin E2 and acetylcholine. Material in this fraction may contribute to some of the claimed therapeutic effects of garlic involving smooth muscle. Its identity is not known, but is different from allyl sulphide, dimethyl sulphide and diallyl disulphide. These compounds eluted earlier on liquid chromatography than the most active fraction, and they showed only modest inhibitory activity against prostaglandin E2 and acetylcholine on rat fundus.
Possible prostaglandin―mediated effect of diethylcarbamazine on rat uterine contractility
Authors: Joseph C A , Dixon P A F
Published: April 2011

The effect of diethylcarbamazine pretreatment on uterine contractility was investigated in both pregnant and nonpregnant rats. The pretreatment potentiated the uterine responses to oxytocin and acetylcholine, and enhanced the spontaneous uterine contraction of rats in oestrus or 17–20 days pregnant. This enhanced contraction was antagonized both in−vivo and in−vitro by indomethacin, suggesting the involvement of prostaglandins.
In―vitro evaluation of the anticandidiasis activity of honey distillate (HY−1) compared with that of some antimycotic agents
Authors: Obaseiki―Ebor E E , Afonya T C A
Published: April 2011

The susceptibility of 72 isolates of Candida albicans to the antimicrobial honey distillate fraction (HY−1) and several antimycotic agents is presented. All the isolates were sensitive to HY−1, H−115 and Jadit, while about 10% of the isolates were variably resistant to nystatin, miconazole nitrate and clotrimazole. The nystatin, miconazole nitrate and clotrimazole resistant isolates were inhibited by HY−1.
Preparation and release kinetics of microencapsulated cisplatin with ethylcellulose
Authors: Hecquet B , Fournier C , Depadt G , Cappelaere P
Published: April 2011

Several kinds of microcapsules containing cisplatin were prepared by the ethylcellulose coacervation process in an attempt to administer cisplatin with chemoembolization. Microcapsules made either with mechanical stirring or with sonication showed similar properties; the chemical structure of cisplatin was not affected by the micro-encapsulation process. The release kinetics of cisplatin from ethylcellulose-walled microcapsules followed different patterns, according to the wall thickness. In each case, the release kinetics did not depend on the stirring rate of the surrounding medium. Only microcapsules with a cisplatin release ratio from 80 to 100% within 24 h were selected for later clinical use.
The effect of ergot alkaloids ergosinine, dihydroergosine and dihydroergotamine on neurotransmission and contractility of the isolated ileum of the guinea-pig
Authors: Radulović S , Djordjević N , Kažić T
Published: April 2011

The effects of ergosinine (ESNN), dihydroergosine (DHESN) and dihydroergotamine (DHE) on contractions of the isolated terminal and middle segments of the guinea-pig ileum were studied in-vitro. Responses to cholinergic (3 Hz) and adrenergic stimulation (30 Hz in the presence of atropine) were inhibited, albeit at high concentrations of all three alkaloids (1–30 μg ml−1). Cholinergic neurotransmission was surprisingly more affected than adrenergic transmission. Noradrenaline (NA) contractions, however, were inhibited at very low concentrations (1–30 ng ml−1) with the following order of potency: DHESN = DHE > ESNN. Prazosin was equally as potent as DHESN in inhibiting NA contractions and similarly potent in inhibiting responses to adrenergic stimulation. ESNN, DHESN and DHE when used at concentrations from 1–30 μg ml−1 were also found to inhibit 5-hydroxytryptamine > histamine > acetylcholine > KCl contractions. The results suggest that the principal pharmacological action of ESNN, DHESN and DHE on the guinea-pig isolated ileum is the antagonism to NA on the postsynaptic and extrajunctional population of α-adrenoceptors. The neurotransmission, adrenergic as well as cholinergic, appeared to be inhibited via a non-specific presynaptic mechanism presumably regulating the transmitter release. Anti-5-hydroxytryptamine, anti-acetylcholine and antihistamine actions were obtained at similar and relatively high concentrations, thus pointing to a non-specific depressant action upon a common mechanism regulating the contractility of the smooth muscle. Finally, ESNN although a derivative of (+)-isolysergic acid (derivatives of which are generally regarded as inactive) was shown to possess a pharmacological activity comparable to DHESN, i.e. to the drug representing active derivatives of (+)-lysergic acid.
Modification of seizures elicited by the benzodiazepine Ro 5–3663—a comparison with picrotoxin
Authors: File Sandra E
Published: April 2011

Ro 5–3663 is a convulsant 1,4-benzodiazepine that does not act at the benzodiazepine, but at the picrotoxin, site. To characterize the behavioural actions of Ro 5–3663, a comparison was made between its effects and those of picrotoxin, when combined with several compounds that act at the GABA-benzodiazepine receptor complex. The quinolines, PK 8165, PK 9084 and CGS 8216 caused myoclonic jerks when combined with subconvulsant doses of Ro 5–3663 or picrotoxin; in combination with picrotoxin they also caused full tonic-clonic convulsions. Ro 15–1788 (1, 10mg kg−1) caused myoclonic jerks when it was given 10 min before, or at the same time as, subconvulsant doses of either compound. Diazepam (2, 4 mg kg1) was anticonvulsant against both compounds. However, Ro 15–1788 (10,20 mg kg−1, 20 min before), PK 8165 (80 mg kg−1) and PK 9084 (60mgkg−1) were effective only against the convulsions induced by Ro 5–3663. It is not possible to determine whether these differences between Ro 5–3663 and picrotoxin are quantitative or qualitative.
Adenosine mechanisms are not affected by antidepressant concentrations of desipramine
Authors: Jonzon Bror , Fredholm Bertil B
Published: April 2011

We have evaluated the proposal that adenosine may mediate some of the effects of tricyclic antidepressant therapy. In-vitro desipramine (DMI) (1–10 μm) did not affect adenosine or 2-chloroadenosine-induced inhibition of lipolysis or the adenosine stimulated formation of cyclic (c)AMP in the hippocampal slice. However, very high concentrations of desipramine (0·2–0·5 mm) as well as some detergents potentiated the stimulatory effect of adenosine on cAMP formation. The ATP, ADP and AMP contents in slices were unaffected as was the electrically evoked release of purines. Long-term treatment in-vivo with antidepressants in clinically relevant doses did not alter the sensitivity of adenosine receptor mediated cAMP formation in-vitro while the β-adrenoceptor-mediated formation was depressed by desipramine or imipramine treatment but not by zimelidine or fluoxetine treatment. It is concluded that actions on central adenosine mechanisms are unlikely to play any important role in the therapeutic effects of tricyclic antidepressants.
The development of a relative hyperthermia during continuous clonidine infusion in the rat
Authors: Maccarrone C , Lewis S J , Jarrott B
Published: April 2011

In rats the continuous infusion of clonidine (10 μg kg−1 h−1) produces a relative hyperthermia of approximately 0·6 °C during the light phases but not the dark phases of a 10 day infusion period. It appears that the relative hyperthermia results from a clonidine infusion-induced attenuation of the fall in body temperature which normally occurs at the onset of the light phases.
The opacity of tablet film coatings
Authors: Rowe R C
Published: April 2011

The opacity of tablet film coatings containing a variety of pigments and fillers has been assessed using a contrast ratio defined as the ratio of the measured reflectance of the incident light when the film is placed on a black substrate to the measured reflectance of the incident light when the film is placed on a white substrate. Films pigmented with calcium carbonate, calcium sulphate or talc had very low contrast ratios and only the inclusion of titanium dioxide imparted opacity. Films pigmented with the coloured lake pigments had contrast ratios dependent on both the parent dye and the dye concentration with the contrast ratios decreasing blue > red > orange > yellow. Films pigmented with the synthetic iron oxides all had very high contrast ratios. The results are consistent with the known theories of light scattering and absorption and illustrate the potential of this accurate, rapid and simple technique in the optimization of film formulations during product development.
Passive inhalation of cannabis smoke
Authors: Law B , Mason P A , Moffat A C , King L J , Marks V
Published: April 2011

Six volunteers each smoked simultaneously, in a small unventilated room (volume 27 950 litre), a cannabis cigarette containing 17·1 mg Δ9-tetrahydrocannabinol (THC). A further four subjects – passive inhalers – remained in the room during smoking and afterwards for a total of 3 h. Blood and urine samples were taken from all ten subjects and analysed by radioimmunoassay for THC metabolites. The blood samples from the passive subjects taken up to 3 h after the start of exposure to cannabis smoke showed a complete absence of cannabinoids. In contrast, their urine samples taken up to 6 h after exposure showed significant concentrations of cannabinoid metabolites (≤6·8 ng ml−1). These data, taken with the results of other workers, show passive inhalation of cannabis smoke to be possible. These results have important implications for forensic toxicologists who are frequently called upon to interpret cannabinoid levels in body fluids.
Sulfinpyrazone increases the number of β-adrenoceptors on intact human lymphocytes
Authors: De Blasi Antonio , Costantini Carlo
Published: April 2011

Sulfinpyrazone increased the number of β-adrenoceptors (+17–40%) on intact human lymphocytes at concentrations ranging from 10−5 to 2 times 10−4  m. It affected the Bmax (187 ± 6 and 142 ± 5 fmol mg−1 protein respectively with and without sulfinpyrazone, P < 0·001) but did not influence KD (4·4 ± 0·3 and 4·6 ± 0·7 nm with and without the drug). This effect was observed on either washed or unwashed lymphocyte membrane preparations. These findings have several pharmacological and therapeutic implications.
Kinetics and distribution of the β-adrenergic agonist salbutamol in rat brain
Authors: Caccia S , Fong M H
Published: April 2011

The kinetics of the β-adrenergic agonist salbutamol and its distribution in the central nervous system were examined in rats by high-performance liquid chromatography with electrochemical detection. After 10 mg kg−1 i.v. salbutamol, the decline in drug plasma concentrations was biphasic and salbutamol was cleare every rapidly with a β-half-life of about 37 min. Salbutamol rapidly penetrated the ‘blood-brain barrier’ and reached brain concentrations amounting to about 5% of the plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands) the drug achieved concentrations more than 100 times those in whole brain. The results support the hypothesis that stimulation of central β-adrenergic sites is responsible for salbutamol’s pharmacological and biochemical effects.
The putative 5-HT1 receptor agonist, RU 24969, inhibits the efflux of 5-hydroxytryptamine from rat frontal cortex slices by stimulation of the 5-HT autoreceptor
Authors: Middlemiss Derek N
Published: April 2011

The putative central 5-HT receptor agonist, 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole succinate (RU 24969), was found to be a potent inhibitor of the continuous K+ evoked efflux of [3H]5-HT from superfused rat frontal cortex slices (pD2 7.45). The effects of RU 24969 were attenuated by the putative 5-HT autoreceptor antagonists, methiothepin, quipazine and (-)-propranolol but not by the α2-adrenoceptor antagonist, idazoxan. It is concluded that RU 24969 inhibits K+ evoked efflux of [3H]5-HT from rat frontal cortex slices by stimulation of the 5-HT autoreceptor. Moreover, since RU 24969 potently displaced ligand binding to the 5-HT1 and 5-HT1B recognition sites but was only weakly active at the 5-HT2 receptor, the results lend support to the claim for a pharmacological resemblance between the 5-HT autoreceptor and the 5-HT1 recognition site and in particular the low affinity 5-HT1B subtype.
Comparative potencies of calcium channel antagonists and antischizophrenic drugs on central and peripheral calcium channel binding sites
Authors: Quirion Rémi , Lafaille F , Nair N P V
Published: April 2011

Dihydropyridines are potent agents on [3H]nitrendipine binding sites in heart and brain membranes. Like the phenylalkylamines, they are slightly more active on heart than on brain [3H]nitrendipine binding sites. On the other hand, the diphenylalkylamines, the diphenylpiperazines and the antischizophrenic drugs of the diphenylbutylpiperidine type are more potent on brain [3H]nitrendipine binding sites. The findings suggest tissue heterogeneity of [3H]nitrendipine binding sites and the possible development of diphenylbutylpiperidine-diphenylbutylpiperazine analogues that could selectively act on brain calcium channel antagonist binding sites.
Influence of serum protein binding on hepatic clearance of S-disopyramide in the rabbit
Authors: Huang Jin-Ding , Øie Svein
Published: April 2011

The effect of changing the protein binding of S-disopyramide, a compound that is highly extracted by the liver on its hepatic clearance in rabbits is described. Using indocyanine green clearance as a means of measuring hepatic blood flow, qualitative changes were observed which are in agreement with the results predicted by both the ‘parallel tube’ and the ‘well-stirred’ models. However, neither model alone could explain the quantitative changes. Suggestions are put forward to explain these results.
Possible mechanisms of inhibitory action of protamine on contractile activity of rat aorta
Authors: Uruno Tsutomu , Matsumoto Ryuji , Okushita Keiko , Sunagane Nobuyoshi , Kubota Kazuhiko
Published: April 2011

Experiments were performed to determine possible mechanisms of inhibitory action of protamine chloride on noradrenaline (10 μM)-, KCl (40 mM)-, BaCl2 (1 mM)- and CaCl2 (10 mM)-induced contractions in rat aorta. Protamine, La3+ and gallopamil (D600), inhibited the K+-induced contractions more effectively than the noradrenaline-induced responses on the basis of the concentrations giving 40% inhibition. Lanthanum (1–5 mM) reduced tissue Ca content in both normal and Ca2+-depleted Tris-buffered solutions and produced an increase in 45Ca efflux from the aortic strip into the Ca2+-depleted Tris solution. Protamine (1–5 mg ml−1) reduced tissue Ca content in normal Tris solution, but to a lesser extent than La3+ in the Ca2+-depleted solution. Furthermore, protamine (2 mg ml−1) produced no increase in 45Ca efflux from aorta. These results suggest that protamine chloride may preferentially inhibit the Ca2+ influx stimulated by K+ depolarization and that its inhibitory action on rat aorta may be due to non-specific displacement of the superficially located bound Ca2+ of the cell membrane, which can also be readily removed by treatment with Ca2+-depleted solution.
Cardiorespiratory depression and haemolysis due to thioridazine overdose in the rat
Authors: Langemeijer J J M , De Wildt D J , De Groot G , Sangster B
Published: April 2011

The cardiovascular and respiratory effects of an intravenous overdose of thioridazine (125 mg kg−1 h−1) were examined in either spontaneously breathing or artificially ventilated urethane-anaesthetized rats. In both groups Po2, heart rate and mean arterial pressure decreased and atrioventricular and intraventricular conduction time, as well as QT time, increased similarly. Pco2 and pH did not differ significantly except in spontaneously breathing rats where a severe acidosis occurred at the end of the experiments. Haemolysis was suspected. The same dose was administered intravenously to artificially ventilated rats. Plasma concentrations of the drug and its main metabolites, haematocrit and free plasma Hb were determined in separate groups. A severe haemolysis was observed. Thioridazine administered in the same doses intragastrically, intraduodenally or intraperitoneally resulted in lower plasma values than after intravenous administration and there was no haemolysis. Much higher oral doses produced haemolysis at 36 h, at which time plasma concentrations were not higher than those recorded after administration via the other non-intravenous routes. It is probable that the observed changes in cardiovascular and respiratory parameters are partly the result of haemolysis following thioridazine administration.