bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolism of isoprenaline in the intestine
Authors: George C F , Blackwell E W , Davies D S
Published: April 2011

A method for the study of drug metabolism in isolated canine gut loops is described. This technique has been used to study the conjugation of isoprenaline with ethereal sulphate. After intraluminal injection of tritiated isoprenaline only 3·6% of the radioactivity in venous effluent appeared as free isoprenaline, and 68·0% as a sulphate conjugate. After pretreatment with salicylamide the proportion of free isoprenaline rose to 73·7% and only 3·3% was accounted for as sulphate conjugate. The significance of these findings is discussed in relation to a possible source of drug interaction.
The depressant action of morphine on transmission at a skeletal neuromuscular junction is non-specific
Authors: Bell Kathryn M , Rees J M H
Published: April 2011

The depressant actions of apomorphine, etorphine, dextromoramide, laevomoramide, naloxone, codeine, morphine and nalorphine have been examined on the rat diaphragm preparation. Their descending order of potency (in the order given above) differed greatly from that published for activity at specific opiate receptors. The depressant action of morphine was not antagonized by naloxone. The stereoisomers dextro- and laevomoramide were equipotent in depressing the preparation. On the transmurally stimulated guinea-pig ileum preparation the depressant action of dextromoramide was antagonized by naloxone. Laevomoramide was 10 000 times less potent than its (+)-isomer, and was not antagonized by naloxone. It is concluded that the effects of narcotic analgesics on transmission at a skeletal neuromuscular junction are not mediated via opiate receptors.
Conditions affecting the interaction of cholinergic agents on the longitudinal muscle of the guinea-pig ileum—unexpected effects with hexamethonium
Authors: Geddes Barbara A , Bogart Laurie F , Hamilton John T
Published: April 2011

Affinity constants were determined for atropine and N-methyl atropine, using both acetylbetamethylcholine and carbaminoylcholine as agonists, on plexus-containing and plexus-free preparations of the guinea-pig ileum. Hexamethonium (1 times 10−4M) decreased the apparent affinity constant of atropine on the plexus-free preparation when carbaminoylcholine but not acetylbetamethylcholine was the agonist. With the latter agonist both antiacetylcholine drugs were equiactive. Hexamethonium’s selective action was associated with a significant shift to the left of the log dose-response curve to carbaminoylcholine on the plexus-free preparation. While others have observed that hexamethonium may be atropine-like, samples of hexamethonium have been reported as being contaminated with a “depolarizing compound”, which may account for the results presented in this study. Nevertheless, the present results are consistent with an allosteric rather than a direct binding mechanism in the blocking action of atropine. The observation that the agonist, acetylbetamethylcholine, was not similarly affected by hexamethonium (or any possible contaminant) suggests that agents with primarily muscarinic activity may not be so affected. This study is another example emphasizing the care needed in interpreting data obtained with the aid of “pharmacological tools”.
Glucose intolerance in thiamine-deficient rats
Authors: Iwata H , Baba A , Baba T , Nishikawa T
Published: April 2011

The mechanism of glucose intolerance in thiamine-deficient rats has been examined. Deficient rats showed marked glucose intolerance. However, the hypoglycaemic effect of insulin (1 i.u. kg−1, i.p.) was similar in the deficient, pair-fed and normal groups, though somewhat weaker in the normal group than in the other two groups. After injection of tolbutamide (40 mg kg−1, i.p.), the hypoglycaemic effects in the three groups were the same. Tyramine (10 mg kg−1, s.c.) restored the impaired glucose tolerance of deficient rats to normal, but not that of alloxan diabetic rats. Furthermore, tyramine did not restore the intolerance of deficient rats pretreated with alloxan. These results suggest that the main factor causing glucose intolerance in the deficient rats may be suppressed insulin secretion.
A pharmacokinetic investigation of the distribution and elimination of diethylpropion and its metabolites in man
Authors: Mihailova D , Rosen A , Testa B , Beckett A H
Published: April 2011

Analogue and digital computing techniques have been used to elucidate the pharmacokinetic parameters involved in the metabolism and excretion of diethylpropion and its metabolites in man. Rate constants for the various processes have been evaluated for the complex reaction scheme. The values of the rate constants are used as a basis for discussion of the relative importance of some of the metabolic routes.
Anthracene derivatives in tissue culture of Cassia senna L.
Authors: Rai P P , Turner T D , Greensmith S L
Published: April 2011

Tissue cultures from Cassia senna L. have been established. Chryso-phanol, physcion, emodin, rhein and aloe emodin have been identified in the oxidative-hydrolysate of the callus. Chrysophanol was the major component. With the exception of physcion all of these compounds were found in the glycosidic as well as the free form. The concentration in the dried callus of the free anthraquinones was 0·8% w/w and of the glycosidic (combined) anthraquinones 0·4% w/w. These results and the absence of sennosides in the cultures emphasize the variation in the anthracene derived constituents of the derived callus and the parent plant.
Shearing and tensile tests on mixtures of pharmaceutical powders
Authors: Arini S Koćova el , Pilpel N
Published: April 2011

Shearing and tensile tests provide information about the mechanical properties of mixtures of fine pharmaceutical powders. They might be used for predicting their flow and compressional characteristics during handling and in the production of capsules and tablets.
A kinetic study of human urinary excretion results for butobarbitone and its metabolites
Authors: Gilbert J N T , Natunen T , Powell J W , Saunders L
Published: April 2011

Experimentally determined concentrations of butobarbitone, and three or its metabolites, in the urine of two volunteers, have been studied using a computer technique, which tests the data for limited capacity or first order kinetics. In both volunteers, the 3′-hydroxy and the 3′-oxo metabolites follow limited capacity kinetics for the first few days of excretion, and unchanged butobarbitone follows first order kinetics. Differing results were found for the two persons with the 3′-carboxylic acid metabolite. An additional calculation is proposed when applying the Levy method for interpreting limited capacity kinetics to data where drug recovery is incomplete.
Application of polarography to the development of a stability-indicating assay method for a new indole derivative and its tablet formulations
Authors: Chan H K
Published: April 2011

A polarographic method has been developed for the determination of an antidepressant, 10-(m-chlorophenyl)-2,3,4,10-tetrahydropyrimido [1, 2a] indol-10-ol hydrochloride. The method is not subject to interference from the immediate precursor in the synthetic route of drug preparation or the products of thermal degradation of the active drug substance. The method may be used to monitor storage stability studies.
The mechanical properties of some binders used in tableting
Authors: Healey J N C , Rubinstein M H , Walters V
Published: April 2011

Films of acacia, gelatin, methylhydroxyethyl cellulose, polyvinylpyrrolidone (PVP) and starch have been prepared with moisture levels of 2·0 to 20·0% w/w obtained by equilibration at relative humidities from 0 to 90%. Tensile strengths of 60 mm × 2 mm strips of these films have been determined by stressing to failure at a constant rate of 6·6 times 10−5 ms−1 in a tensile strength apparatus. From the stress-strain curves the modulus of elasticity, yield strength and the work done in breaking unit cross-sectional area of the films have been calculated. This has given an indication of the binders’ mechanical behaviour over the range of moisture contents likely to be encountered in tableting.
The effects of moisture content and gelatin binding agent on the mechanical and failure properties of an Oxytetracycline formulation
Authors: Esezobo S
Published: April 2011

N PILPEL

A study has been made of the effects of gelatin as a binding agent and of moisture content on the mechanical and failure properties of an oxytetracycline tablet formulation, using measurements of the shear strengths and tensile strengths. As the concentration of gelatin at any moisture level between 0 and 25 % w/w is increased, the tensile strength of the formulation increases. Its cohesion and angle of internal friction also increase with gelatin concentration at moisture levels between 2 and 4% w/w. The results are discussed in the light of current theories concerning the bonding of particles by moisture and binding agents.
Improvement of solubility and dissolution rate of poorly water-soluble salicylic acid by a spray-drying technique
Authors: Kawashima Y , Saito M , Takenaka H
Published: April 2011

Spray drying techniques have been applied to improve the solubility and dissolution rate of poorly water-soluble salicylic acid. Spray drying of the acid dispersed in acacia solutions resulted in as much as a 50% improvement in the solubility of the product. Solubility improvement was closely related not only to the concentration of acacia but also the amount of amorphous material in the spray-dried products. The heat of solution was inversely related to these parameters. The dissolution rate of spray-dried product was almost instantaneous being about 60 times faster than that of the original powder. A great improvement in the wettability of the spray-dried material seemed to be mainly responsible for the increase of dissolution rate.
A crystallographic and theoretical study of the conformation of DOET and its significance for the hallucinogenic amphetamines
Authors: Horn Alan S , Post Michael L , Kennard Olga , di Sanseverino L Riva
Published: April 2011

The crystal and molecular structure of 2,5-dimethoxy-4-ethyl-α-methyl-phenylethylamine (DOET) has been determined by X-ray crystallography and the conformation of the side chain has been examined theoretically by the use of a potential energy calculation. There is no indication in the solid state of any intra or inter-molecular hydrogen bonding. The isopropylamine side chain is staggered to the plane of the benzene ring. The α-methyl group is fully extended (antiplanar) whereas the amino group is orientated back towards the ring (synclinal). The potential energy calculations show the existence of 6 minima, one of which corresponds to the crystal position. The calculations also show that the energy differences between the various minima of the side chain are very small. The relationship of these data to the conformations of the hallucinogens, mescaline and 2,4,5,-trimethoxyamphetamine is discussed.
The role of p-hydroxylation of amphetamine in its peripheral mode of action
Authors: Freeman J J , Sulser F
Published: April 2011

Desipramine completely abolished the blood pressure response to (+)-amphetamine in the rat, whereas the tricyclic antidepressant iprindole did not reduce this response. Since both tricyclic drugs inhibit the aromatic hydroxylation of amphetamine, these studies do not support the hypothesis that hydroxylated metabolites of amphetamine, p-hydroxyamphetamine and p-hydroxynorephedrine are essential for the peripheral sympathomimetic effects of amphetamine.
Pharmacokinetics of haloalkylamines: cyclization and distribution in blood in vitro and in vivo
Authors: Ross Svante B
Published: April 2011

The cyclization of N-(5-chloropentyl)-N-methylaniinoaceto-2,6-xylidide hydrochloride (RAD 150) and N-(5-bromopentyl)-N-methylaminoaceto-2,6-xylidide hydrobromide (RAD 154) in red blood cells of rats and rabbits was examined under in vitro and in vivo conditions. The rate of cyclization was much slower in plasma and blood than in a buffer solution, probably due to influence of protein binding of the compounds. The tertiary amines disappeared rapidly from the blood cells in vitro and in vivo and the piperidinium derivative (RAD 179) formed from the haloalkylamines disappeared almost as rapidly as the tertiary amines from the plasma in vivo. In contrast, the efflux of RAD 179 formed in the blood cells was slow (T½ for rabbit erythrocytes: 9 h in vitro; 8 h in vivo) following a 1st order reaction. RAD 179 itself was only to a small extent taken up in the blood cells.
Skin irritants of Euphorbia fortissima
Authors: Kinghorn A D , Evans F J
Published: April 2011

By means of a combination of partition and chromatographic methods six irritant constituents were isolated from the fresh latex of Euphorbia fortissima. Compounds A-D were di-esters of the common parent diterpene 12-deoxyphorbol, and compounds E and F were mono-esters of the same diterpene. The fresh latex had an irritant dose 50% (ID50) on mice of 0.64 μg μ1−1. Compounds A-D are short-acting irritants reaching a maximum activity within 4 h of application to the skin, whilst the monoesters maintained potent irritant effects for up to 24 h. Selective hydrolysis of the di-esters at the C–20 primary ester group also produced mono-esters of greater potency after 24 h. An increase in the length of the fatty acid located at C–13 produced greater biological activity in both the mono- and di-ester groups.
Metabolism of phenothiazines: identification of N-oxygenated products by gas chromatography and mass spectrometry
Authors: Essien E E , Cowan D A , Beckett A H
Published: April 2011

The solid inlet mass spectra of the N-oxide and N-oxide sulphoxide metabolites of promazine, chlorpromazine and methotrimeprazine have been determined at different temperatures and compared with the mass spectra of the main thermolytic product of the N-oxides and N-oxide sulphoxides obtained during combined gas chromatographymass spectrometry. Diagnostic ions were produced by direct insertion of the compounds at ambient temperature into the mass spectrometer. These ions distinguish the N-oxides of arylalkyl tertiary amines from the N-oxygenated derivatives of primary and secondary arylalkylamines.
The diffusion of penicillin G and ampicillin through phospholipid sols
Authors: Padfield John M , Kellaway I W
Published: April 2011

The self-diffusion coefficients of penicillin G and ampicillin have been determined at 25° in water and in the presence of a swamping concentration of electrolyte. The antibiotics diffused through phospholipid dispersions at a reduced rate due to interaction with the lipid aggregates. Ampicillin diffused through the phosphatidylcholine and phosphatidylethanolamine dispersions more rapidly than penicillin G, whereas the latter diffused more rapidly through the lysophosphatidylcholine dispersions. Estimates of binding have been made from these data and compared with those obtained from equilibrium dialysis studies. Surface tension measurements indicated that the antibiotics exhibited minimal surface activity. These results have been correlated with data obtained in other studies and a possible explanation has been advanced for the reported differences in in vivo activity of penicillin G and ampicillin.
The instrumentation of a Zanasi LZ/64 capsule filling machine
Authors: Cole G C , May G
Published: April 2011

The dosator system of a Zanasi LZ/64 capsule filling machine was modified and strain gauges were fitted. These were used to measure the forces on the powder being filled during compaction and ejection. The patterns of those forces produced were shown to differ between different materials and between lubricated and unlubricated materials. Tentative reasons for the observed differences have been suggested.
Emulsion stabilization by non-ionic surfactants: the relevance of surfactant cloud point
Authors: Florence A T , Madsen Florence , Puisieux F
Published: April 2011

The effect of various additives, electrolytes and non-electrolytes, on the cloud point of non-ionic surfactants has been studied. Additives which salt-out the polyoxyethylene chains of the surfactants cause decreased stability of oil-in-water emulsions by decreasing the true hydrophile-lipophile balance (HLB) of the surfactant; additives such as sodium iodide and propanol salt-in the non-ionic surfactants and result in an increase in the effective or true HLB of the system. The latter additives do not increase the hydration of the polyoxyethylene chains but their effect must be on the structure of water so that the heat of hydration of the chains is altered. Experiments with free films of the aqueous surfactant (Brij 96) show that thinning rates are markedly affected by the additives, but there is little effect on the equilibrium thickness of the films (ca 11 nm). Nonetheless the thickness at the transition from thick film to equilibrium black film decreases with increasing cloud point of the solution indicating increased stability. The importance of structure formation in the liquid film separating the emulsion globules was demonstrated.
The evaluation of a column-type dissolution apparatus
Authors: Groves M J , Alkan M H , Deer M A
Published: April 2011

An improved column-type dissolution apparatus is described. The column of the apparatus is built from standard screw-cap connected ‘Sovirel’ glass tubes which should enable inter-apparatus variability to be reduced. The main problem with this type of device is the build up of back pressure as fragments from the disintegrating solid dosage form progressively block the filtration system, itself necessary to stop the solution process and present the solution for analysis. A simple type of light-activated switch is therefore used which works across the indicator float of a flow meter to drive a motor connected to a needle valve. As the float falls the motor is switched on to open the valve and increase the flow rate until the float rises again and causes the motor to switch off. Observation on the dissolution characteristic of dyed lactose tablets and the injection of dye solutions into the flowing stream of liquid around tablets showed that there was back-flow of solution at Reynolds Numbers below 10 but visible instability of flow at Re > 100. Over a range of flow rates between Re 10–70 the mass of drug released at a given time was a direct function of flow rate for a film coated product but an inverse function for a sugar coated tablet. The results are discussed in relation to the main problems which can be experienced with a column-type dissolution apparatus.
Microiontophoretic studies of the effects of false transmitter candidates and amphetamine on cerebellar Purkinje cells
Authors: Kostopoulos G K , Yarbrough G G
Published: April 2011

The effects of microiontophoretic applications of equivalent doses (ejection times and currents) of noradrenaline, amphetamine, octop-amine and p-hydroxynorephedrine on the spontaneous firing of Purkinje and unidentified cells in the cerebellum of rats were examined. In addition, the effects of amphetamine on Purkinje cells were examined in nimals pretreated with the tyrosine hydroxylase inhibitor, α-methyl-tyrosine (α-MpT) or with a combination of reserpine plus α-MpT. The results indicate that the “false transmitters” are weak agonists when compared to noradrenaline in inhibiting the firing of Purkinje cells. The results of the iontophoretic studies with amphetamine are not consistent with a pre-synaptic releasing effect by amphetamine at noradrenergic synapses in the cns since the efficacy of amphetamine on Purkinje cells was unaltered after pretreatment with α-MpT or α-MpT plus reserpine.
Intra- and extraneuronal formation of the two major noradrenaline metabolites in the cns of rats
Authors: Braestrup C , Nielsen M
Published: April 2011

The two major noradrenaline metabolites in the rat brain, total 3-methoxy-4-hydroxyphenylglycol(MOPEG) and total 3,4-dihydroxy-phenylglycol (DOPEG), were measured by a new analytical procedure after intraventricular (i.v.t.) injection of [3H]noradrenaline or [3H]dopamine. I.v.t. injection of [3H]noradrenaline to rats with a 6-hydroxydopamine-induced destruction of nerve terminals in the central nervous system, resulted in an increased accumulation of 3H-MOPEG compared to 3H-DOPEG. On the contrary, reserpine induced a greater increase in 3H-DOPEG than in 3H-MOPEG accumulation when these two metabolites were formed from [3H]noradrenaline synthesized in vivo by i.v.t. injection of [3H]dopamine. These results indicate that the formation of DOPEG and MOPEG occur with some preference intra- and extraneuronally, respectively. The results, however, also show that these two formations sites should not be considered as specific.
The gas chromatographic determination of atenolol in biological samples
Authors: Scales Bryan , Copsey Paul B
Published: April 2011

Methods are described for the gas chromatographic determination of the β-adrenoceptor blocking agent atenolol (ICI 66,082 Tenormin) in whole blood, serum, tissue and urine. The method involves the extraction of the free base from the prepared biological sample into an organic solvent mixture. Further purification is done by back-extracting the base into dilute acid from which, after basification it is extracted again into organic solvent. Any atenolol in the residue remaining after solvent evaporation is converted into a heptafluoro-butyrate derivative ready for gas chromatography. Use of an electron-capture detector enables concentrations as low as 0.01 μg ml−1 body fluid and 0.04 μg ml−1 tissue to be measured.
The development of a radioimmunoassay for cannabinoids in blood and urine
Authors: Teale J D , Forman Elvyne J , King L J , Piall Evelyn M , Marks V
Published: April 2011

Antibodies, for use in radioimmunoassay, have been raised in sheep by immunization with a conjugate of Δ9-tetrahydrocannabinol hemisuccinate and bovine serum albumin. Antiserum titre and avidity were increased by successive booster doses of conjugate. The high degree of non-specific binding encountered in the radioimmunoassay of cannabinoids was reduced by the use of the solubilizing detergent Triton X-405 and by restricting protein concentration in the assay medium. Plasma samples were deproteinized with ethanol before assay, but urine was directly assayed. High avidity antibodies and high specific activity [3H]- Δ9-tetrahydrocannabinol permitted the detection of 50 pg of cross-reacting cannabinoids–-a sensitivity of 7.5 ng ml−1 of plasma and 1.0 ng ml−1 of urine. Whilst apparently specific for the three-ringed cannabinoid nucleus, the assay antiserum cross-reacted with several cannabinoids, both natural compounds and metabolites. Partial identification of cross-reacting cannabinoids was achieved by the use of pure compounds and by the assay of plasma and urine samples collected from rabbits given pure cannabinoids intravenously.
Characterization of an angiotensin II-fluorescamine derivative
Authors: Forget Gilles , Heisler Seymour , Park Won Kil , Sirois Pierre , Gagnon Denis , Regoli Domenico
Published: April 2011

The coupling of fluorescamine (4-phenylspiro[furan-2(3H),l′-phthalan]-3,3′ dione) to angiotensin II to form a fluorescent derivative was studied. Complete reaction of the peptide below concentrations of 10−4m could be achieved with a fluorescamine concentration of 0.3 mg ml−1 of acetone at pH 8.3, and the lowest concentration detectable by fluorescence spectroscopy was 100 pmol ml−1. The derivative, as prepared did not react with ninhydrin, and no fluorescence was generated when fluorescamine was reacted with (1-Sar)-ATII. These data suggest that fluorescence is generated only through the coupling of fluorescamine to the N-terminal primary amine of ATII. The ATII-fluorescamine derivative has the same intrinsic activity on the contraction of rat colon (elevenfold loss of affinity), and on the release of fluorogenic corticosteroids from bovine adrenal cortical slices (sixfold loss of affinity) compared to ATII. Water-hydrolysed fluorescamine and Asp-fluorescamine did not contract rat colon preparations; the contractile response to ATII-fluorescamine was blocked by (8-Leu)-ATII, a specific ATII antagonist. These findings suggest that the ATII fluorophore shares a common receptor site with the native octapeptide. The rate loss of biological activity of the ATII-fluorescamine derivative was appreciably lower than that observed for ATII. The present study suggests that the ATII fluorescamine derivative can be substituted for radioactively-labelled ATII for use in a variety of applications.
The interaction of aminoalkylaminoanthraquinones with deoxyribonucleic acid
Authors: Double J C , Brown J R
Published: April 2011

A series of aminoalkylaminoanthraquinones have been prepared as potential intercalating agents. The binding to DNA of these compounds and the known intercalating drugs chloroquine, lucanthone, daunorubicin and doxorubicin has been characterized by spectrophotometric titration. The association constant for the interaction with DNA has been determined for each compound from a Scatchard plot. The compounds synthesized had association constants between 0.5 and 4.2 × 106 compared with 0.93, 0.90, 3.10 and 2.49 × 106 for chloroquine, lucanthone, daunorubicin and doxorubicin respectively.
The effect of mucin on the bioavailability of tetracycline from the gastrointestinal tract; in vivo, in vitro correlations
Authors: Braybrooks M P , Barry B W , Abbs E T
Published: April 2011

The bioavailability of tetracycline in the presence and absence of a porcine gastric mucin dispersion (1% w/v) has been studied by in vivo perfusion of the rat small intestine, the rat everted gut, a diffusion cell technique and the Sartorius Absorption Simulator Apparatus. In the presence of the mucin preparation an approximate 50% reduction in the numerical values of each of the parameters used to measure the tetracycline movement across the membrane was found. The physiological significance of each technique and the methods themselves are discussed. Interaction of tetracycline with the porcine gastric mucin preparation is considered in relation to the molecular structure of mucus. The results suggest the drug is bound in some way, as yet undefined, to the mucin macromolecule.
An improved implantation pellet for rapid induction of morphine dependence in mice
Authors: Hui K S , Roberts M B
Published: April 2011

A new type of morphine implantation pellet for the rapid induction of physical dependence in mice can be prepared by absorbing 7 mg morphine sulphate onto molecular sieves Type 4A (BDH). The small cylindrical pellets can be implanted subcutaneously without trauma and the need for anaesthesia, and are easily removed at any time from the animals. The peak of physical dependence is reached 24 h after implantation, and mortality is negligible. Withdrawal symptoms can be precipitated by intraperitoneal injection of naloxone, without removal of the pellet, and up to 70% of a group of mice show the characteristic urge to jump off a raised platform. This type of pellet has definite advantages over some other sustained-release preparations used in studies on morphine addiction in small animals.
Dissolution and bioavailability of the anhydrate and trihydrate forms of ampicillin
Authors: Hill S A , Jones K H , Seager H , Taskis C B
Published: April 2011

The solubilities and intrinsic dissolution rates of ampicillin anhydrate and trihydrate in distilled water and dilute hydrochloric acid at 37° have been measured. The dissolution rates of these materials from loose filled hard gelatin capsules were determined and the in vivo bioavailabilities of the compounds compared. Small differences in the in vitro behaviour of the anhydrate and trihydrate forms were recorded but the in vivo availability of the two compounds was the same.
The determination of phenothiazine drugs in pharmaceutical preparations by a difference spectrophotometric method
Authors: Davidson A G
Published: April 2011

A method is described for the rapid determination of phenothiazine drugs in a wide variety of pharmaceutical preparations. The drugs are determined by a difference spectrophotometric technique based upon the absorbance of the sulphoxide derivative of the drug relative to the absorbance of a solution of the underivatized drug. The sulphoxide derivatives are formed rapidly and quantitatively at room temperature by the addition of a solution of peroxyacetic acid, prepared by the slow reaction of hydrogen peroxide and glacial acetic acid on standing. The difference absorbance of the solutions is proportional to the concentration of the phenothiazine drug in the preparation and is specific for the intact drug in the presence of oxidative and photochemical decomposition products, colouring and flavouring agents, excipients and most co-formulated drugs.
In vitro metabolism of l-phenyl-2-(n-propylamino) propane (N-propylamphetamine) by rat liver homogenates
Authors: Coutts R T , Dawson G W , Beckett A H
Published: April 2011

In vitro incubation of (±)-N-(n-propyl)amphetamine (NPA) with the 12 000 g supernatant fraction of rat liver homogenate resulted in the formation of two N-oxygenated products identified as N-hydroxy-1-phenyl-2-(n-propylamino)propane and N-[(1-methyl-2-phenyl) ethyl]-1-propanimine N-oxide by g.l.c, g.l.c.-m.s. and t.l.c. Amphetamine, phenylacetone, benzyl methyl ketoxime, and a previously unreported metabolite N-(2-hydroxy-n-propyl) amphetamine were also isolated. Increasing the pH of the incubation mixture from 7·4 to 8·4, or in vivo pretreatment of rats with 3-methylcholanthrene caused an increase in the in vitro metabolic N-oxidation of NPA, whereas pretreatment with phenobarbitone or NPA did not. The presence of SKF 525-A in incubation mixtures reduced the amount of C-oxidation and to a lesser degree of N-oxidation. When (+)-NPA or (–)-NPA was used as substrate, C-oxidation was favoured with the former and N-oxidation with the latter.
A proposed mechanism for the biphasic vasoconstrictor responses to 5-hydroxytryptamine and methysergide in the rabbit ear artery
Authors: Apperley Eira , Humphrey P P A
Published: April 2011

Rabbit ear arteries were isolated and perfused at a constant flow rate so that the perfusate flowed into the fluid bathing the adventitial surface of the artery. Submaximal doses of intraluminally applied noradrenaline injected as a bolus into the perfusion fluid produced transient monophasic vascoconstrictor responses. In contrast, similarly administered 5-hydroxytryptamine (5-HT) or methysergide caused prolonged biphasic vascoconstrictor responses. The extraluminal/intraluminal potency ratios for noradrenaline, 5-HT and methysergide were 230, 15 and 6 respectively, which indicates that 5-HT and methysergide are relatively more potent when administered extraluminally than noradrenaline. Cocaine (3·10 × 10−5 mol litre−1) markedly increased the potency of extraluminally administered noradrenaline and converted the monophasic responses produced by noradrenaline to biphasic responses. It is concluded that under the experimental conditions used 5-HT and methysergide produced biphasic responses by an action on the medial smooth muscle firstly via the intraluminal surface and secondly an additional direct action via the adventitial surface. Noradrenaline's extraluminal potency is low because of its neuronal uptake and hence the responses are normally monophasic.
Enhancement of ethanol-induced withdrawal convulsions by blockade of 5-hydroxytryptamine receptors
Authors: Blum Kenneth , Wallace Jack E , Schwertner Harvey A , Eubanks J D
Published: April 2011

Male Swiss-Webster mice were made physically dependent on ethanol using the ethanol vapour inhalation technique. Animals pretreated with methysergide, a known 5-hydroxytryptamine receptor blocking agent, had significantly greater alcohol-induced withdrawal convulsions than saline pretreated controls. These findings suggest that the reduction of 5-HT at receptor sites may result in the augmentation of the withdrawal convulsions.
Some biological and pharmacological properties of inflammatory exudates
Authors: Doherty N S , Robinson B V
Published: April 2011

Inflammatory exudates were obtained from polyester sponges which had been implanted subcutaneously in rats four days previously. This material was found to be anti-inflammatory when injected into other rats in which carrageenan pleurisy had been induced. At a dose of 600 mg kg−1 exudate inhibited the formation of pleural effusion, emigration of both neutrophils and mononuclear cells and the accumulation of β-glucuronidase and lactic dehydrogenase. The same dose of sponge exudate did not however inhibit the increased vascular permeability induced in the rat skin or rat foot following injection of 5-hydroxytryptamine, histamine, prostaglandin E1, or bradykinin. Furthermore sponge exudate did not reduce the haemolytic complement titre of rat serum either in vivo or in vitro. The possible mechanism of anti-inflammatory action of exudate is discussed.
Potentiation of dopaminergic transmission by phosphodiesterase inhibitors and cyclic nucleotides
Authors: Pentreath V W , Berry M S
Published: April 2011

Experiments were made to determine whether cyclic AMP plays a role in transmission at identified dopaminergic synapses in the water snail Planorbis corneus. Intracellular stimulation of a specific dopamine neuron produces direct inhibitory postsynaptic potentials (ipsps) in a number of other neurons. These ipsps, which are mediated by dopamine, were potentiated by as much as 120% by caffeine, theophylline or dibutyryl cyclic AMP, although they were unaffected by cyclic AMP and prostaglandin E1. Caffeine and theophylline also potentiated the inhibitory response to dopamine, applied to the postsynaptic neurons by perfusion or iontophoresis, but the effects were generally much smaller (maximum potentiation 30%). The results provide evidence that postsynaptic cyclic AMP is involved in transmission at these synapses, but that the phosphodiesterase inhibitors may also have a presynaptic effect.
Size analysis of metered suspension pressurized aerosols with the Quantimet 720
Authors: Hallworth G W , Hamilton R R
Published: April 2011

A method is described for particle sizing of pressurized metered suspension aerosols by collection in a settling drum followed by microscopic evaluation of the slides with a Quantimet 720 automatic image analyser. The method gives satisfactory representation of the distribution of particles settling to the drum base, and demonstrates the excellent stability and reproducibility between and within aerosol packs for two widely used inhalation products. There is much drug deposition of somewhat finer size distribution on the wall of the drum than on the drum base. In spite of this wall loss, the method gives only slightly higher results for the weight and number mean diameters, than when both wall and base distributions are considered. The Quantimet was found to be suitable for particle sizing salbutamol used in preparing aerosol products.
The granulation of binary mixtures: the effects of the properties of the component powders on granules
Authors: Opakunle W O , Spring M S
Published: April 2011

Sulphanilamide and citric acid individually and in various proportions with lactose, have been granulated by massing and screening. There was an optimum blend, that produced granules of maximum mean size and strength, for each binary system examined. The proportion of the components of this optimal blend was dependent on the physical properties of the second component in a mixture with lactose. Results from three systems, lactose: boric acid, lactose: sulphanilamide and lactose: citric acid indicate that although part dissolution of powder during granulation is a factor affecting granule properties, in some systems other physical properties of the second component may become dominant. It is suggested that the combined effect of cohesiveness and wettability of the powders may make the major contribution to granule strength with the sulphanilamide systems. The ultimate mean granule size produced is determined by the wettability or solubility of the powders, or both, in all cases examined. The great affinity of citric acid for aqueous binder solution was the dominant factor determining the properties of granules prepared from lactose: citric acid mixtures.
Studies with the International Pyrogen Standard on the sensitivity and reproducibility of pharmacopoeial pyrogen testing
Authors: Simon S , Tóth M , Wallerstein Gy , Remény Zs
Published: April 2011

Rabbits, 27 or 36 in each experiment, were injected with the International Pyrogen Standard (I. P. St.) in different seasons. The maximum temperature rises were registered, randomized and interpreted according to the requirements of the B.P. (1973), U.S.P. (1970), P. Hung. (1970) and P. Nord. (1962). Although the dose of 3·5 ng kg−1 I. P. St, proved to be non-pyrogenic as tested in summer, when tested in winter the same dose was qualified pyrogenic (to be rejected) by up to one third of the combinations by the criteria of the four Pharmacopoeias. In the spring experiment “to be rejected” qualifications predominated as based on the response of large groups of rabbits. Exclusion of the rabbits showing low sensitivity (before randomization) barely influenced the results with 3·5 ng kg−1 I. P. St. in the experiment in which the mean temperature rise was 0·49°. If, however, the mean temperature rise was higher (0·57 or 0·69°), such a selection practically resulted in the disappearance of “passable” qualifications in the triplet groups and a great predominance of “to be rejected” qualifications in the larger groups. The dose 7·0 ng kg−1 consistently proved to be pyrogenic in large groups of rabbits.
Use of the mouse jumping test for estimating antagonistic potencies of morphine antagonists
Authors: Cowan Alan
Published: April 2011

The potencies of 19 reference morphine antagonists have been compared in a modified version of the mouse jumping test. Mice were each implanted subcutaneously with one 75 mg pellet of morphine. Antagonist challenge took place 72 h later and the incidence of repetitive vertical-jumping was monitored over 1 h. A high Pearson correlation coefficient (r = 0·997) was found between quantitative assays based on the total number of jumps per mouse and quantal assays based on mice jumping at least 6 times. A comparison of relative potencies obtained with the mouse test and with non-withdrawn morphine-dependent monkeys gave a Spearman rank order coefficient of 0·91 while a similar comparison with values obtained with the guinea-pig isolated ileum preparation also gave a high correlation coefficient (r = 0·92). Whereas it is difficult to assess the antagonistic component of buprenorphine and cyclorphan with the ileum preparation, both compounds can be satisfactorily assayed in the mouse jumping test. The reported antagonistic properties of ketocyclazocine and profadol could not be confirmed in the mouse model.
The narcotic discriminative stimulus complex: relation to analgesic activity
Authors: Colpaert F C , Niemegeers C J E , Janssen P A J
Published: April 2011

The ability of drugs to produce the narcotic discriminative stimulus complex is found to be highly correlated with their analgesic activity; in contrast, no relation with their antidiarrhoeal activity is evident. The findings suggest that the narcotic discriminative stimulus complex is a centrally mediated effect of narcotic drugs.
Acetylcholinesterase and responses to acetylcholine in the embryonic chicken heart
Authors: Lelorier J , Shideman F E
Published: April 2011

Three and 4 day old embryonic chicken hearts were examined for their responsiveness to acetylcholine and presence of acetylcholinesterase (AChE) to determine the role of the enzyme in the cardiac effects of the transmitter. The effects of acetylcholine on rate and contractility of 3 day old hearts were indistinguishable from those on 4 day old hearts. These effects were readily blocked by atropine at both stages of development. In 3 day old hearts the responses to acetylcholine were not affected by the AChE inhibitor physostigmine but in 4 day old hearts they were considerably potentiated. The effect of acetylcholine on the rates of 4 day old hearts is of short duration (5 min or less). In 3 day old hearts it persists for a much longer time. Thus, the appearance of AChE in the embryonic heart of the chicken does not seem to modify the responsiveness of the cholinergic receptor to the transmitter.
Some effects of urea on drug dissolution
Authors: Collett J H , Flood B L
Published: April 2011

Solubilities and dissolution rates of salicylic acid have been determined in urea solutions at different pH values. Solubilities increased with pH and urea concentration; a solubilization mechanism was considered to be operating. The solubilization effect of urea was greatest on the non-ionized moieties of the solute. Dissolution rates of salicylic acid increased with pH and urea concentration. The increase in dissolution rate paralleled increases in solubility. The role of solubilizing effect in the enhancement of dissolution rate by urea is discussed.
Solubilization of hydrocortisone, dexamethasone, testosterone and progesterone by long-chain polyoxyethylene surfactants
Authors: Barry B W , Eini D I D El
Published: April 2011

Solubility and dialysis methods were used to study the solubilization of hydrocortisone, dexamethasone, testosterone and progesterone in aqueous long-chain polyoxyethylene non-ionic surfactant solutions. Partition coefficients, Km, between micellar and aqueous phases were calculated between 10–50°. Km decreased with temperature and polyoxyethylene chain length but increased with decrease in steroid polarity. The standard free energy change, ΔGos, for the solubilization of the steroids decreased with decrease in steroid polarity and surfactant hydrophilic chain length but was essentially independent of temperature. The enthalpies and entropies for the process were determined from the variation of Km with temperature. ΔHos and ΔSos increased with decreasing steroid polarity but were essentially independent of temperature and polyoxyethylene chain length.
Oxytetracycline tablet formulations: the effect of wet mixing time, particle size and batch variation on granule and tablet properties
Authors: Chalmers A A , Elworthy P H
Published: April 2011

The wet mixing time has been shown to influence the properties of an oxytetracycline dihydrate tablet formulation, wet granulated with PVP solution. Increased time of wet mixing produced larger, stronger and more dense granules, which compressed into tablets with longer disintegration and dissolution times. Decreased drug particle size aggravated these trends. A decrease in drug particle size also produced larger, stronger and more dense granules. Above an oxytetracycline mean particle diameter of about 6 μm, the tablet dissolution was satisfactory. As the oxytetracycline particle size was decreased further, however, the distintegration and dissolution of the corresponding tablets was markedly slower.
Fluorimetric assay of tetracycline mixtures
Authors: Hall D
Published: April 2011

A simple and precise fluorimetric method is described for the simultaneous assay in plasma of a mixture containing chlortetracycline, demethylchlortetracycline and tetracycline. Assay within the therapeutic ranges of 0–5 mg litre−1 is achieved by formation of strongly fluorescent aluminium/tetracycline complexes, without prior extraction or separation of the individual antibiotics. This is performed by determinations at the peak excitation and fluorescence emission wavelengths of each tetracycline chelate. The method can be similarly applied to the assay of oxytetracycline, rolitetracycline and minocycline.
Differential effect of neuroleptic drugs on dopamine turnover in the extrapyramidal and limbic system
Authors: Bartholini Giuseppe
Published: April 2011

In gallamine-immobilized cats, the caudate nucleus and the nucleus accumbens septi were perfused by means of a push-pull cannula and dopamine was measured in the perfusate. Chlorpromazine (10 mg kg−1) and clozapine (20 mg kg−1), administered intravenously, enhanced the release of dopamine. The effect of chlorpromazine was similar in both regions whereas that of clozapine was more pronounced in the nucleus accumbens than in the caudate nucleus. Furthermore, in the rat, sulpiride, clozapine and thioridazine increased the homovanillic acid concentration in striatum and limbic system to a similar extent. However, following probenecid administration, the net effect of these drugs on homovanillic acid accumulation was more marked in the limbic system than in the striatum whereas haloperidol and chlorpromazine had a similar effect in the two regions. It is concluded that, in contrast to haloperidol and chlorpromazine, sulpiride, clozapine and thioridazine may preferentially affect the limbic dopaminergic transmission. This possibly accounts for the fact that sulpiride, clozapine and thioridazine display an antipsychotic action and yet cause less extrapyramidal side effects than haloperidol and chlorpromazine.
Effects of α-methyldopa on blood pressure in the anaesthetized dog
Authors: Blower P R , Poyser R H , Robertson M I
Published: April 2011

Intravenous infusion over 1 h of 20 mg kg−1 of α-methyldopa produced hypotension in the anaesthetized dog. The magnitude of this effect was, however, inversely correlated with bodyweight. Either rapid intravenous injection of α-methyldopa or slow infusion of α-methyldopate was less effective in lowering blood pressure than infusion of free α-methyldopa, in dogs of equivalent bodyweight. Infusion of α-methyldopa into a vertebral or internal carotid artery produced hypotensive responses but these were no greater and generally less than those obtained to intravenous infusion. α-Methyldopa was therefore capable of producing hypotension in the dog but no evidence was obtained for this being the result of an action within the brain.
Release kinetics of sparingly soluble drugs from ethyl cellulose-walled microcapsules: theophylline microcapsules
Authors: BENITA S , DONBROW M
Published: April 2011

Release rates of theophylline from ethyl cellulose-coated microcapsules were measured as a function of wall thickness and core particle size. The kinetic data conformed with first order release and also the Higuchi matrix model. However, application of the differential rate treatment, hitherto applied only to drug matrix dispersions, showed that release from the microcapsules definitely followed the first order equation. For the purpose of confirming that the release process was membrane-controlled, the experimental rate constants were transformed into effective permeability constants (P1) with the aid of the microcapsule dimensional parameters needed in the relevant equations and compared with the permeability constant (P) of theophylline measured experimentally using planar ethyl cellulose membranes. P1 values decreased linearly to a moderate extent with wall thickness, probably due to decrease in porosity during wall-formation. P1 values of the thicker-walled microcapsules were found to be of the same order as the membrane P value, supporting a release mechanism of membrane control under non-steady state conditions.