bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydrolysis of digoxin by acid
Authors: Gault M H , Charles J D , Sugden D L , Kepkay D C
Published: April 2011

Predictable hydrolysis of [3H]digoxin-12α occurred in vitro with incubation in HCl or gastric juice. Hydrolysis varied with pH, time, temperature and agitation. Digoxin, the bis- and mono-digitoxosides of digoxigenin and digoxigenin were separated by silica gel thin-layer chromatography using chloroform-ethyl acetate-glacial acetic acid (25:25:1 v/v) and were quantitated by liquid scintillation spectrometry. Hydrolysis with incubation at 37° and pH 3 for 90 min was minimal, but increased with increasing acidity until >70% was hydrolysed at pH 1·2 after 30 min and >96% after 90 min incubation. At pH 0·9, 87% was hydrolysed after 30 min. In vitro hydrolysis in gastric fluid was slightly less than in HCl at the same pH. A volunteer was given 150 μCi[3H]digoxin-12α by nasogastric tube during a pentagastrin infusion when gastric pH was 0·94. He remained on his left side and samples were aspirated at intervals and immediately neutralized. Ethanol-chloroform 50:50 (v/v) extracts of the gastric fluid aspirated after 90 min and of all the urine specimens collected for 5 days were applied to a DEAE Sephadex LH-20 column. The radioactivity appeared in a single peak as digoxigenin in the 90 min gastric aspirate and in all urine specimens. Extensive intragastric hydrolysis of digoxin may occur under conditions of maximum acid output.
Papaver bracteatum Lindley: thebaine content in relation to plant development
Authors: Fairbairn J W , Helliwell K
Published: April 2011

Four thebaine-rich varieties of P. bracteatum have been grown in the open over two seasons and the thebaine distribution in aerial parts examined to determine the most suitable source material for commercial production. The leaves contained only 0·1 to 0·15%; the capsules 0·5 to 3·0% and the bled latex 28 to 53%. The maximum for the latter occurred about 3–4 weeks after petal opening and during the day, at about 15.00 h. A product ‘bractium’ prepared exactly as opium from P. somniferum contained up to 55% thebaine and calculations from the 1974 results gave theoretical yields up to 58 kg of thebaine per hectare. However this is a very labour intensive method; furthermore bled latex only represents about 46% of the total thebaine of the capsule. In addition the pedicels contain significant amounts of thebaine, so that fruiting tops may be recommended as source material. In the capsule the thebaine content reaches a peak 3 to 4 weeks after petal opening and again two weeks later. At this fully ripe stage there is a theoretical yield of 50 kg per hectare. Two further advantages accrue from collection at this time: the ripe seeds can probably be used for similar purposes as poppy seed; and the pericarps at this stage contain no ‘bound thebaine’ (i.e., thebaine insoluble in MeOH:NH4OH but soluble in acetic acid—in unripe capsules bound thebaine represents 18 to 36% of the total thebaine). There is some evidence that, as this perennial plant increases in age, the capacity for thebaine production seems to continue increasing. Storage of raw material, even in ideal conditions, led to a loss of thebaine of 12 to 20% in one year.
Moisture and gelatin effects on the interparticle attractive forces and the compression behaviour of oxytetracycline formulations
Authors: Esezobo S , Pilpel N
Published: April 2011

The tensile strengths of compacts and/or tablets of the individual components and of granules prepared from an oxytetracycline formulation have been measured using the diametral compression test. Employing the theory of tensile strength, proposed by Cheng, it has been shown that increases in both moisture and gelatin contents of compacts and tablets increase the range of the attractive forces that operate between the granules. By studying the effects of moisture and gelatin on the compressional behaviour of the granules, it has been possible to classify them into different types. Fragmentation of granules occurs at packing fractions between 0·745 and 0·835, depending on their gelatin content.
The identification and quantitation of the major metabolites of ethylamphetamine, produced by rabbit liver microsomal preparations
Authors: Beckett A H , Haya K
Published: April 2011

Amphetamine (I), 1-phenylpropan-2-ol (III), phenylacetone (V), N-hydroxyethylamphetamine (VII), and α-methyl-N-(1′-phenylprop-2′-yl)nitrone (VIII) were obtained as metabolic products from the incubation of ethylamphetamine (II) with fortified male rabbit liver 9000 g supernatant fractions. These metabolites were identified by comparing their t.l.c., g.l.c. and g.l.c.-m.s. behaviour to that of reference compounds. A method for the quantitative analysis of the metabolites in mixtures using g.l.c. techniques is described.
Blood and brain concentrations of imipramine, clomipramine and their monomethylated metabolites after oral and intramuscular administration in rats
Authors: Nagy Adam
Published: April 2011

Imipramine and clomipramine were administered to rats by the oral and intramuscular routes as single and multiple doses. The concentrations of both drugs and their active demethylated metabolites desipramine and desmethylclomipramine were measured in blood plasma, blood cells and brain. The concentrations of the metabolites were higher and the concentrations of the parent substances lower after oral than after parenteral administration, both in blood and in brain. In brain imipramine, desipramine and clomipramine during continuous treatment exceeded their plasma concentrations by six to ten times. The corresponding figure for desmethylclomipramine was 1·7. The extent of accumulation of the investigated substances in the brain was independent of the route of administration.
Effect of lofepramine and other antidepressants on the uptake of 5-hydroxytryptamine and noradrenaline into rat brain monoaminergic neurons
Authors: Segawa Tomio , Nomura Yasuyuki , Tanaka Akiyoshi , Murakami Hiroko
Published: April 2011

Lofepramine, (N-methyl-N-[4-chlorobenzoylmethyl]-3-[10, 11-dihydro-5H-dibenz(b,f)-azepin-5-yl]-propylamine hydrochloride), is a new antidepressant with low toxicity and no peripheral anticholinergic activity. Its effect on 5-hydroxytryptamine (5-HT) and noradrenaline uptake into rat brain monoaminergic neurons was studied and compared with that of other antidepressants, particularly with that of imipramine and desipramine. Lofepramine inhibited both 5-HT and noradrenaline uptake into synaptosomal fractions in vitro but was 4 times more potent in inhibiting noradrenaline than 5-HT uptake, indicating the effect resembles that of desipramine. Noradrenaline uptake was also preferentially inhibited in synaptosomes from brain of rats treated previously with lofepramine or desipramine (i.p.). Pretreatment with SKF 525A (i.p.) did not diminish the effect of lofepramine but rather potentiated it. Therefore it is suggested that the formation of desipramine is not necessary for lofepramine to exhibit the effect on amine uptake in vivo. Both lofepramine and desipramine inhibited intraventricular noradrenaline uptake into synaptosomes without any effect on 5-HT uptake. These results suggest that lofepramine is qualitatively similar to desipramine with respect to preferential inhibition of noradrenaline uptake into central noradrenergic neurons.
Conformational analysis of dopamine by the INDO molecular orbital method
Authors: Grol Cor J , Rollema Hans
Published: April 2011

The results of INDO calculations on dopamine are reported. A conformational energy map and an isodistance map for the key distances N—OH1, N—OH2 in dopamine as functions of the two main torsion angles τ1 and τ2 were constructed. In addition to the three known minima of dopamine corresponding to the trans and gauche forms, two new minima were found. The key distances of the rigid analogues of dopamine, apomorphine, isoapomorphine, 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene and isoquinoline were plotted on the isodistance map of dopamine. By taking the corresponding τ values as coordinates on the energy map, conformations of dopamine, resembling the rigid analogues, could be found. When a conformation is close to a local minimum it is assumed that this conformation is energetically favourable. The possible relation between the energy minima and the biological action of dopamine is discussed. An explanation is suggested for the lack of dopaminergic activity of isoapomorphine.
Pharmaceutical suspensions: micro electrophoretic properties
Authors: Kayes J B
Published: April 2011

The microelectrophoretic properties of the drugs griseofulvin, betamethasone, nalidixic acid and thiabendazole in aqueous dispersion have been examined and the zeta potentials calculated from the measured mobilities. Variation in magnitude of particle charge with pH of dispersion is reported and related to the chemical structure and surface characteristics. The effect of adding anionic (sodium dodecyl sulphate) cationic (dodecyl trimethyl bromide) and non-ionic (polyoxyethylene glycol monoethers of hexadecanol) surface-active agents, and mixtures of these ionic and non-ionic species, on the electrophoretic properties of the drug dispersions has been measured. The results reported agree with those found previously for a model polystyrene latex suspension system under the same conditions.
Dissolution from tablets prepared using ethyl cellulose microcapsules
Authors: Jalsenjak I , Nicolaidou Constantia F , Nixon J R
Published: April 2011

Microcapsules containing sodium phenobarbitone cores in ethyl cellulose have been used to prepare tablets at from 3·9 to 358·9 MPa compression pressures. The tensile strength of these tablets is related linearly to the core: wall ratio and to the microcapsule size. Dissolution of the drug from the microcapsules is also related to the core: wall ratio and microcapsule size, but except at low compression pressures is almost independent of the pressure used during preparation. The tablet matrix remains intact during the dissolution and the equations developed by Schwartz, Simonelli & Higuchi (1968) are followed. Large microcapsules of 1:2 core:wall ratio produce friable tablets with rapid release of contents.
Caffeine-phenacetin interaction in the rat: effects on absorption, metabolism and locomotor activity
Authors: Collins Catherine , Richards P T , Starmer G A
Published: April 2011

The interactive effects of caffeine and phenacetin on the locomotor activity of the DA rat involved changes in absorption and metabolism as well as effects possibly exerted at the cns level. Phenacetin initially retarded the absorption of caffeine when coadministered by gavage but not when caffeine was given intraperitoneally and phenacetin orally. Phenacetin also increased the time for the plasma/caffeine concentration to peak, increased its peak concentration and prolonged its presence in the plasma. Urinary excretion patterns, suggested a blockade of the N-demethylation of caffeine by phenacetin. In contrast, caffeine had only a minor influence on the absorption and metabolism of phenacetin. The locomotor effects of the caffeine-phenacetin combination reflected the absorptive and metabolic interactions which occurred. Caffeine-induced hyperactivity was initially masked by phenacetin in a dose-dependent manner but after 2 h, when the plasma phenacetin concentrations were much lower, its retarding influence on caffeine metabolism became apparent and hyperactivity consequent upon an elevated plasma caffeine concentration was seen. Phenacetin also antagonized the hyperactive effects of theophylline and of (+)-amphetamine.
The interaction between clonidine and various neuroleptic agents and some benzodiazepine tranquillizers
Authors: van Zwieten P A
Published: April 2011

The central hypotensive action of clonidine, infused into the vertebral artery of chloralose-anaesthetized cats was antagonized by several phenothiazine-neuroleptics (chlorpromazine, promazine, promethazine, thiethylperazine, thioridazine), by chlorprothixene and to a limited extent by haloperidol administered via the same route. Pimozide and some benzodiazepines (chlordiazepoxide, diazepam and flurazepam) hardly influenced the central hypotensive response to clonidine. The antagonism between clonidine and the psychotropic drugs is probably associated with central α-adrenoceptors, clonidine being the agonist and the neuroleptic agents the antagonists at these receptors. Virtually the same type of antagonism was observed in conscious, spontaneously hypertensive rats where both clonidine and the neuroleptic drugs were injected intravenously. The phenothiazines and also piperoxane effectively diminished the centrally induced hypotensive response to clonidine, whereas the initial pressor effect to clonidine was not reduced.
Stereoselective drug distribution and anticoagulant potency of the enantiomers of phenprocoumon in rats
Authors: Schmidt W , Jähnchen E
Published: April 2011

The elimination, distribution and anticoagulant activity of S(—)-, R(+)-, and R,S(±)-phenprocoumon were determined in male Wistar-Lewis rats after intravenous injection of a single dose of 0·6 mg kg−1. From the plasma concentrations which elicited the same anticoagulant effect, S(—)-phenprocoumon was 4 to 5 times more potent than R(+)-phenprocoumon. The potency of the racemate was between those of the enantiomers. The mean biologic half-life of the S(—)-enantiomer was shorter (12·5 h) than that of R(+)-phenprocoumon (17·8 h). No differences were observed in the apparent volume of distribution. However, the mean liver: plasma concentration ratio was higher for the S(—)-(6·9) than for the R(+)-enantiomer (5·2). At a total concentration of 16·8 μg ml−1 the percentage of unbound drug in rat serum was significantly higher for the S(—)- (1·13%) than that for the R(+)-enantiomer (0·76%). Values obtained for the racemate were always between those of the enantiomers. It is concluded that stereoselective differences in the distribution between plasma and liver, and consequently in the rate of elimination are most likely due to stereoselective differences in serum protein binding. The greater anticoagulant potency of the S(—)- over the R(+)-enantiomer, cannot be explained primarily by the observed pharmacokinetic differences.
The effects of prostaglandins E1, E2, F1α and F2α on guinea-pig ileal and colonic peristalsis
Authors: Eley Kenneth G , Bennett Alan , Stockley Helen L
Published: April 2011

Prostaglandins (PGE1, E2, F1α and F2α) have been tested on the peristaltic reflex in isolated segments of guinea-pig ileum and colon using simultaneous recordings of fluid propulsion and longitudinal and circular muscle activity. Propulsion and circular muscle peristaltic activity were increased by serosally applied PGF compounds in the ileum and PGE or PGF compounds in the colon following initial contraction of the longitudinal muscle. This is consistent with a role for prostaglandins in peristalsis. Mucosally applied PGF compounds had no significant effect.
Application of orthogonal functions to the spectrophotometric determination of phenytoin in pharmaceutical preparations
Authors: Amer M M , Ahmed A K S , Hassan S M
Published: April 2011

A simple ultraviolet spectrophotometric method for the determination of phenytoin in pharmaceutical preparations has been developed. The mean was 100·9% (6 determinations) and the coefficient of variation was 1·2%. The method was applied successfully to the determination of phenytoin in capsules and suspensions.
The influence of additives on the presentation of a drug in hard gelatin capsules
Authors: Newton J M , Razzo F N
Published: April 2011

The influence of the concentration of lactose, magnesium stearate and sodium lauryl sulphate on the in vitro dissolution and the drug content of hard gelatin capsules filled under conditions which result in a maximum tapped bulk density, has been evaluated by a factorially-designed experiment. The 3 factors have a significant effect on both drug release and capsule filling. Interactions between the 3 factors, however, limit the exact quantification of the magnitude of their influence by a simple linear model. A quadratic relation, when only 2 factors are considered, can be used to provide a prediction of the influence of these factors. The relations between 2 factors are demonstrated as contours of equal in vitro drug release and equal drug content of capsule, at constant concentrations of the third factor. The contours show the important influence of lactose concentration on drug release and capsule filling, and the large changes in response which can occur by the addition of a third factor. They also provide a clear guide to the formulation of hard gelatin capsules.
Autoxidation of N-hydroxyphenylalkylamines: the inhibitory effect of some anions on copper catalysed autoxidation of N-hydroxyphentermine
Authors: Jonsson Ulf , Lundkvist Gunilla , Eriksson Sven O , Lindeke Björn
Published: April 2011

The inhibitory effect of certain electrolytes and buffers on the copper catalysed autoxidation of N-hydroxyphentermine (2-hydroxylamino-2-methyl-1-phenylpropane) has been investigated. The presence of ions such as SO42−, Cl− or Br− markedly reduced the rate of oxidation. Phosphate and carbonate buffers had a similar effect with halides and phosphate buffers being the most inhibitory. The occurrence of 2-methyl-2-nitro-1-phenylpropane and 2-methyl-1-phenylpropene-(1) as secondary oxidation products was also established.
Binder distribution onto binary mixtures of glass spheres
Authors: Dingwall D , Ismail S I
Published: April 2011

Glass spheres (0·8 and 0·4 cm diam.) in differing weight ratios were treated in a rotating pan with four pharmaceutical binder fluids. Binder uptake for a sphere of 1 g was greater onto the smaller spheres irrespective of binder or wt ratio used. There were differences in uniformity of uptake, the solution binders (PVP and gelatin) being more evenly distributed than the mucilaginous binders (starch and methylcellulose). Binder distribution on the basis of unit surface area showed less obvious differences between the sphere sizes. Possible consequences of such binder distribution through powder aggregates are discussed.
Permeation of oestrone, oestradiol, oestriol and dexamethasone across cellulose acetate membrane
Authors: Barry B W , Brace A R
Published: April 2011

The permeation across cellulose acetate of three oestrogens, differing only in the number of hydroxyl groups attached to the nucleus, and a ‘standard’ steroid, dexamethasone, was investigated using the lag-time method for calculating diffusion parameters, between 10 and 40°. Diffusion coefficients for the similarly-sized oestrogens were relatively insensitive to marked changes in polarity, but increased permeation was correlated with increased partition coefficients, decreased polarity and fewer hydroxyl groups on the nucleus. Permeation increased with temperature and energies of activation were calculated from Arrhenius-type plots. Ep values ranged from 4·84 k cal mol−1 (20 kJ mol−1) for the least polar steroid (oestrone) to 6·91 k cal mol−1 (29 kJ mol−1) for the most polar steroid (oestriol). The results implied that steroid diffusion occurred through aqueous membrane channels, but that it was impeded to various extents by both obstruction and polar interaction effects.
The effect of tris buffers on rat liver mitochondrial monoamine oxidase
Authors: Fowler C J , Callingham B A , Houslay M D
Published: April 2011

The effect of tris buffers upon the monoamine oxidase (MAO) activity in rat liver mitochondria has been investigated. Tris buffer was shown to inhibit MAO in a non-competitive manner with a Ki of 15–25 mm. Tyramine, 5-hydroxytryptamine and β-phenethylamine but not benzylamine oxidations were all inhibited by tris buffer. All inhibitions, except that of 5-HT, were completely reversible. It is suggested that these effects are produced by conformational changes in the structure of the MAO. The significance of these results is discussed with respect to the use of tris buffers in the extraction and estimation of the activity of MAO.
The effects of diethylcarbamazine citrate on smooth muscle
Authors: Abaitey A K , Parratt J R
Published: April 2011

The effect of the anthelmintic drug diethylcarbamazine citrate (DECC) was examined on the guinea-pig isolated ileum, rabbit duodenum, chick oesophagus, rat portal vein and pig coronary artery. DECC contracted all the gastrointestinal smooth muscle preparations. The contractions were antagonized by hexamethonium and atropine but they were not affected by mepyramine or methysergide in concentrations that abolished, or markedly reduced, responses to histamine and 5-hydroxytryptamine. DECC inhibited the responses of the guinea-pig ileum to other spasmogens, namely, acetylcholine, histamine and nicotine. Physostigmine markedly potentiated the responses of the chick oesophagus and the rabbit duodenum to DECC. DECC relaxed the potassium chloride-induced contractions of the pig coronary artery strips; these relaxations were not modified by propranolol or calcium chloride. There was no evidence that DECC released histamine from skin or muscle.
The extraction and analysis of benzodiazepines in tissues by enzymic digestion and high-performance liquid chromatography
Authors: Osselton M D , Hammond M D , Twitchett P J
Published: April 2011

A simple, rapid and sensitive method is described for the analysis of unchanged benzodiazepine drugs and their metabolites, in human and animal tissues, using the proteolytic enzyme subtilisin Carlsberg followed by reverse-phase liquid chromatography. The enzymic digestion yields far higher recoveries than conventional extraction methods, while the liquid chromatographic analysis allows the rapid separation and detection of nanogram quantities of these drugs without the need for elaborate “clean-up” procedures.
Weight and activity in male mice after daily inhalation of cannabis smoke in an automated smoke exposure chamber
Authors: Weinberg A D , Dimen E , Borzelleca J F , Harris L S
Published: April 2011

An automatic smoking machine capable of delivering marihuana smoke to groups of 10 mice at a time at a constant concentration of Δ9-THC is described. In all cases the flow rate (50 ml s−1 or 100 ml s-1) of a smoke: air mixture, and the dilution factor (1:20 or 1:10 smoke:air) was adjusted to give the same equilibrium concentration of Δ9-THC in the chamber atmosphere. At a concentration of 0–123 mg Δ9-THC litre−1 of exposure chamber atmosphere (1:20 smoke: air; 100 ml s−1 flow rate), a seven day schedule of 20 min daily treatments significantly decreased activity of the marihuana-treated animals by the sixth day over both air and placebo smoke controls. This concentration and exposure schedule failed to affect weight gain during this same period. A significant decrease in activity, although not as great as in the marihuana-treated group, was also seen in the placebo control group compared with the air control animals, indicating the need for a smoke control group in all experiments involving the administration of marihuana via inhalation. An exposure period of 102 min, with marihuana smoke diluted with air 1:10 (50 ml s-1 flow rate), at the same equilibrium concentration of 0·123 mg Δ9-THC litre−1, resulted in a mortality of 90% following administration or within 48 h. 102 min of exposure to an atmosphere of placebo smoke at a smoke:air dilution of 1:10 (50 ml s-1 flow rate), resulted in no mortality.
Identification of di- and tri-substituted hydroxy and ketone metabolites of Δ1-tetrahydrocannabinol in mouse liver
Authors: Harvey D J , Martin B R , Paton W D M
Published: April 2011

In vivo liver metabolites of Δ1-tetrahydrocannabinol (Δ1-THC) were examined with a gas chromatograph—mass spectrometer—computer system as trimethylsilyl (TMS), [2H9]TMS and methyloxime-TMS derivatives. In addition to the reported monohydroxy, acid, and hydroxyacid metabolites, the following multiply substituted metabolites were identified: 2“,7-, 3”,7-, and 6β,7-dihydroxy-Δ1-THC; 2“,6α,7-, and 3”,6α,7-trihydroxy-Δ1-THC; 2“-, 3”-, and 7-hydroxy-6-oxo-Δ1-THC, and 2“,7- and 3”,7-dihydroxy-6-oxo-Δ1-THC. The ketones and hydroxyacids were reduced to common alcohols with lithium aluminium deuteride and the number of deuterium atoms in the product was used to distinguish the metabolic alcohols from those produced by reduction.
Dilute solution properties of clindamycin 2-palmitate hydrochloride
Authors: Abbott Teresa I , Benton D P , Hampson C A
Published: April 2011

Clindamycin 2-palmitate hydrochloride forms micelles in aqueous solution at concentrations above 2·2 times 10−3  m. Dilution of micellar solutions of the drug to concentrations less than 2·0 times 10−3  m produces turbid systems. Turbidity is caused by unionized drug, produced by hydrolysis of the salt, phasing out of solution at concentrations too low for micelles to be formed. Changes in specific conductivity and turbidity associated with the phasing-out process have been measured and explained in terms of the rates of the various processes involved, including demicellization and emulsion stability. The phenomenon of phasing-out, below a critical concentration in aqueous solution, is predicted to be a general one for weakly ionized surfactants where the unionized species possesses low water solubility.
Effect of two non tricyclic antidepressant drugs on [14C]5-hydroxytryptamine uptake by rat platelets
Authors: Wielosz Marian , Dall'Olio Alberto , de Gaetano Giovanni , Garattini Silvio
Published: April 2011

The uptake of 14C-5-HT by rat blood platelets was examined in vitro in experimental conditions which allowed measurement of the initial velocity and excluded other passive processes across the cell membrane. In these conditions, the effect of two non tricyclic antidepressant drugs (Lilly 110140 and trazodone) was investigated. Lilly 110140 was as active as chlorimipramine and several times more active than imipramine as an inhibitor of 14C-5-HT uptake. Like chlorimipramine, Lilly 110140 appeared to be either a non-competitive or an uncompetitive inhibitor, according to the concentration of drug used. Trazodone also inhibited 14C-5-HT uptake by platelets but to a lesser extent than chlorimipramine, imipramine or Lilly 110140. m-Chlorophenylpiperazine, a possible metabolite of trazodone, was about 3 times more potent an inhibitor than the parent molecule. Both compounds acted non-competitively. Compared with published data on the effect of Lilly 110140 and trazodone on brain 5-HT, the present results support the suggestion that rat platelets are a useful pharmacological model of serotoninergic nerve endings.
Biochemical and pharmacological studies on amineptine (S 1694) and (+)-amphetamine in the rat
Authors: Samanin R , Jori A , Bernasconi S , Morpugo E , Garattini S
Published: April 2011

The pharmacological activities of amineptine (S 1694) and (+)-amphetamine and their interaction with biogenic amines have been examined in rats. The locomotor activity, stereotyped behaviour and hypothermia induced by amineptine were similar to but not as marked as those produced by (+)-amphetamine, and there was little or no anorectic action. Amineptine does not modify the concentrations of brain noradrenaline or acetylcholine which are respectively reduced and increased by (+)-amphetamine. Moreover, amineptine does not affect significantly the decrease of brain noradrenaline induced by an intraventricular injection of 6-hydroxydopamine, an effect significantly antagonized by (+)-amphetamine. On the other hand, like amphetamine, amineptine significantly reduces the effect of 6-hydroxydopamine on brain dopamine. Both drugs increase the striatal concentrations of homovanillic acid and show a cross tolerance in this action. Therefore they could act similarly on the striatal dopaminergine system. Amineptine thus appears to be a new type of antidepressant with a brain biochemical profile differing from that of other drugs used in depressive disorders.
Plasma concentrations and excretion of zipeprol in man under acidic urine conditions
Authors: Beckett A H , Achari R
Published: April 2011

Plasma concentrations of zipeprol, and the urinary excretion of it and two of its basic metabolites, compound II and compound III were examined after oral administration of zipeprol hydrochloride to man. The drug was rapidly and extensively metabolized, and the amount of unchanged drug excreted in the acidic urine varied from 1–5% of the dose; the two basic metabolites accounted for 19–38% of the dose.
Evidence from agonist and antagonist studies to suggest that the β1-adrenoceptors subserving the positive inotropic and chronotropic responses of the heart do not belong to two separate subgroups
Authors: Lumley P , Broadley K J
Published: April 2011

The positive inotropic and chronotropic responses of guinea-pig isolated left and right atria to 17 sympathomimetic amines were examined under conditions selected to control the pharmacological environment. Each agonist was compared with (-)-isoprenaline as the reference by constructing dose-response curves. Equiactive molar concentration ratios relative to (-)-isoprenaline were calculated at the EC50 for rate and tension responses. Statistical analysis revealed that (-)-noradrenaline and (±)-α-methylnoradrenaline were tension selective whereas (±)-α-ethylisoprenaline and N-methyldopamine were rate selective relative to (-)-isoprenaline. However, no structural trends emerged. The rank order of potency varied slightly between rate and tension, but an analysis of the regression and correlation coefficients indicated respectively that the equiactive molar concentration ratios and the rank orders could be considered identical on rate and tension. Antagonism of the (-)-isoprenaline-induced rate and tension responses by acebutolol, atenolol, practolol and propranolol was assessed from the pA2 values which were almost identical for both parameters with each antagonist. It is concluded that the β1-adrenoceptors mediating the positive inotropic and chronotropic responses do not warrant subdivision into two separate groups.
The role of dopaminergic systems in γ-hydroxybutyrate-induced electrocorticogram hypersynchronization in the rat
Authors: Godschalk M , Dzoljic M R , Bonta I L
Published: April 2011

The effects of dopaminergic agonists and antagonists on the duration of hypersynchronization induced in the electrocorticogram (ecog) by γ-hydroxybutyrate (γ-HB) were tested in rats. Apomorphine (0·2–8 mg kg−1), piribedil (2·5–10 mg kg−1) and haloperidol (0·5–1 mg kg−1) had no influence on the duration of the hypersynchrony. Amphetamine (1·5–6 mg kg−1) inhibited the hypersynchrony, while (3,4-dihydroxyphenylamino)-2-imidazoline (DPI; 5, but not 1, mg kg−1) prolonged its duration. The lack of effect of the dopamine receptor agonists apomorphine and piribedil, and the dopamine receptor blocker haloperidol, on the γ-HB-induced hypersynchrony might indicate that the inhibition of the impulse flow in the nigrostriatal dopamine system by γ-HB is not involved in the generation of the hypersynchrony. DPI is thought to be an agonist at a dopamine receptor not sensitive to apomorphine, and its facilitatory effect on γ-HB-hypersynchrony can be interpreted in terms of a possible involvement of another dopamine system in the ecog hypersynchrony induced by γ-HB. The antagonism of γ-HB by amphetamine is possibly due to an indirect stimulatory effect on noradrenergic receptors.
Some antagonists of dantrolene sodium on the isolated diaphragm muscle of the rat
Authors: Bowman W C , Khan H H , Savage A O
Published: April 2011

The effects of a number of potential antagonists of dantrolene sodium have been studied on twitches of the isolated hemidiaphragm preparation of the rat stimulated directly at a frequency of 0·1 Hz, after complete neuromuscular block produced by tubocurarine or erabutoxin a. The substances selected as possible dantrolene antagonists were uranyl ions, thiocyanate ions, adrenaline, caffeine, quazodine, quinine, 4-aminopyridine and the calcium ionophore A23187, all of which facilitate excitation-contraction coupling in one way or another. Contracture was the main feature of the response to A23187, the increase in the tension of the dantrolene-depressed twitches being very slight. All the remaining compounds increased the amplitude of the twitches, but only 4-aminopyridine, quinine, quazodine and caffeine were capable of restoring to the control amplitude twitches that had been maximally depressed by dantrolene. Of these, 4-aminopyridine and quinine were the most potent on a molar basis.
Loss of antibacterial preservatives from contact lens solutions during storage
Authors: Richardson N E , Davies D J G , Meakin B J , Norton D A
Published: April 2011

The preservative content of 34 commercially available contact lens solutions has been determined. Over half of the solutions contained less than 90% of the stated preservative content. Storage tests conducted at 40°, using both simulated and commercially available contact lens solutions in plastics containers of the type used to present these products showed that thiomersal and chlorbutol appeared to be sorbed by these containers in contrast to benzalkonium chloride and chlorhexidine gluconate which interacted mainly by a surface adsorption process. The extent of any interactions was dependent upon the type of plastics material used to fabricate the container.
The adhesion of film coatings to tablet surfaces - the effect of some direct compression excipients and lubricants
Authors: Rowe R C
Published: April 2011

The effect of some direct compression excipients and lubricants on the adhesion of hydroxypropyl methyl cellulose films has been examined using a specially designed tensile testing apparatus (Fisher & Rowe, 1976). The adhesion was found to be influenced by both the roughness, including microporosity, of the tablet surface and its polarity. Tablets prepared from microcrystalline cellulose showed very high adhesions despite having relatively smooth surfaces, owing to the surface being saturated with hydroxyl groups able to form hydrogen bonds with the corresponding groups on the polymer. The addition of magnesium or calcium stearate to the tablet was found to decrease the adhesion, but the addition of stearic acid caused a significant increase. The effect of lubricant concentration on the adhesion could be expressed by an equation similar to that proposed by Hofrichter & McLaren (1948) for the adhesion of vinyl chloride/vinyl acetate copolymers to regenerated cellulose.
The effects of p-chlorophenylalanine and ethanolamine-O-sulphate in an animal test of anxiety
Authors: File Sandra E , Hyde J R G
Published: April 2011

p-Chlorophenylalanine, which produces a depletion of brain 5-HT concentration, had effects qualitatively similar to those previously found with chronic chlordiazepoxide and with acute ethanol in the social interaction test of anxiety. This result is compatible with the idea that a reduced turnover of 5-HT is important in anxiety reduction. On the same test, ethanol-amine-O-sulphate, which raises brain γ-aminobutyric acid, was without effect, suggesting raised concentrations of this acid are not essential for anxiety reduction.
Renal clearance procedure for the rat: effect of dopamine and standard saluretics
Authors: Brennan Francis T , Sosnowski Genevieve F , Mann William A , Sulat Lynn , Wiebelhaus Virgil D
Published: April 2011

Four standard diuretic compounds were evaluated for electrolyte output, effects on glomerular filtration rate (GFR), and effective renal plasma flow (RPF) in an anaesthetized rat preparation. Triamterene, hydrochlorothiazide, acetazoleamide and furosemide exerted their characteristic diuretic effects at doses which did not significantly change GFR or RPF. Regulation of the rate of a 3% mannitol-0·9% NaCl infusion to rats permitted the establishment of GFR and RPF values which were approximately in the middle of the reported range for this species. A significant increase in RPF without a concurrent rise in GFR was produced with dopamine. This was effectively blocked by the peripheral dopamine inhibitor, bulbocapnine.
Effect of drugs on rats exposed to cold—restraint stress
Authors: Beattie Doreen
Published: April 2011

The extent of protection afforded by over 40 drugs of various pharmacological groups against the development of gastric erosions induced in rats by a combination of cold and restraint has been investigated. Some drugs offered good protection, others had no effect on, or exacerbated, the lesions. Attempts are made to explain the mode of action of the protective drugs.
Identification of the in vitro N-oxidized metabolites of (+)- and (−)-N-benzylamphetamine
Authors: Beckett A H , Gibson G G
Published: April 2011

This study has identified (+)- and (-)-N-benzyl-N-hydroxyamphetamine as metabolites after incubation of both (+)- and (-)-N-benzylamphetamine with fortified rabbit liver homogenates. The isomeric hydroxylamine metabolites were identified using the techniques of g.l.c., t.l.c. and combined g.l.c.-mass spectrometry (ms) and by comparison with results from reference samples. An additional novel metabolic product was identified after incubation of N-benzylamphetamine which had properties consistent with that of N-benzyl-amphetamine nitrone.
Temperature dependence of the disintegration times of compressed tablets containing hydroxypropyl-cellulose as binder
Authors: Stafford J W , Pickard J F , Zink R
Published: April 2011

The dependence of the disintegration times of placebo and active tablets containing hydroxy-propylcellulose (HPC), as binder on the temperature of the test medium in the region of 37° is reported. The degree of temperature dependence varied with the HPC lot and concentration in the formulations. These dependences could be accentuated by the presence in the formulation of certain drugs, such as caffeine. The extent of the temperature dependence could be diminished by reducing the HPC concentration in the formulations. Corresponding trends were observed in drug release behaviour from some of these formulations. The effects observed were interpreted in terms of the thermodynamic behaviour of HPC systems and a specific drug-HPC interaction.
The effect of drug concentration on the thermal (dark) degradation of promethazine hydrochloride in aqueous solution
Authors: Meakin B J , Stevens John , Davies D J G
Published: April 2011

The thermal (dark) degradation of promethazine hydrochloride in aqueous solution presents a complex kinetic picture. The process is oxygen dependent and is modified by EDTA. In citrate buffer, pH 4·0, ionic strength 0·5m, containing 0·1 % EDTA, the thermal degradation at 90° can be fitted to first order rate plots at drug concentrations up to 1·56 × 10−2m (0·5%) and to zero order rate plots at drug concentrations greater than 9·35 × 10−2m (3·0%). At intermediate concentrations no simple equation can describe the data. These effects have been correlated with the formation of drug micelles and the rate data have been interpreted on the basis of a first order monomer process and a half order micellar process occurring simultaneously.
The determination of salicylic acid and benzoic acid in pharmaceutical formulations by spectrofluorimetry
Authors: Adams S , Miller J H Mc B
Published: April 2011

Methods of extraction from pharmaceutical formulations and subsequent determination of benzoic acid and salicylic acid by spectrofluorimetry are described. The recovery of benzoic acid, in the presence of salicylic acid, was 99·3%, with a coefficient of variation of 1·04%, while the recovery of salicylic acid, in the presence of benzoic acid, was 97·7%, with a coefficient of variation of 0·68%.
Gastric erosions induced by analgesic drug mixtures in the rat
Authors: Seegers A J M , Jager L P , van Noordwijk J
Published: April 2011

Gastric erosions after oral administration of analgesics separately and in admixture have been examined in adult rats. After administration of acetylsalicylic acid (aspirin), phenacetin, paracetamol and caffeine as single drugs, gastric erosions were only observed with aspirin. The combination of aspirin with phenacetin did not change, that of aspirin with caffeine significantly increased, and aspirin with paracetamol significantly decreased the incidence of gastric lesions compared with aspirin alone. The results for aspirin with paracetamol did not differ from those for the vehicle. Addition of caffeine to the combination of aspirin and phenacetin caused a significant increase in erosions, but when given with aspirin and paracetamol no erosions occurred. The mechanisms underlying the effects of these drugs on aspirin-induced erosions are discussed.
Effect of tolerance to morphine, ethanol and barbiturate on amphetamine circling in rats with a striatal dopamine lesion
Authors: Slater P
Published: April 2011

The (+)-amphetamine circling rate of rats with unilateral 6-OHDA lesions in the striatum was recorded. Morphine tablets were implanted subcutaneously for chronic treatment. In the morphine-dependent animal the circling rate to amphetamine given 4 days after morphine was first implanted was depressed but after withdrawal with naloxone a day later the rate increased, returning to normal after 21 days. Barbiturate physical dependence was induced by adding increasing amounts of barbitone to the drinking water of lesioned rats over four weeks after which the amphetamine circling response was depressed and remained so after the barbiturate was withdrawn. Ethanol tolerance was induced by adding ethanol to the drinking water of lesioned rats for four weeks. Neither the induction of tolerance over this period nor ethanol withdrawal had any effect on the circling response to amphetamine. The change in the response of striatal dopamine neurons to amphetamine that occurs after chronic morphine treatment, cannot be produced by chronic treatment with either barbitone or ethanol. The neurochemical bases of barbiturate and ethanol tolerance are different from morphine tolerance.
A membrane model of the human oral mucosa as derived from buccal absorption performance and physicochemical properties of the β-blocking drugs atenolol and propranolol
Authors: Schürmann W , Turner P
Published: April 2011

The buccal absorption characteristics and physicochemical properties of the β-adrenoceptor blocking agents propranolol and atenolol have been investigated to evaluate their permeation properties across biological lipid membranes. The dissociation constants, solubilities of free base, and n-heptane partition coefficients show that propranolol in its unionized form is much more lipophilic than atenolol, both drugs being bases with a similar pKa. Buccal absorption was studied under conditions of varying drug concentration, contact time, and pH, and controlled through the use of a non-absorbable marker. The absorption findings are in general agreement with the pH-partition theory. A new compartmental diffusional model that includes membrane storage and a hypothetical ‘aqueous pH-buffering surface system’ allowed a more exhaustive interpretation to be made. A method for the estimation of the intrinsic pH and buffer capacity of the postulated surface system from drug pH-absorption data and partition coefficients alone is described. With human oral mucosa the intrinsic pH was near 6·7, and the buffering capacity of the system (expressed as the ratio ΔpH/ΔpH eff) about 2·86. The method was validated using published absorption data from the rat small intestine. Absorption of unionized drug through pores is shown to be negligible in the buccal absorption situation. The time course of absorption suggests membrane storage of lipophilic compounds; the in vivo partition coefficient of unionized propranolol relative to the mucous membrane could be calculated for the peusdo-steady state of absorption, i.e. the partition equilibrium between mouth content and membrane, to be approximately 776; this value is of the same order as the in vitro partition coefficient for the erythrocyte/plasma system. The lipid biophase of the buccal membrane is estimated semiquantitatively to be of intermediate polarity (ɛ = 3–4).
Possible differences in α-adrenoceptors in rabbit ileum and spleen
Authors: Harper Barbara , Hughes I E , Noormohamed F H
Published: April 2011

In isolated tissues from reserpinized rabbits (5 mg kg−1, i.m. 20 h before experiment) and in the presence of cocaine (3 × 10−5 m), corticosterone (2·8 × 10−5 m), tropolone (3 × 10−5m), propranolol (4 × 10−6m) and disodium EDTA (3 × 10−5m), the potency ratios (relative to (—)-noradrenaline) of (—)adrenaline, (—)-phenylephrine and (±)-methoxamine were (m ± s.e.) 203 ±0·13, 0·045 ± 0·003 and 0·0062 ± 0·0018 respectively in splenic strips and 1·77 ± 0·41, 0·093 ± 0·018 and 0·029 ± 0·004 respectively in isolated ileum. Although the pA2 values for phentolamine and thymoxamine against (—)-noradrenaline in the two tissues were very similar there was a statistically significant difference when using yohimbine as the α-adrenoceptor blocking agent (pA2 = 6·80 ± 0·30 in spleen; 5·60 ± 0·12 in ileum). These differences suggest that the α-adrenoceptor in the two tissues is not identical. The pA2 value of phentolamine in rabbit ileum was not significantly different whether (—)-noradrenaline or (±)-methoxamine was used as agonist (7·91 ± 0·07 and 7·97 ± 0·06 respectively) while that of yohimbine was 5·56 ± 0·10 using (—)-noradrenaline and 6·19 ± 0·12 using (±)-methoxamine. In the light of this latter result and, considering the scatter of the experimentally determined values, there may be two α-adrenoceptors in rabbit ileum and either or both may not be identical in all respects to the α-adrenoceptor found in rabbit spleen.
Aggregation of antidepressant drugs in aqueous solution
Authors: Attwood D , Gibson J
Published: April 2011

Light scattering, conductivity and pH methods have been used to examine the aggregation in aqueous solution of a series of antidepressant drugs. The drugs investigated included the hydrochlorides of amitriptyline, butriptyline, protriptyline, nortriptyline, imipramine, desipramine, clomipramine, dothiepin, dibenzepin, opipramol, iprindole, doxepin, mianserin and maprotiline. No significant association of dibenzepin, mianserin or maprotiline hydrochlorides could be detected up to their respective solubility limits. A micellar pattern of association was established for all other compounds. Critical micelle concentrations and micellar properties are reported.
Formation of liquid crystal and other non-fluid phases in emulsions containing non-ionic surfactants
Authors: Ali A A , Mulley B A
Published: April 2011

The relation between the phase distribution of components and the nature and properties of dispersions formed in a four-component system containing dodecane, water and two homogeneous non-ionic surfactants has been investigated by phase-rule techniques. Phase equilibrium diagrams for the four ternary systems were investigated and the phase boundaries for the various regions formed in these systems were defined by synthetic and analytical methods. In some of the ternary diagrams a narrow three-phase region occurs where ‘gel’ or liquid crystal as well as two isotropic liquid phases are present. Dispersions containing the gel phase were very stable. The four-component system has not been fully investigated due to the presence of extensive liquid crystal phases and three-phase regions. However, some distribution data for the quaternary system was obtained. In the presence of sufficient amounts of the short chain non-ionic surfactant C10H21(O.CH2.CH2)3OH, a three-liquid phase region occurs where multiple drops readily form.
Factors affecting the disintegration and dissolution of chloroquine phosphate/starch tablets
Authors: Pilpel N , Otuyemi S O , Kurup T R R
Published: April 2011

A study has been made of the effects produced on the disintegration and dissolution times of chloroquine phosphate tablets by varying their moisture and starch contents and the distribution of the starch in the formulation. 3 to 5% w/w of moisture produces a maximum in the disintegration and dissolution times. Starch added externally as a powder acts only as a disintegrating agent for the tablets, but starch added internally as a paste during granulation acts both as a binding agent and as a disintegrant.