bluuebunny/crossref_metadata_2025 huggingface dataset:
Particle slippage and rearrangement during compression of pharmaceutical powders
Authors: York P
Published: April 2011

Compression data from different size fractions of lactose, chloroquine diphosphate, stearic acid and calcium carbonate have been analysed using the Walker and the Heckel compression equations. Points of inflection in graphs of log applied pressure vs the reciprocal of the packing fraction at low pressures corresponded closely to figures for theoretical packing conditions for equisized spheres and are attributed to a change in the stage of compression. The degree of particle slippage and rearrangement taking place during compression has been shown to increase as the particle size of the powder decreases and to be more extensive for powders composed of non-spherical particles. In addition, three types of compression behaviour have been distinguished for the four powders studied.
A model for short term drug absorption studies; comparison of sulphadiazine tablets
Authors: Saunders L , Ahmed M , Enever R P , Natunen T
Published: April 2011

The four parameter equation, applicable to drug absorption kinetics over a limited time period, has been used to interpret plasma concentration, time results following oral dosage with three different formulations of sulphadiazine tablets, to each of five subjects. Assessment parameters for the formulations, the time for ten percent absorption, the time interval between 10–90% absorption and the plasma concentration with no disposition (relative availability) have been estimated. Intersubject variation obscured many of the differences between formulations. To blank off this variation, plasma concentrations at each time were averaged and then random variation corresponding to the error of the assay method was applied so as to generate a number of sets of data which including the mean concentrations was equal to the number of sets in the original measurements. Kinetic analysis of these sets indicated a number of significant differences between the formulations.
Delay of castor oil diarrhoea in rats: a new way to evaluate inhibitors of prostaglandin biosynthesis
Authors: Awouters F , Niemegeers C J E , Lenaerts F M , Janssen P A J
Published: April 2011

Forty-four non-steroidal anti-inflammatory compounds were tested for possible effects on castor oil-induced diarrhoea in rats. A small but significant delay of intestinal evacuations was found with all compounds. Quantitatively, the oral doses required to delay diarrhoea beyond the first hour after castor oil challenge reflected the acute anti-inflammatory potency of the tested compounds. Qualitatively, the evolution of the effective doses with increasing delay was linear for potent inhibitors of prostaglandin biosynthesis. The evolution for less potent compounds was markedly different and suggested the earlier occurrence of nonspecific drug effects. Suprofen, the most potent of the series of compounds, produced the 1 h delay at an oral dose of 1·11 mg kg−1; the ED50 increased linearly to 115 mg kg−1 for a 4 h delay. Compared with other compounds the activity pattern of suprofen was consistent with that of a very potent, short-acting inhibitor of prostaglandin biosynthesis, which maintains its specific action over a wide dose range. It is concluded that delay of castor oil-induced diarrhoea in rats allows a detailed characterization of aspirin-like compounds, and that inhibition of prostaglandin biosynthesis is insufficient to suppress the intestinal effects of the oil.
Dopamine-β-hydroxylase release following acute selective sympathetic nerve stimulation of the heart, spleen and mesentery
Authors: Algate D R , Leach G D H
Published: April 2011

An increase in the concentration of dopamine-β-hydroxylase (DBH) in the blood perfusates of the heart, spleen and mesentery of pithed rats was detected following selective sympathetic nerve stimulation. Furthermore, the concentration of enzyme released by each organ correlated with the stimulation frequency. The results provide further corroborative evidence that the concentration of DBH in the plasma is related to the degree of sympathetic tone. If the sampling methods described were applied to non-spinalized animals, the concentrations of DBH in organ perfusates could be used as an index of sympathetic nervous tone and thus provide a useful preparation for the study of drugs on the sympathetic nervous system.
Isolation and identification of the fluorescent degradation product of some β-lactam antibiotics
Authors: Barbhaiya R H , Brown R C , Payling D W , Turner P
Published: April 2011

A fluorescent degradation product of cephalexin, recently employed in the determination of this antibiotic in aqueous solution and human plasma, has been isolated and identified as 2-hydroxy-3-phenyl-6-methylpyrazine. Spectroscopically and chromatographically the product is indistinguishable from that obtained by the same method from a series of other cephalosporins and penicillins bearing an α-amino group on the side-chain, and from the pyrazine structure produced by synthesis. Two reported methods for the fluorimetric determination of ampicillin have also been found to yield the same degradation product and not the suggested diketopiperazine structure.
Fate of [14C]warfarin in guinea-pigs: effect of a concomitant single dose of salicylate
Authors: Wong L T , Solomonraj G , Thomas B H
Published: April 2011

When a single dose of sodium salicylate (177·8 mg kg−1, by mouth) was given with [14C] warfarin (1 mg kg−1, i.p.) to guinea-pigs, the salicylate depressed the blood concentrations of 14C for 6 h. At 1 h, salicylate increased the distribution of 14C in the liver and brain, but at 1 and 6 h it was decreased in the blood and kidney. A significant portion of the 14C was excreted into the bile, but was subject to enterohepatic circulation and then excreted by the kidney. There was an enhancement of the biliary elimination of 14C in the first 5 h after salicylate and a decrease in 14C concentration in blood; the proportion of warfarin to its metabolites excreted in the urine and bile was unchanged. Salicylate displaced serum protein bound [14C]warfarin in vitro. Salicylate increases the initial biliary elimination of warfarin by displacing some of that bound to plasma protein. This facilitated uptake of warfarin by the liver where it was metabolized. This effect of salicylate did not modify the hypoprothrombinaemia produced by warfarin.
Rectal absorption of homatropine [14C]methylbromide in the rat
Authors: Cramer M B , Cates L A , Clarke D E
Published: April 2011

Homatropine[14C]methylbromide (HMB-14C) was administered to rats by intramuscular injection, oral gavage and rectal suppository. Plasma concentrations of 14C were measured over the subsequent 12 h. Peak plasma concentrations were higher and achieved more rapidly after rectal administration than by the other routes whether HMB-14C was administered in a water-soluble suppository base or in aqueous solution. Twelve h after the suppositories were inserted and retained 28% of the 14C had been excreted in the urine while 56% remained in the large intestine. Unlabelled HMB, given in rectal suppositories to anaesthetized rats, caused prompt blockade of the effects of vagal stimulation on pulse rate and of intravenous acetylcholine on blood pressure. These results confirm the rapid rectal absorption of the drug.
The determination of sulphoxide in degraded phenothiazine formulations by difference spectrophotometry
Authors: Davidson A G
Published: April 2011

A method is described for the assay of phenothiazine sulphoxides which may be formed in phenothiazine formulations during storage under unfavourable conditions. The assay is based upon the measurement of difference absorbance of the sulphoxide solution in 0·2 m hydrochloric acid relative to an equimolar solution reduced with zinc dust. A solvent extraction procedure avoids interference from colouring agents and coloured photolytic breakdown products of the phenothiazines. The assay is specific in the presence of intact drug, sulphone and co-formulated drugs for the formulations examined and is sensitive to 0·5% of the total phenothiazine present as sulphoxide. Many aqueous formulations stored in partially filled containers have been shown to contain up to 31·5% of the total phenothiazine as sulphoxide.
The percutaneous absorption of phenolic compounds: the mechanism of diffusion across the stratum corneum
Authors: Roberts M S , Anderson R A , Swarbrick J , Moore D E
Published: April 2011

The effect of temperature on the permeation of phenolic compounds from aqueous solution through excised human skin has been examined. From a thermodynamic analysis of the data, a mechanism is postulated by which these solutes penetrate through human skin. For the more polar solutes it is suggested that the main resistance to penetration is the lipid barriers in the stratum corneum. Diffusion of these substances through the stratum corneum appears to depend on the breaking of hydrogen bonds in the desolvation of the solute during this penetration process and by the overall ‘viscosity’ of the stratum corneum. With non-polar solutes, the aqueous boundary layers appear to provide an additional barrier to the penetration of phenolic compounds.
Baclofen (β-p-chlorophenyl-γ-aminobutyric acid) enhances [3H]γ-aminobutyric acid (3H-GABA) release from rat globus pallidus in vitro
Authors: Kerwin R , Pycock C
Published: April 2011

The rat globus pallidus has been investigated as a possible model in which to study pre-synaptic G AB A mechanisms in vitro. (±)-Baclofen (300 μM-1 mM) significantly enhanced the release of radioactivity from superfused slices of rat globus pallidus prelabelled with 3H-GABA in vitro. This releasing action was specific to the (+)-isomer of baclofen: neither the (—)-isomer nor another neuronal depressant DL-α-∞-diaminopimelic acid had any significant effect. The releasing effect of baclofen appeared unrelated to the phenethylamine moiety of its structure as neither β–phenethylamine nor dopamine evoked release of 3H-GABA from pallidal slices. Baclofen increased the efflux of radioactivity from pallidal slices prelabelled with either [3H]β-alanine or [3H]diaminobutyric acid in vitro. The use of specific glial and neuronal GABA uptake blocking compounds (β-alanine and (±)-cis-1,3-amino-cyclohexanecarboxylic acid) did not permit resolution of the elements from which baclofen was evoking [3H]GABA release. Baclofen also inhibited uptake of [3H]GABA into pallidal slices with an IC50 value of 6 × 10−4 M. The GABA-like properties of baclofen may be related to the (+)-isomer while non-specific neuronal depressant actions are an effect of the (—)-isomer. The potential of the (+)-isomer as an antipsychotic agent while (—)-baclofen remains the effective antispastic drug free from unwanted side-effects, is discussed.
Differences in responsiveness to adipokinetic agents between white epididymal and brown interscapula adipose tissue from rats
Authors: Itaya Koichi
Published: April 2011

Lipolytic activity was studied in brown and white adipose tissue of rats in vitro. 5-Hydroxytryptamine (5-HT), phenylephrine, noradrenaline, adrenaline and isoprenaline were used as adipokinetic agents. All stimulated lipolysis in brown adipose tissue, but 5-HT and phenylephrine did not in white adipose tissue. A β-blocking drug, propranolol, inhibited the stimulatory effect of the agents in both adipose tissues. However, an α-blocking drug, phentolamine, further increased the lipolysis induced by noradrenaline or adrenaline in brown adipose tissue and inhibited the effect of isoprenaline. In white adipose tissue, its action was to marginally decrease the effect of adrenaline and noradrenaline. Increase in the pH of the incubation medium stimulated FFA and glycerol release in brown adipose tissue, but not in the epididymal adipose tissue. This effect of pH on lipolysis was further enhanced by phentolamine and decreased by propranolol. Increase of lipolysis with pH was not seen with brown fat tissue from the reserpine-treated rats. These results show that brown adipose tissue of the rat has an α-receptor with inhibitory effects on lipolysis that is affected by α- or mixed-type adrenergic agonists, noradrenaline and adrenaline.
The effect of PGE1 on peristalsis and on perivascular nerve inhibition of peristaltic activity in guinea-pig isolated ileum
Authors: Sanger G J , Watt A J
Published: April 2011

The effect of PGE1 on peristalsis of guinea-pig isolated ileum was examined using a modified Trendelenburg method to evoke and record peristaltic activity. PGE1 (14 nm, 0·11 μm and 0·56 μm) increased peristaltic activity of both longitudinal and circular muscle, mainly by increasing the amplitude of contraction. Preparations of ileum subjected to a ‘minimal’ peristaltic stimulus were more sensitive to the effects of PGE, than were preparations subjected to a ‘just-maximal’ peristaltic stimulus. The inhibition of peristaltic activity caused by perivascular nerve stimulation was antagonized by 0·56 μm PGE1 but slightly increased by 14 nm PGE1.
Percutaneous absorption: theoretical description
Authors: Albery W John , Hadgraft Jonathan
Published: April 2011

Equations are derived to describe the percutaneous absorption of a substance through the epidermal barrier. The treatment includes interfacial barriers and allows for the depletion of the substance in the external phase. The equations are derived both for the continuous application and for pulse experiments where the drug is applied for a time, then removed, and the response occurs some time after the removal of the drug. Competition between the drug diffusing through the keratinized cells (transcellular route) and diffusing in the interstitial channels around the cells (intercellular route) is also considered.
Depletion of brain noradrenaline, but not dopamine, by intracerebral 6-hydroxydopamine potentiates convulsions induced by electroshock
Authors: Mason Stephen T , Corcoran Michael E
Published: April 2011

Intracerebral injection in rats of 4 μg of the catecholamine neurotoxin 6-hydroxydopamine was used to deplete forebrain noradrenaline to less than 10% of control values and separately to deplete brain dopamine to less than 15% of control. The susceptibility of these animals to electroconvulsive shock-induced convulsions was examined, and a significant potentiation of the response was seen in the rats depleted of noradrenaline but not in those depleted of dopamine. The duration of the convulsion was significantly increased as a result of loss of forebrain noradrenaline.
The effects of treatment and of withdrawal of treatment with guanfacine and clonidine on blood pressure and heart rate in normotensive and renal hypertensive rats
Authors: Salzmann R
Published: April 2011

Disagreement in the literature about the occurrence of rebound hypertension (hypertensive overshoot) in animal models initiated this investigation. Oral doses of clonidine (0.03 mg kg−1) or guanfacine (0.3 mg kg−1) were administered twice daily during three weeks to groups of normotensive and renal hypertensive rats. Blood pressure and heart rate were measured immediately before and 3 h after the first daily dose, and compared with values obtained from placebo-treated control rats. Treatment with either drug induced large daily fluctuations rather than sustained falls in blood pressure. In the normotensive, but not in the hypertensive groups, the morning blood pressures measured before the first daily dose were significantly elevated over those of the control groups after 9 and 5 days of treatment with clonidine or guanfacine. This elevation persisted for 3 days after drug withdrawal. It is concluded that in the rat the duration of action of both drugs was short, so that twice daily administration of both drugs similarly produced large daily fluctuations rather than sustained falls in blood pressure. Blood pressure rises developed during treatment rather than after withdrawal in normotensive rats only. Therefore, this type of study does not relate well to the human situation and different experimental approaches to this problem are needed.
Effect of naloxone on the sensitivity of the vas deferens to various agonists
Authors: Ramaswamy S , Nazimudeen S K , Kameswaran L
Published: April 2011

The effect of naloxone in vitro, on noradrenaline (NA)-induced responses in guinea-pig isolated vas deferens was studied. The responses of NA were potentiated by naloxone (3 μm). It potentiated the responses to methoxamine which has least affinity for uptake sites. Responses induced by acetylcholine and potassium chloride were also potentiated by naloxone. Low calcium (0.8 mM) in the medium antagonized the potentiating action of naloxone. It is suggested that naloxone produces non-specific potentiation, by promoting calcium influx at the post-synaptic site.
More acidic metabolites of Δ1-tetrahydrocannabinol isolated from rabbit urine
Authors: Nordqvist Marianne , Agurell Stig , Rydberg Maria , Falk Lena , Ryman Torsten
Published: April 2011

The in vivo metabolism of Δ1-trahydrocannabinol (Δ1-THC) was further investigated in the rabbit after i.v. administration. Nine acidic metabolites were isolated from a previously not investigated fraction of the urine and identified by gas chromatography-mass spectrometry and by proton magnetic resonance spectroscopy. The major metabolites were side-chain hydroxylated monocarboxylic acids. Three side-chain monocarboxylic acids hydroxylated in allylic positions in the isoprene moiety were also characterized. The metabolites 4″-hydroxy-Δ1-THC-7-oic acid and 7-hydroxy-4”,5″-bisnor-Δ1-THC-3”-oic acid were hitherto not identified. An earlier described dicarboxylic metabolite was present in high concentration. Further, the identity of an O-glucuronide as an in vivo urinary metabolite of Δ1-THC was here for the first time unambiguously established by m.s. and p.m.r.
An in vitro study of drug displacement interactions: warfarin-salicylate and warfarin-phenylbutazone
Authors: Aarons Leon J , Schary William L , Rowland Malcolm
Published: April 2011

The binding interactions between warfarin-salicylate and warfarin-phenylbutazone in the presence of 4 g percent bovine serum albumin at 37 °C were studied using equilibrium dialysis. Methods of representing and analysing drug binding interactions are discussed. Scatchard plots, double reciprocal plots and the like are shown to be of no use in representing drug displacement interactions since they display only one drug and they can be potentially misleading. It is argued that a preferable method of analysing drug displacement interaction data is in terms of a stepwise multiple equilibria model. The numerical problems associated with fitting this kind of model to the data are discussed. A three-dimensional representation of the binding surface is proposed as a superior means of visualizing drug displacement interactions.
The distribution of amylobarbitone, butobarbitone, pentobarbitone and quinalbarbitone and the hydroxylated metabolites in man
Authors: Robinson Ann E , McDowall R D
Published: April 2011

Fluid and tissue specimens collected from 30 subjects at autopsy have been assayed for their content of common sedative barbiturates and the corresponding hydroxylated metabolites by g.l.c. Where one barbiturate had been ingested an inverse relationship between lipid solubility of the drug and the distribution in fluids and tissues was observed. In most cases the liver, and in the remainder the spleen, contained the highest concentrations of barbiturate. Bile concentrations were often in excess of those in the corresponding liver. The metabolites of the four sedative barbiturates were usually present in lower amounts than the parent drugs in the fluids and tissues of most subjects but urine often contained much higher concentrations of metabolites—sometimes exceeding that of the parent drug in the liver. Administration of two or more barbiturates together did not appear to affect the distribution and metabolism of the individual drugs.
Effects of the non-steroidal anti-inflammatory drug benoxaprofen on leucocyte migration
Authors: Meacock S C R , Kitchen E Ann
Published: April 2011

Possible modes of action of the anti-inflammatory drug, benoxaprofen, have been explored. The drug caused inhibition of leucocyte migration, principally of mononuclear cells into the pleural cavity of rats undergoing carrageenan-induced pleurisy. Evidence was obtained from in vitro leucocyte migration and chemotaxis models that the drug acted directly on the mononuclear cells rather than by inhibition of chemotactic factors.
Catalytic tritiation of drugs and analysis of the tritium distribution by 3H n.m.r. spectroscopy
Authors: Elvidge J A , Jones J R , Saljoughian M
Published: April 2011

Propranolol, phenobartitone, diphenylhydantoin, amphetamine, imipramine and propoxyphene have been tritiated using tritiated water and platinum catalyst (from the dioxide and sodium borohydride), and the pattern of labelling has been ascertained by 3H n.m.r. spectroscopy. The results show that this exchange procedure can lead to satisfactory incorporation of tritium at ‘stable’ aromatic positions. For imipramine where incorporation of tritium was low, an alternative acid-catalysed procedure was satisfactory.
Biological effectiveness, in goldfish, of some p-substituted acetanilides alone and in the presence of poloxamers
Authors: Collett J H , Tobin Elizabeth A
Published: April 2011

The death times of goldfish have been measured in aqueous solutions containing different concentrations of p-substituted acetanilides alone or in the presence of poloxamers. Plots of reciprocal death time versus concentration were linear with a positive concentration intercept, the minimum effective concentration (MEC). The MEC values were directly related to the π value (hydrophobic-lipophilic constant) of the functional group on the acetanilide indicating that activity is directly related to lipophilicity. Slopes of reciprocal death time versus drug concentration were linearly related to π values but there was no direct dependence. The presence of poloxamers in aqueous acetanilide solutions reduced the goldfish death time. The effect of the poloxamers is believed to be one of rendering the goldfish membrane more permeable to drugs.
Effect of ethanol on adrenaline-stimulated glucose uptake in rat white adipose tissue
Authors: Itaya Koichi
Published: April 2011

The effect of ethanol on adrenaline-stimulated glucose uptake by rat white adipose tissue has been examined in vitro. Ethanol (3%) inhibited the stimulatory effect of adrenaline on glucose uptake whereas it failed to inhibit the effect of adrenaline on free fatty acid production. Addition of calcium (12·5mM) to the incubation medium restored adrenaline's effect on glucose uptake. Addition of propranolol also restored the effect of adrenaline inhibited by ethanol. Ethanol did not inhibit insulin-stimulated glucose uptake. These results suggest that ethanol modifies the coupling of the adrenoceptor to the glucose transport system in adipose tissue that is stimulated by adrenaline.
The effects of some sweetening agents and osmotic pressure on the intestinal absorption of sulfafurazole in the rat
Authors: Marvola Martti , Reinikainen Aini , Heliövaara Marja-Leena , Huikari Ansa
Published: April 2011

The effects of some sugars and osmotic pressure have been examined on the absorption of sulfafurazole in the rat. Statistically significant correlations were found among the hypertonic solutions between the reciprocal of osmotic pressure and AUCO-∞ or Cmax. In addition, negative correlation existed between plasma concentrations at 15 min and osmotic pressure. No significant correlations were noted among the hypotonic solutions. More attention should be paid to the osmotic pressure of formulations. The osmotic pressure of hypertonic solutions, especially, might affect absorption of drug from its dosage form.
Inter-relationships between solubilities, distribution coefficients and melting points of some substituted benzoic and phenylacetic acids
Authors: Armstrong N A , James K C , Wong C K
Published: April 2011

Ten 4-hydroxy and 4-alkoxy benzoic and phenylalkanoic acids have been investigated. Solubilities in aqueous buffer at pH 1·2 were determined, together with distribution coefficients between the buffer and either octanol or isopropyl myristate. When plotted against the total number of carbon atoms in the side chains, log octanol/water distribution coefficients gave two parallel straight lines, one for the substituted benzoic acids, and the other for the substituted phenylalkanoic acids. The slopes approximated to 0·5, the generally accepted value for methylene. Similar plots could be obtained with isopropyl myristate, provided the hydroxy acid results were ignored, and also when log aqueous solubilities were plotted against carbon number, although there was considerable scatter. The differences between the distribution coefficient results were explained in terms of solute-solvent interactions, and the scatter attributed to variations in the heats of fusion of the solutes. Yalkowsky's equation (1977), linking aqueous solubilities and melting points with distribution coefficients, was applied to the results, and found to be of limited predictive value.
The effects of physicochemical properties of pethidine and its basic metabolites on their buccal absorption and renal elimination
Authors: Chan Kelvin
Published: April 2011

The pKa values, RF values, partition coefficients between n-heptane and phosphate buffer (pH = 7·4), and buccal absorption tests of pethidine and its basic metabolites, norpethidine and pethidine N-oxide, have been determined. The amounts of these compounds recovered in the 48 h urine samples after intramuscular administration of pethidine (1·5 mg kg−1) to six healthy subjects varies with urinary pH values: the recovery from acidic urine (pH 5·0) is 15·2 to 52·0%, 6·7 to 12·9% and 0·2 to 2·3% of dose for pethidine, norpethidine and pethidine N-oxide respectively; in alkaline urine (pH 8·0) the values are 0·8 to 1·8%, 0·6 to 2·8% and 0·3 to 2·1% respectively. The physicochemical properties (pKa values, RF values, partition coefficients) and buccal absorption of pethidine, norpethidine and pethidine N-oxide are in good agreement with the pattern of their renal elimination in acidic and alkaline urine conditions. The contribution of the physicochemical properties of pethidine and its metabolites to the drug's disposition in the body and the effect of urinary pH on its metabolism should be taken into account in pharmacokinetic studies and interpretation of intersubject variation in response to pethidine.
Role of the dopaminergic system in the cataleptogenic action of bulbocapnine
Authors: Massotti M , Longo V G
Published: April 2011

Time courses of the behavioural and biochemical effects of a cataleptogenic dose (50mgkg−1 i.p.) of bulbocapnine have been studied in the rat. Catalepsy ensues immediately after administration of the drug and lasts 1 h. Concomitant with the onset of catalepsy there is a rise in HVA and DOPAC concentrations in whole and discrete parts of the brain (striatum, limbic system). Dopamine content does not change in whole brain but it decreases in the striatum and increases in the cortex and hippocampus. No significant effects on NA, 5-HT and 5 HIAA concentrations were observed.
Age and strain differences in the rate of development of functional tolerance to ethanol by mice
Authors: Grieve Susan J , Littleton John M
Published: April 2011

The time course of development of functional tolerance to ethanol was investigated in mice during the inhalation of ethanol vapour, using loss of righting reflex as the behavioural end-point. In male mice of the TO Swiss strain, weanling mice (18 days) showed no development of tolerance during continuous or repeated exposure to ethanol vapour for 6 h. Adolescent TO Swiss mice (35–40 days) showed rapid development of functional tolerance, reaching a state where 2x the original effective concentration of ethanol in blood was required to produce loss of righting reflex within 5 h. Older adult mice (150–200 days) showed some development of tolerance during continuous or repeated exposure to ethanol for 5 h but this was much less than that seen in adolescent mice. When adolescent males of the C57BL, TO Swiss and DBA2 strains were compared, marked differences were observed. C57BL mice showed very rapid development of functional tolerance to ethanol in which more than 2 × the original effective dose was required to produce loss of righting reflex after about 3 h of ethanol exposure. TO Swiss mice showed somewhat slower development of ethanol tolerance. DBA2 mice showed little evidence of development of functional tolerance over the time course of these experiments. Evidence was also obtained that similar age and strain differences may exist with respect to tolerance to the hypothermic effects of ethanol. These results are discussed in relation to current concepts of ethanol sensitivity, tolerance and physical dependence.
Serum and peritoneal fluid concentrations of clindamycin and lincomycin in the mouse
Authors: Rosen A , Kanwar R S , Dempsey G , Brookes L G
Published: April 2011

Serum concentrations of drug were obtained at various times after intramuscular dosing of healthy mice with either clindamycin or lincomycin hydrochlorides. Washings from the peritoneal cavity were taken at the same time as the serum samples. Changes in drug concentration in the peritoneal fluid with time mimic those for the serum, but concentrations in peritoneal fluid are much greater than the corresponding serum concentrations. The total volume of peritoneal fluid was estimated to be 0·05 ml.
Selective influences of age and thyroid hormones on Type A monoamine oxidase of the rat heart
Authors: Lyles G A , Callingham B A
Published: April 2011

The specific activity of rat heart MAO, towards both tyramine and benzylamine as substrates, was found to increase with the age of the animal, and also after administration of (−)-thyroxine to young male rats. Conversely, enzyme activity was decreased in animals made hypothyroid by including 2-thiouracil in their diet. However, with both age and altered thyroid status, relatively greater changes in the deamination of tyramine rather than in that of benzylamine, were obtained. Clorgyline and deprenyl, used as inhibitors of rat heart MAO, indicated that tyramine is metabolized solely by MAO-A, whereas benzylamine is a substrate for both MAO-A and -B, and also a clorgyline- and deprenyl-resistant enzymic activity. The proportional contribution of MAO-A, -B and the clorgyline-resistant enzyme towards the total benzylamine deamination in the rat heart was found to vary with the age and with altered thyroid status of the animal in such a way that selective changes in the activity of MAO-A appear to be largely responsible for the overall changes in the specific activity of rat heart MAO which occur in response to these developmental factors.
Inhibitory effect of 5-hydroxytryptamine on lipogenesis in rat adipose tissues
Authors: Itaya Koichi
Published: April 2011

5-Hydroxytryptamine (5-HT) inhibited the incorporation of 14C from 14C-labelIed glucose, pyruvate, citrate and acetate into fatty acids but it did not inhibit the conversion of 14C from citrate and acetate into CO2, and the citrate conversion into glyceride-glycerol in epididymal and mesenteric adipose tissue from 24h-fasted rats. 5-HT stimulated the formation of lactate from glucose and pyruvate, and increased the ratio of lactate produced/pyruvate taken up. This ratio was similar to the NADH:NAD ratio. These results indicate that 5-HT inhibits fatty acid synthesis in rat white adipose tissue by mechanisms similar to those of the catecholamines.
The effect of low- and high-humidity ageing on the hardness, disintegration time and dissolution rate of dibasic calcium phosphate-based tablets
Authors: Chowhan Z T
Published: April 2011

The effect of low- and high-humidity ageing on hardness, disintegration time and dissolution rate of dibasic calcium phosphate dihydrate-based tablets prepared at different initial moisture concentrations was studied. Hardness increased while disintegration and dissolution rate decreased on ageing in low humidity. The dissolution rate of tablets containing higher initial moisture was slower than the tablets containing lower initial moisture. On ageing in high humidity, hardness, disintegration and dissolution rates decreased at all initial moistures. The results suggest that the effects of moisture and humidity should be thoroughly investigated for dibasic calcium phosphate dihydrate-based tablets in order to ensure stability and bioavailability of the drug.
Sympathomimetic effects of exo- and endo- isomers of 2-aminobenzonorbornene in vitro and in vivo
Authors: Burn P , Crooks P A , Ratcliffe B L , Rees J M H
Published: April 2011

A stereospecific synthesis of endo-2-aminobenzornorbornene is described. Its sympathomimetic activities and those of its N-methyl derivative were compared with the equivalent exo- isomers using the isolated rat anococcygeus muscle and the anaesthetized rat blood pressure preparations. On the anococcygeus muscle preparation the endo- and exo-isomers of the primary amines had similar indirectly acting sympathomimetic activities. In contrast the exo-N-methyl derivative was a far more potent sympathometic in vitro than the endo-N methyl isomer. In the anaesthetized rat the exo- and endo-isomers of 2-aminobenzonorbornene and their N-methyl derivatives all had similar pressor activities, though the successive injections of the two exo-derivatives suggested an additional α-adrenoceptor blocking activity. The actions of these rigid sympathomimetics are compared with those of the flexible amphetamine structure.
Facilitatory effect of nicotine on adrenergic neuroeffector transmission in the isolated ear artery of the rabbit
Authors: Sarantos-Laska Catherine , McCulloch Marian W , Rand Michael J
Published: April 2011

The effects of nicotine were studied on perfusion pressure and vasoconstrictor responses to sympathetic nerve stimulation in the isolated ear artery of the rabbit. Infusions of nicotine (50 μM) produced a transient increase in perfusion pressure and potentiated responses to nerve stimulation; these effects of nicotine were unaffected by atropine (0–3 μM) and abolished or significantly reduced respectively by hexamethonium (300 μM) or mecamylamine (1 μM). In experiments with ear arteries previously labelled with [3 H] noradrenaline an infusion of nicotine (50 μM) produced a transient increase in tritium efflux and the potentiation of responses to nerve stimulation in the presence of nicotine was accompanied by a statistically significant increase in stimulation-induced tritium efflux; these effects of nicotine were abolished by hexamethonium (300 μM) or mecamylamine (1 μM).
Mechanism of mesaconitine-induced contractile response in guinea-pig ileum
Authors: Sato Hiroshi , Ito Tomoko , Ohizumi Yasushi , Hikino Hiroshi
Published: April 2011

Mesaconitine (MA) caused contractions of the guinea-pig isolated ileum in a dose-dependent manner (10−8 −10−5 g ml−1), slightly potentiated the contractile response to acetylcholine (ACh) and histamine and enhanced responses to electrical stimulation. Repeated application of MA (10−5 g ml−1) produced tachyphylaxis. Atropine blocked contractions to MA (3 times 10−7 g ml−1), but only partially those to MA (10−5 g ml−1). Morphine, strychnine and hemicholinium-3, but not hexamethonium, also inhibited MA-induced contractions. Contractions produced by both doses of MA were abolished by cocaine, tetrodotoxin, or noradrenaline, or by previous cooling of the ileum. The atropine-resistant contractions produced by MA (10−5 g ml−1) were blocked by indomethacin. MA (3 times 10−7 −10−5 g ml−1) elicited a dose-dependent release of ACh from the isolated ileum which was blocked by treatment with tetrodotoxin or cocaine, or exclusion of calcium ions from the bath. It is concluded that the contractions induced by lower doses of MA are brought about by the release of ACh from the postganglionic cholinergic nerve and that the contractions by higher doses could also be mediated by release of prostaglandins from the ileum.
The influence of molecular size and pH on the macrocationic inhibition of pepsin by polylysine
Authors: Anderson W , Harthill J E , Rahmatalla R
Published: April 2011

Polylysines of 7–371 lysine residues inhibited pepsin over the pH range 3·6-5·0 in a system using azocoll as substrate. Tetralysine was inactive. An almost 1: 1 molar ratio with pepsin gave maximum inhibition for a polylysine containing 59 lysine residues but increase in polylysine molecular size beyond this size was not accompanied by increase in activity on a weight basis although the polylysine: pepsin molar ratio for maximum inhibition decreased and inhibition mechanism varied. Polylysines of 59 and 158 lysine residues which were intermediate in the series were non-competitive inhibitors, whilst polylysines of greater and smaller molecular size were competitive inhibitors, although only the smallest inhibitory polylysine, containing 7 lysine residues, was a pure competitive inhibitor. Polylysine inhibition of pepsin was found to be strongest at pH 5·0 and the pH dependence appeared to be associated with the relative concentrations of the enzyme and inhibitors in ionized form. For each polylysine it was possible to detect a polylysine: pepsin concentration ratio for which inhibition was pH-independent over the range 3·6-5·0.
Dose-dependent behavioural changes induced by apomorphine in selected members of a primate social colony
Authors: Schlemmer R Francis , Narasimhachari Nedathur , Davis John M
Published: April 2011

The effect of six acute doses of the dopamine receptor agonist apomorphine on non-human primate social and individual behaviour was studied in a social colony of four adult Stumptail macaques. Apomorphine was administered intramuscularly to 2 monkeys/day in doses ranging from 0·05 to 3·00 mg kg−1 15 min before a 1 h observation period. Apomorphine induced hyperactivity, hypervigilance, and stereotyped behaviour at doses of 0·50 mg kg−1 and greater in all 4 monkeys. In addition it also caused a dose-dependent disruption of normal behavioural patterns. Social grooming was eliminated while the submissive gestures were significantly increased. It also induced an increase in vocalizations and suppression of food forage behaviours. The results demonstrate the role of dopamine systems in the mediation of affiliative behaviour as well as motor behaviour in a primate species. Also, since similar behavioural changes are induced in this species during chronic (+)-amphetamine treatment, it is suggested that dopamine systems play a predominant role in amphetamineinduced behaviour in primates.
The effect of steroidal and non-steroidal antiinflammatory drugs on chronic muscle inflammation
Authors: Green A P , Mangan F R
Published: April 2011

Zymosan (400 μg) and thioglycollate medium (0·1 ml of 2·4% w/v) have each been shown to induce a chronic inflammation when injected into the hamstring muscle of the mouse. The inflammation is characterized by an increase in muscle weight and N-acetylglucosaminidase concentrations. The response is not inhibited by oral treatment with hydrocortisone, dexamethasone or naproxen, but is inhibited by the local injection of methylprednisolone. The relevance of this model to polymyositis and fibrositis is discussed.
Responses to arachidonic acid and other dilator agonists and their modification by inhibition of prostaglandin synthesis in the canine hindlimb
Authors: Morcillo E
Published: April 2011

The influence of indomethacin, in doses that completely inhibit the response to arachidonic acid, has been examined on canine hindlimb vascular responses to intra-arterial administration of bradykinin, histamine, nitroglycerin, isoprenaline and papaverine. The hindlimb was perfused at constant flow. Dose-response curves to intra-arterial administration of arachidonic acid (12 to 200 μg kg−1), bradykinin (0·4 to 100 ng kg−1), histamine (1·8 to 120 ng kg−1), nitroglycerin (15 to 100 ng kg−1), isoprenaline (12 to 100 ng kg−1) and papaverine (1·2 to 160 μg kg−1) (all n = 4) were compared before and 30 min after indomethacin (5 mg kg−1 i.v.). All the drugs produced dose-related decreases in hindlimb perfusion pressure. After indomethacin, responses for all dilator agonists except arachidonic acid, were significantly greater than control (P < 0·05), both in terms of absolute (mmHg) or percent change. Doseresponse curves after indomethacin had a left upward shift compared with control. Arachidonic acid responses were completely blocked by indomethacin. These findings suggest that indomethacin produces a non-specific increase in responsiveness of the hindlimb vascular bed to dilator substances, except arachidonic acid. The data presented do not support the hypothesis that the peripheral vasodilatation produced by bradykinin, nitroglycerin and histamine could be mediated by endogenous prostaglandin release.
The granulation of ternary mixtures: the effect of the wettability of the powders
Authors: Jaiyeoba K T , Spring M S
Published: April 2011

Granules have been prepared by a standard method from ternary mixtures of lactose, boric acid and either sulphanilamide, heavy kaolin or salicylic acid, using an aqueous solution of polyvinylpyrrolidone as binder. The granules were examined for size distribution and for the work required to crush larger granules from each batch. For the same binder volume the mean granule sizes and resistance to crushing of the granules increased as the wettability of the third component increased. The detailed results are discussed in relation to powder wetting and the packing properties of powder mixtures.
Micellar properties and surface activity of some bolaform drugs in aqueous solution
Authors: Attwood D , Natarajan R
Published: April 2011

The micellar properties of a series of dicationic drugs with structures resembling those of the bolaform electrolytes have been examined using light scattering, surface tension and conductivity techniques. The compounds investigated included, demecarium bromide, ambenonium chloride, dequalinium acetate, distigmine bromide and chlorhexidine acetate. Demecarium and dequalinium formed micelles at critical concentrations of 9 times 10−3 and 4 times 10−3 mol kg−1 respectively. No significant association of chlorhexidine acetate could be detected, contrary to previous reports.
On the anomalous sorption behaviour of chlorhexidine with poly(2-hydroxyethyl methacrylate)
Authors: Plaut B S , Meakin B J , Davies D J G
Published: April 2011

General observations of solute: plastic interactions would suggest that the sorption of the cationic preservative, chlorhexidine, with poly (2-hydroxyethyl methacrylate) (PHEMA) is not only unexpected but also atypical in its properties. The polymer and preservative were investigated independently and the sorption of PHEMA with simple solutes, namely benzoic acid, benzocaine and aniline found to exhibit conventional properties. The single exception was the uptake of small amounts of benzocaine and aniline cations at acidic pH's. In order to elucidate the sorption characteristics of chlorhexidine a series of N1-(p-chlorophenyl)-N5-alkylbiguanide acetates were synthesized. The anomalous sorption behaviour observed between PHEMA and the bis biguanide, chlorhexidine, was also found to be characteristic of these monofunctional biguanide derivatives. The extent of the interactions increased with increasing alkyl chain length (R = methyl to n-octyl), this being interpreted in terms of an interaction binding mechanism via the biguanide functional group stabilized by van der Waal's forces between the alkyl chain and the polymer backbone. Atypical sorption behaviour was observed for simple organic cations, biguanide and N1-phenylbiguanide acetate with PHEMA, a possible inference being that this is a general characteristic of all cationic sorption with PHEMA.
Analgesic and other pharmacological activities of a new narcotic antagonist analgesic (-)-1-(3-methyl-2-butenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine and its enantiomorph in experimental animals
Authors: Nakamura Hideo , Ishii Katsumi , Yokoyama Yuichi , Motoyoshi Satoru , Natsuka Kagayaki , Shimizu Masanao
Published: April 2011

Of 1-cyclohexyl-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine (I) and its 1-(3-methyl-2-butenyl) derivative (II), the S(+)-isomers were analgesically more active than either their R (-)-isomers or their racemates, having 15 to 44 times the potency of morphine in mice and rats. R (-)-I had comparable analgesic activity to morphine R (-)-II to pentazocine in mice, rats and dogs and they were nearly equipotent with pentazocine in reversing some actions of morphine. The S (+)-isomers and racemates lacked this action. R (-)-II required about 10 times more naloxone to reverse its analgesic activity than was needed to antagonise the S (+)-isomers, morphine and pentazocine. The S (+)-isomers and racemates produce a typical Straub tail reaction and increased spontaneous locomotor activity in mice, but the R (-)-isomers did not. R (-)-II had no significant physical dependence liability in mice, rats and monkeys. From these results, it is suggested that the compounds show an uncommon stereoselectivity in comparison with morphine and its surrogates, and that R (-)-II is worth investigating further as a narcotic antagonist analgesic.
The effects of nefopam on blood acid-base status in the rabbit: interactions with morphine in the mouse and rabbit
Authors: Stainthorp S F , Morton A K , Pleuvry B J
Published: April 2011

Nefopam, a non-narcotic analgesic, had only minor effects upon the blood pH, Pco2 and standard bicarbonate of the conscious rabbit. In contrast morphine caused a dose-dependent increase in Pco2 and standard bicarbonate. When nefopam was administered in conjunction with morphine (2·5 mg kg−1 and 1 mg kg−1 i.v. respectively) the increase in Pco2 was greater than with morphine alone. Nefopam also increased the antinociceptive and respiratory frequency depressant effects of morphine in the mouse.
Age related changes in the clearance and oral absorption of sodium cromoglycate in the developing albino rat
Authors: Smith Dennis A , Fisher Anthony N
Published: April 2011

A dual radioisotope method was used to investigate the clearance and oral abso***rption of sodium cromoglycate. Radiolabelled sodium cromoglycate was administered orally at a dose of 100 mg kg 1 (14 C-labelled) and simultaneously subcutaneously at a dose of 2 mg kg−1 (3 H-labelled) to rat pups 5, 9, 14, 20, 29 and 75 days old. Blood concentrations of 14 C and 3 H were measured at intervals for 24 h after dosing. Since the compound is not metabolized the blood concentrations of 14 C were taken as a measure of the sodium cromoglycate absorbed orally and the blood concentrations of 3 H as a measure of the subcutaneously administered material. Using the area under the oral 14 C blood curve (AUC) as an index of bioavailability, the calculated bioavailability of sodium cromoglycate (692·9−945·9 min μg ml−1) in 5, 9 and 14 day old pups was 4–8 times greater than that observed (61·0-118·8 min μg ml−1) in 20, 29 and 75 day old pups. The blood clearance of sodium cromoglycate was increased four-fold in 75 day old animals (43·9 ml min−1 kg−1) and three-fold in 20 and 29 day old pups when compared to the clearance in 5, 9 and 14 day old pups. The clearance in 5, 9 and 14 day old pups was relatively constant (10·8 − 9·9 ml min−1 kg−1). In rats less than 14 days old the systemic absorption of sodium cromoglycate after oral administration was 2–3 times greater (6·8-9·2%) than in rats aged 20, 29 or 75 days old (2·7-3·3%). The reduction in oral bioavailability of sodium cromoglycate as the pups grew older was, therefore, due to both an increased blood clearance and a decreased absorption of the compound.