bluuebunny/crossref_metadata_2025 huggingface dataset:
Corticosterone - an anxiogenic or an anxiolytic agent?
Authors: File Sandra E , Vellucci Sandra V , Wendlandt Sabine
Published: April 2011

Corticosterone (3–12 mg kg−1, i.p., giving rise to plasma corticosterone concentrations from 26.7 to 89.0 μg/100 ml) failed to have a significant anxiogenic action. Instead, corticosterone (3 mg kg−1) had a significant anxiolytic effect in the social interaction test of anxiety.

Adrenalectomized rats had very low levels of social interaction; but adrenalectomized rats that had been given replacement corticosterone therapy did not differ from the shamoperated controls. Thus, corticosterone appears to have the opposite effect to that previously reported for ACTH. Possible mechanisms for the observed results are discussed.
Muscimol and related GABA receptor agonists: the potency of GABAergic drugs in vivo determined after intranigral injection
Authors: Arnt J , Scheel-Krüger J , Magelund G , Krogsgaard-Larsen P
Published: April 2011

Contralateral turning behaviour following unilateral intranigral injection of a large series of GABA analogues was investigated. The results indicated that the turning behaviour was induced stereospecifically and was selectively antagonized by the GABA antagonist bicuculline methochloride. The comparative potencies of a series of GABA agonists related to muscimol in general corresponded well to the affinity for 3H-GABA receptor sites and to the depressant action on single neurons using microelectrophoretic administration. However, the GABA agonists trans-aminocrotonic acid and 3-aminopropanesulphonic acid were much weaker than expected from in vitro studies. The GABA-uptake inhibitors nipecotic acid and guvacine showed only weak and short-lasting effects. The GABA-transaminase inhibitor γ-acetylenic GABA showed delayed effects compared with the agonists which acted immediately. It is proposed that this behavioural effect may be a sensitive and quantitative method for evaluation of GABA agonists in vivo.
Hypothermic effects of apomorphine homologues in mice
Authors: Menon M K , Clark W G , Cannon J G
Published: April 2011

A single intraperitoneal (i.p.) injection in mice of apomorphine (I) and its analogues norapomorphine (II), N-ethylnorapomorphine (III), N-n-propylnorapomorphine (IV) and apocodeine (V), caused dose-related decreases in deep-core body temperature. The neuroleptic agent haloperidol blocked the hypothermia produced by these apomorphines but α-methyl-p-tyrosine failed to do so. This indicated a direct post-synaptic stimulation of dopamine receptors. Methysergide potentiated the hypothermic effect of the apomorphine analogues. Taking the amount of apomorphine to produce a 3 °C fall in temperature at 30 min as unity, the approximate relative potencies were: I 1.00, II 0.06, III 47.50, IV 85.00, V 0.340. The doses of the apomorphines needed to produce hypothermia were much less than those needed to cause stereotypy. The ratios of the minimal doses required to produce hypothermia, to those producing stereotypy were: I 8.82, II 4.00, III 125.00, IV 28.50, V 1.43.
The surface activity and self-association of some β-adrenoceptor blocking agents in aqueous solution
Authors: Attwood D , Agarwal S P
Published: April 2011

The surface activity at the air-solution interface of a series of β-adrenoceptor blocking agents has been determined. The drugs investigated included, propranolol, sotalol, oxprenolol, labetolol, timolol, metoprolol and acebutolol. Correlation between surface activity and local anaesthetic potency of the drugs is examined. Light scattering measurements have indicated self-association of sotalol, oxprenolol, acebutolol and metoprolol in 0.5 mol kg−1 sodium chloride. Critical micelle concentrations and aggregation numbers are reported.
Placebo granules as cores for timed release drug delivery systems
Authors: Friedman M , Donbrow M , Samuelov Y
Published: April 2011

A drug delivery system is proposed constituted of spherical placebo granules as cores with polymeric surface films containing drug. This timed release dosage form has been prepared by means of a fluidized bed coating technique using ethyl cellulose as the polymeric film and caffeine and salicylic acid as model drugs. The release of the drugs from the dosage form (a) at different drug concentrations and (b) into solutions of different pH showed that drug release was linearly related to the square root of time. Good agreement was found between the theoretical release rate of caffeine, calculated according to Higuchi's equation for a homogenous matrix using membrane permeation parameters measured on linear films, and the experimental results in the case of low drug concentrations. Deviation of the release rate from the homogenous model at high drug concentrations could be explained by crystallization of the drug from the film.
The stability of betamethasone-17-valerate in semi-solid bases
Authors: Yip Y W , Po A Li Wan
Published: April 2011

The stability of betamethasone-17-valerate in semi-solid bases has been investigated. Emphasis has been placed on the stability problems which could arise upon dilution of proprietary preparations by the use of model systems. Betamethasone-17-valerate has been shown to decompose to betamethasone-21-valerate and betamethasone alcohol. Quantitation of the decomposition was by direct densitometry on thin layer chromatographic plates. The decomposition was found to be an apparent first order process and to depend on the diluent used and its concentration. Attempts were also made to relate the rate of decomposition to the pH of the base used, and to stabilize the products.
The determination of aluminium in antacid formulations by Gran's Plot titration with sodium fluoride
Authors: Cooper M E A , Ballantine J , Woolfson A D
Published: April 2011

The aluminium content of a number of proprietary antacid formulations has been determined by titration with sodium fluoride, using the fluoride activity electrode as an end-point detector. Results compared favourably with the official method. The fluoride titration, however, involved less sample manipulation and was more rapid to carry out. End-point detection was made easier by treating titration data by the Gran's Plot method.
The influence of binder concentration on the bond formation of pharmaceutical granules
Authors: Stanley-Wood N G , Shubair M S
Published: April 2011

The formation of particle mucilage bonds with dicalcium phosphate dihydrate and starch mucilage binder reduces the B.E.T. nitrogen adsorption surface area from 1.6 to 0.96 m2 g−1. The maximum reduction (40%) of granule surface area at a binder concentration of 10% w/w corresponded to similar optima in friability, compressability and median granule size. Surface and pore-void structural analysis by mercury intrusion could not discriminate between pore-void sizes in the range 0.5–100 nm. Nitrogen adsorption measurements showed, however, that the microporous surface area decreased from 0.3 to 0.18 m2 g−1 as binder surface coverage increased over the concentration range 2 to 20% w/w starch mucilage.
Isolation and identification of a fluorophore from ampicillin degradation
Authors: Lebelle M J , Vilim A , Wilson W L
Published: April 2011

A fluorescent impurity in ampicillin has been isolated and identified as 2-hydroxy-3-phenyl-pyrazine. The product is formed under acidic conditions similar to those employed in some fluorometric assay procedures. The mechanism of the reaction is proposed to involve cyclization by condensation of the penilloaldehyde of ampicillin. The structure was confirmed by independent synthesis.
The detection of enzyme induction by rat liver microsomes prepared by isoelectric precipitation
Authors: Parkinson Andrew , Safe Stephen
Published: April 2011

A comparison was made of various indices of the hepatic drug-metabolizing apparatus associated with the postmitochondrial supernatant, microsomes harvested by differential centrifugation, and microsomes harvested by isoelectric precipitation from control, phenobarbitone-pretreated and 3-methylcholanthrene-pretreated rats. The metabolic capabilities and distinctions between control and induced rats for each of the three liver preparations compared favourably as determined by the concentration of cytochrome b5 and P-450 and by the activity of NADPH-cytochrome c reductase, 4-dimethylaminoantipyrine N-demethylase and aryl hydrocarbon (benzo[a]pyrene) hydroxylase. The results suggest that the relatively simple isoelectric precipitation technique is a useful alternative to the conventional method of differential centrifugation for the preparation of hepatic microsomes.
A radioreceptor assay for benzodiazepines
Authors: Hunt Peter , Husson Jean-Marc , Raynaud Jean-Pierre
Published: April 2011

A simple, rapid and sensitive radioreceptor assay for determining benzodiazepines in serum is based on the displacement by the drug of specific [3H]diazepam binding to a membrane fraction from rat brain. The limit of detection of the more active benzodiazepines is about 0.5 ng. Diazepam, nitrazepam, clobazam and HR 458t have been assayed in human serum after a single oral clinical dose. The results can be used for determining pharmacokinetic parameters. The technique measures not only the parent benzodiazepine but also clinically active metabolites.
Determination of erythrocyte membrane-buffer partition coefficients by numerical analysis of multicomponent spectra
Authors: Grìnbauer H J M , Bultsma T , Bijloo G J , Rekker R F
Published: April 2011

A method suitable for the measurement of erythrocyte membrane-buffer partition coefficients by u.v.-spectrophotometry is described. This method is characterized by a proper correction for inconstant background absorption in case of bad signal to noise ratios. For this purpose the multicomponent u.v.-spectrum of a compound in the presence of absorbing materials lost by erythrocyte membranes is decomposed into its constituent spectra by means of numerical analysis. Application of this method to the determination of partition coefficients of benzhydrol, 4-bromophenol and benzyl alcohol yields satisfactory agreement with literature values for the latter two coefficients.
An in vitro study of the effects of calcium on the cardiovascular actions of thiopentone, Althesin and ketamine in the rat
Authors: Hall P J , Pleuvry Barbara J
Published: April 2011

The actions of three intravenous anaesthetics, Althesin, thiopentone and ketamine have been compared on the rat isolated atria and portal vein. Although the three anaesthetics had grossly similar actions on the two preparations, i.e. depression of atrial rate and depression of the amplitude of myogenic activity in the portal vein, there were enough differences to suggest that they produced their effects by different mechanisms. These differences were particularly obvious in interactions with noradrenaline and the effects of changes in calcium ion concentration on the concentration effect relationships for the agents on the atria and portal vein. Generally Althesin was unaffected by changes in calcium ion concentration, whilst ketamine and thiopentone were affected, but in qualitatively different ways.
Role of taurine as a possible transmitter in the thermoregulatory pathways of the rat
Authors: Win R W Ker , Pycock C J
Published: April 2011

Taurine (10 and 20 μg) injected unilaterally into the lateral ventricle of rats caused an increase in core temperature. Bilateral injection of taurine 2.5 and 5 into the preoptic region of the anterior hypothalamus induced a dose-related hyperthermia: higher doses (10 μg) caused hypothermia. Intrahypothalamically taurine-induced hyperthermia was blocked by prior injection of strychnine hydrochloride (5 and 15 μg); doses which alone had no effect on core temperature. Of the other inhibitory amino acids injected intrahypothalamically hypotaurine also induced a hyperthermia. GABA (10 μg) caused hypothermia; glycine (10 μg) had no effect. Potassium (50 mM) stimulated release of radioactivity from superfused slices of anterior hypothalamus prelabelled with [3H]taurine in a calcium-dependent manner. A high affinity uptake mechanism with a Km of 8.5 μM was demonstrated with [3H]taurine into slices of anterior hypothalamus. Taurine may have a neurotransmitter role in the anterior hypothalamus but whether the body temperature effects represent physiological or pharmacological events remains to be established.
Evaluation of changes in drug particle size during tableting by measurement of dissolution of disintegrated tablets
Authors: Kitamori Nobuyuki , Makino Tadashi
Published: April 2011

Three poorly soluble drugs (chloramphenicol, phenacetin and prednisolone) were compressed into tablets of 10% drug content on a physical testing instrument at three different compression pressures. The dissolution profiles were determined by a modification of the U.S.P. method for drug suspensions, granules before compression, disintegrated and intact tablets. By comparison of the dissolution rates for disintegrated tablets with those for granules before compression, or suspensions, it is possible to separate the change in particle size during compression from the pressure-dependent dissolution behaviour of intact tablets. A comparative measurement of dissolution for disintegrated tablets with that for granules provides a useful method for elucidating the particle bonding or cleavage within the tablet during compression.
Effect of drug content and drug particle size on the change in particle size during tablet compression
Authors: Kitamori Nobuyuki , Makino Tadashi
Published: April 2011

Three size fractions for each of three poorly soluble drugs were compressed into 10 mm diameter tablets of four different dilution ratios. The compression was carried out on a physical testing instrument at four compression levels of 49·0, 98·1, 196·2 and 294·3 MN m−2. The effect of drug content and drug particle size on the change in particle size during tableting was examined by the determination of the dissolution rate for disintegrated tablets. A linear relation was obtained when plotting ***1n(T80%) versus drug content. There was a critical particle size where the phenomena of cleavage and bonding during tableting balanced each other, but this varied with drug content.
Effect of taurine on release of 3H-GABA by depolarizing stimuli from superfused slices of rat brain cerebral cortex in vitro
Authors: Leach Michael J
Published: April 2011

The effect of taurine on potassium (30 mM), veratrine (10 μg ml−1) and ouabain (100 μM) induced release of 3H-GABA from superfused slices of rat brain cerebral cortex has been studied. Taurine (10–100 mM) potentiated K+-induced release of 3H-GABA but was more potent in potentiating veratrine- and ouabain-induced release, having significant effects at 5 mM and 1 mM respectively. The potentiation of stimulus induced release does not appear to be due to inhibition of reuptake and the effect is consistent with both a ‘modulatory’ role and anticonvulsant action for taurine.
The disposition of [14C]metronidazole in rats following vaginal and oral administration
Authors: Buttar H S , Siddiqui W H , Moffatt J H
Published: April 2011

The absorption, tissue distribution and excretion of [14C]metronidazole (14C-MTZ) were compared during the first 4 h after administration of 10 mg kg−1 of 14C-MTZ either orally or intravaginally (i.v.g.) to rats. Peak 14C blood concentrations were reached at 1 h in both groups. Blood samples collected at 0·5, 3 and 4 h had a higher 14C concentration in orally dosed rats (P <0·05) than in i.v.g.-treated animals. About 3% of the i.v.g. applied dose remained in the vagina at 4 h. After 4 h, the plasma, liver, kidney, brain, lung and uterus concentrations of 14C were similar in both groups, whereas the blood, skeletal muscle and fat 14C values were significantly greater in the orally dosed rats. The total recoveries of 14C in the urine and faeces did not differ (ca 38% over 4 h) between the two groups. These results suggest that the kinetics of metronidazole are similar after the administration of equal amounts of this drug by either route.
Dopamine receptor changes after long-term haloperidol treatment in rats
Authors: Ebstein Richard P , Pickholz Dalia , Belmaker Robert H
Published: April 2011

Tardive dyskinesia is a neurological syndrome associated with prolonged neuroleptic treatment of schizophrenic patients (Crane 1968; Faurbye 1970; Faurbye et al 1964). It has been suggested that tardive dyskinesia results from chemical denervation of central dopamine neurons and subsequent development of supersensitivity of the postsynaptic receptor (Rubovits & Klawans 1972). Experiments based on animal models of tardive dyskinesia support this hypothesis. Chronic neuroleptic treatment increases postsynaptic dopamine receptor sensitivity when measured either behaviourally or biochemically (Christensen et al 1976; Klawans & Rubovits 1972; Moore & Thornburg 1975; Sayers et al 1975; Tarsy & Baldessarini 1974; Von Voigtlander et al 1975). The molecular basis for this behavioural change has been reported to be an increase in the number of receptor sites with no change in their affinity as measured by 3H-neuroleptic binding to striatal membrane homogenates (Burt et al 1977; Klawans et al 1977; Muller & Seeman 1977). Previous biochemical reports of the development of model tardive dyskinesia after neuroleptic treatment of animals have generally used treatment periods of 3 weeks or less (Burt et al 1977; Klawans et al 1977; Muller & Seeman 1977). Only one report treated animals for longer periods (Clow et al 1978). In the present experiments we studied the kinetics of [3H]spiroperidol binding to rat caudate nucleus homogenates after 3 and 10 weeks of haloperidol treatment.
The effect of some new antidepressants on apomorphine-induced hypothermia in mice
Authors: Przegalinski E , Bigajska K , Siwanowicz J
Published: April 2011

Imipramine-like tricyclic antidepressants antagonize hypothermia induced by apomorphine in mice (Lapin & Samsonova 1968; Schelkunov 1968, 1977; Fuxe & Sjöqvist 1972; Maj et al 1974; Puech et al 1978); this phenomenon has been used by some authors as a test for the antidepressant activity. Therefore, we have examined the effect of some new antidepressants in this test, especially as some of them differ in their mechanism of action from imipramine-like drugs. The drugs used were: nomifensine, an inhibitor of the dopamine and noradrenaline (NA) uptake (Hunt et al 1974; Schacht & Heptner 1974), two specific inhibitors of 5-hydroxytryptamine (5-HT) uptake, femoxetine (FG 4963) (Buus Lassen et al 1975) and poroxetine (FG 7051) (Petersen et al 1977), two other antidepressants whose main characteristic was the blockade of central 5-HT receptors, i.e. mianserin (van Riezen 1972) and trazodone (Baran et al 1979). We also included pizotifen, a drug used in migraine prophylaxis (see Speight & Avery 1972) but exerting an antidepressant effect (Standal 1977; Banki 1978) and a potent central anti 5-HT activity (Dixon et al 1977; Przegalinski et al 1979). For comparison, the effect of four tricyclic antidepressants (imipramine, desipramine, amitriptyline and chlorimipramine) was also studied.
Haemodynamic effects of the carboxylic ionophore monensin when administered before and during shock induced by E. coli endotoxin
Authors: McCaig Dorothy J , Parratt J R
Published: April 2011

The haemodynamic effects of the carboxylic ionophore monensin have been examined in cats anaesthetized with sodium pentobarbitone. Marked increases in left ventricular dP/dtmax (and dP/dt at fixed isovolumic pressures) and slight increases in cardiac output and stroke volume occurred, indicating increased myocardial contractility. Heart rate was unchanged but systemic arterial pressure was substantially increased. Satisfactory increases in contractility and arterial pressure were obtained when monensin was infused intravenously in a total dose of 0·25 mg kg−1 over 10 min. Larger doses, especially if rapidly injected, resulted in very marked increases in myocardial contractility leading eventually to cardiac failure. The haemodynamic effects of monensin were markedly reduced during shock induced by E. coli endotoxin and there was unfortunately no evidence to suggest that this extremely potent compound might be potentially beneficial in this form of profound cardiovascular shock.
Non-competitive-non-equilibrium α-adrenoceptor blocking properties of N-benzyl iodoacetamide, betsamide
Authors: Huidobko-Toro J Pablo , Huidobro F , Miranda H
Published: April 2011

N-Benzyl iodoacetamide, betsamide, at 10 mg kg−1 i.v. blocked the hypertensive and contractile responses of the nictitating membrane of the cat to adrenaline. The blockade had a lag period before full development. Pretreatment of cats with betsamide for 7 or 18 h showed a non-equilibrium type of α-adrenoceptor blockade. The responses of the nictitating membrane to adrenaline were markedly depressed and did not recover after high doses of adrenaline. In the same cats, adrenaline caused a profound hypotension. The effect of betsamide lasted for at least 72 h. In the rat isolated vas deferens, 3 times 10−5 M betsamide non-competitively blocked the contractile responses to noradrenaline; the adrenoceptor blockade was less effective when betsamide was applied with noradrenaline. The blockade lasted for more than 24 h, and was not reversible after extensive washing. Betsamide antagonized the contractile effects of carbachol and 5-hydroxytryptamine on the rat vas deferens, but not the β-responses of the guinea-pig trachea to adrenaline and isoproenaline. Results are discussed in relation to a probable mechanism of action.
Potentiation of the diabetogenic effect of streptozocin by phentolamine in the rat
Authors: Walker P K Tal , Kaul C L , Grewal R S
Published: April 2011

The effect of α- and β-adrenoceptor blocking agents and a β2-agonist, salbutamol, on the diabetogenic effects of streptozocin (threshold doses) was investigated in the rat. Phentolamine and salbutamol potentiated the diabetogenic effect of streptozocin but phenoxybenzamine, tolazoline, Oxprenolol and propranolol were without effect. The potentiating effect of phentolamine was blocked by Oxprenolol. Potentiation of the diabetogenic effect by phentolamine is not related to α-adrenoceptor block, vasodilatation or insulin release. But it may be related to its ability to stimulate β-adrenoceptors.
Effect of 5-hydroxytryptamine on blood glucose and cyclic AMP in the rat
Authors: Itaya Koichi , Itoh Madoka
Published: April 2011

The effects of 5-hydroxytryptamine (5-HT) on plasma cyclic AMP (cAMP) and glucose concentrations were studied in rats in vivo. 5-HT injected i.p. increased plasma cAMP and glucose. Injections of propranolol, hexamethonium, and cyproheptadine inhibited the 5-HT-induced increase in glucose but not in cAMP. Atropine did not inhibit the action of 5-HT. These effects of 5-HT were not seen in adrenomedullectomized rats, and 5-HT did not elevate the concentration of plasma cAMP in anti-glucagon antiserum-injected rats. These results confirm the previously reported finding that 5-HT-induced increase in blood glucose is mediated via adrenaline released from adrenal medulla by 5-HT and suggest that the increase in plasma cAMP, induced by 5-HT, is due to glucagon released by an unknown factor, or factors other than adrenaline released from the adrenal medulla by 5-HT.
Dissolution of bupivacaine 3-hydroxy-2-naphthoate into phosphate buffers
Authors: Nakano Naomi I , Setoya Akiko
Published: April 2011

Dissolution behaviour of bupivacaine 3-hydroxy-2-naphthoate (BUPNH) into phosphate buffers, pH 7·4 was investigated at 25° and 37°C. Although the dissolution pattern of the salt at 25°C was normal, i.e. the concentrations of the acid and base component agreed, during the entire dissolution period, that at 37°C was anomalous. The dissolution consisted of two phases, i.e. an initial normal phase was followed by a second slower phase in which the concentration of the acid became, at equilibrium, markedly higher than that of the base. This unusual dissolution behaviour at 37°C was shown to be due to the precipitation of the base, which, in turn, is attributed to the unusual temperature dependency of the solubility of the base in phosphate buffers, i.e. decrease in solubility with increasing temperature.
An in vitro model for assessing drug availability from lipophilic vehicles
Authors: Armstrong N A , James K C , Wong C K
Published: April 2011

An apparatus for studying the rate of release of a solute from a water-immiscible solvent into an acidic, aqueous liquid, followed by permeation through a simulated lipid membrane, is described. The object was to imitate the absorption of a drug after oral administration in a soft gelatin capsule. Rate constants of transfer were determined for a series of substituted benzoic acids, using octanol and isopropyl myristate as solvents. The quantity of solute in the acidic phase did not correlate with the solvent-water distribution coefficient, but was linearly related to the rate constant for transfer from solvent to water. A dynamic system was therefore postulated, rather than one in which the two phases are in equilibrium. In vivo studies on two of the solutes confirmed the in vitro observations. No simple relationship could be derived between blood concentrations and any in vitro parameter, but the rank order of magnitude of the blood concentrations fitted the postulated dynamic mechanism.
Precise spectrophotometry of small quantities of drugs in the presence of irreproducible quantities of impurities
Authors: Vezin W R
Published: April 2011

A variety of methods of spectrophotometric assay of compounds in the presence of one or more irrelevant impurities have been recently described, employing, for example, the use of Legendre polynomials and trigonometric functions. The use of least-squares solutions of overdetermined systems (Scheid 1968) in spectrophotometry is outlined, with conditions under which simplified overdetermined systems have been used for precise spectrophotometric assay of small quantities of drug substances in the presence of largely irreproducible quantities of irrelevant impurities.
Effect of ricinoleic acid and other laxatives on net water flux and prostaglandin E release by the rat colon
Authors: Beubler E , Juan H
Published: April 2011

Ricinoleic acid, oleic acid, dioctyl sodium sulphosuccinate, deoxycholic acid, sennoside A + B and mannitol reduced or reversed water flux from lumen to blood in rat colon in situ. Stearinic acid was without any effect. Ricinoleic acid, oleic acid, dioctyl sodium sulphosuccinate, deoxycholic acid and sennoside A + B stimulated release of PGE-like material into the colonic lumen whereas the osmotic laxative mannitol and stearinic acid did not. Inhibition of PGE biosynthesis by pretreatment of the rats with indomethacin significantly reduced (but did not abolish) the effect of ricinoleic, oleic and deoxycholic acids on net water flux and PGE release. Indomethacin reduced the effect of dioctyl sodium sulphosuccinate and of sennoside A + B on PGE release but not their effect on the net water flux. The effect of mannitol was not influenced by indomethacin. The amount of PGE release in experiments with ricinoleic acid, oleic acid, stearinic acid and dioctyl sodium sulphosuccinate (with and without indomethacin) showed a good correlation (r = 0·99) with the change in net water flux. Deoxycholic acid, sennoside A + B and mannitol did not show this correlation. It is assumed that the action of non-osmotic laxatives is partially mediated by PGE, although other mechanisms also seem to be involved in their mode of action.
Interactions of parenteral solutions with sulphur-treated glass bottles
Authors: Passl W J
Published: April 2011

Concern about limited surface durability has been the main reason for recommendations by advisory committees and government health authorities, not to re-use sulphur-treated soda-lime glass (type II) bottles for intravenous solutions. In order to contribute specific data, the interactions of slightly acid and neutral parenteral solutions with ammonium sulphate-treated type II glass bottles have been investigated. It was established that the amounts of silica, sodium and calcium released into the solution are not greater than the potential background contamination from the raw materials. The number of particles in the solution was well below the limits set by the British Pharmacopoeia and not much higher than the lowest background count practically achievable. On an average, bottle surfaces released less material after the first time of use. Bottle-to-bottle variations revealed by scanning electron microscopy point at problems in achieving smooth, evenly surface-treated bottle surfaces during bottle manufacture.
Correlation of bioavailability in man with simulated absorption data for three doxantrazole preparations
Authors: Jones H , Bye A
Published: April 2011

The in vitro and in vivo availability of doxantrazole, a potential antiallergic compound has been evaluated. A solution was significantly less bioavailable than either tablet or suspension formulations and it is suggested that this is associated with the large volume of the solution vehicle altering the hydrophilicity of the gastrointestinal fluids. In vitro availability was determined from absorption rate constants and absorption profiles obtained using the Sartorius absorption and solubility simulators. A statistically significant correlation was found between the percentage absorbed in vitro at 1 h and both total urinary recovery and area under plasma curve values in vivo. It is considered that in vitro determination of diffusion through artificial lipid membranes may be a useful predictive method of in vivo availability.
Effects of acute or chronic administration of chlordiazepoxide on feeding parameters using two food textures in the rat
Authors: Cooper Steven J , Francis Raymond L
Published: April 2011

The effects of acute or chronic administration of chlordiazepoxide on several feeding parameters were studied in the rat. Given acutely, chlordiazepoxide reduced the rate of feeding, at lower dose levels (5·0 or 10·0 mg kg−1) tended to prolong feeding duration, and at a higher dose (15·0 mg kg−1) reduced the amount of food intake. Food texture can influence feeding parameters too; but the effects of the drug did not interact with the effects of food texture. After 9 daily injections of the drug, there were several indications of the development of tolerance to the effects of the drug on the feeding parameters. A possible role of 5-HT mechanisms in the reduction of eating rate produced by the drug is considered.
Catecholamine uptake blockade in anaesthetized dogs: influence on cardiovascular responses
Authors: Brown R A , Solca Anne M , Wilson J
Published: April 2011

The effects of differential and combined catecholamine uptake antagonism on cardiovascular responses of anaesthetized dogs to isoprenaline, noradrenaline, and electrical stimulation of the left ansa subclavia nerve have been studied. Uptake1 inhibition by cocaine HCl (5 mg kg−1 and 1 mg kg−1 every 45 min) enhanced responses to noradrenaline (0·1 to 2·0 μg kg−1 i.v.) and sympathetic nerve stimulation (1 to 20 Hz), but did not affect those to isoprenaline. Uptake2 inhibition by metanephrine (40 μg kg−1 min−1) enhanced cardiac responses to isoprenaline (0·05 to 1·0 μg kg−1 i.v.), but did not significantly alter those to noradrenaline or nerve stimulation. Responses to all agonist interventions were increased by the combined administration of cocaine and metanephrine. Cocaine preferentially enhanced the positive chronotropic cardiac response to noradrenaline, but metanephrine did not differentiate between heart rate and contractility. These results have been discussed in the light of the mechanism of drug action involved.
Effects of pyroxamidine and guanethidine on contractile responses to field stimulation and to noradrenaline in the anococcygeus muscle and vas deferens of the rat
Authors: Doggrell Sheila A
Published: April 2011

The effects of pyroxamidine (EMD 21192) and guanethidine on contractile responses were studied in the anococcygeus muscle and vas deferens of the rat. Pyroxamidine (10−6 and 10−5 M) and guanethidine (6 times 10−6 and 10−5 M) potentiated the responses to low concentrations of acetylcholine in the rat anococcygeus muscle. Following incubation of the muscle with 6-hydroxydopamine (10−3M for 3 h), pyroxamidine (10−5 M) and guanethidine (10−5 M) had no effect on responses to acetylcholine. This suggests that the potentiating effect of pyroxamidine and guanethidine on responses to acetylcholine is due to the release of subthreshold concentrations of noradrenaline.

In the anococcygeus, pyroxamidine (10−6 and 10−5 M) and guanethidine (10−6 and 10−5 M) inhibited responses to field stimulation and potentiated responses to exogenously applied (−)-noradrenaline. The responses to field stimulation in the vas deferens were also inhibited by 10−5M pyroxamidine and by 10−5 M guanethidine. 10−6 M guanethidine, but not 10−5 M pyroxamidine, potentiated responses to (−)-noradrenaline in the vas deferens. In the presence of nortriptyline (10−6 M), a potent inhibitor of neuronal uptake, the inhibitory effects of pyroxamidine and guanethidine on responses to field stimulation were reduced or reversed and these drugs had no effect on responses to (−)-noradrenaline. This suggests that pyroxamidine is a noradrenergic neuron blocker and that its action is dependent on continued neuronal uptake. Following 6-hydroxydopamine incubation, 10−5 M pyroxamidine and 10−5 M guanethidine inhibited the responses to (−)-noradrenaline in the rat anococcygeus muscle. Thus it seems likely, at high concentrations, that these compounds have postsynaptic blocking activity.
The neuromuscular and autonomic blocking activities of pancuronium, Org NC 45, and other pancuronium analogues, in the cat
Authors: Durant Nicholas N , Marshall Ian G , Savage David S , Nelson David J , Sleigh Thomas , Carlyle Ian C
Published: April 2011

Twenty-six mono-or bis-quaternary salts of 3,17-dioxy-2β,16β-dipiperidino-5α-androstanes (including pancuronium) and one 17-desoxy congener were tested for neuromuscular blocking and autonomic blocking activities in the chloralose-anaesthetized cat. The 17β-acetoxy series, all the members of which contain an acetylcholine-like fragment in the steroidal D-ring, was most selective for effecting neuromuscular blockade. The salient member of this series is 3α,17β-diacetoxy-2β,16β-dipiperidino-5α-androstane 16β-N-monomethobromide (Org NC 45) which is highly selective in blocking neuromuscular transmission in that a dose approximately sixty times greater than the neuromuscular blocking dose was required to block responses to vagal stimulation. In contrast, in doses sufficient to produce neuromuscular block, pancuronium simultaneously blocked responses to vagal stimulation. Moreover, pancuronium and Org NC 45 exhibited the same order of neuromuscular blocking activity and therefore the latter potentially represents a useful addition to the armamentarium of neuromuscular blocking agents currently in clinical use.
Effects of phenacetin, paracetamol and caffeine on the erosive activity of acetylsalicylic acid in the rat stomach: dose-response relationships, time course of erosion development and effects on acid secretion
Authors: Seegers A J M , Jager L P , van Noordwijk J
Published: April 2011

Adult male and female Wistar rats were equally susceptible to gastric injury induced with acetylsalicylic acid (aspirin). Both in male and in female rats simultaneous administration of caffeine and aspirin caused significantly more gastric erosions than the same dose of aspirin alone; likewise addition of paracetamol to aspirin decreased the incidence of gastric lesions in either sex, and addition of phenacetin to aspirin had no effect. The potentiation by caffeine and the inhibition by paracetamol were both dose-dependent and only markedly influenced the development of erosions after 3–4 h. Pretreatment with phenacetin or paracetamol 1 h before administration of aspirin did not affect its erosive activity. Administration of benorylate caused no more gastric erosions than the vehicle or than equivalent mixtures of aspirin and paracetamol. The histamine-stimulated acid output of the stomach during gastric perfusion with aspirin was rapidly diminished. Neither paracetamol nor caffeine initially affected this decrease in acid output. However, 30 min after perfusion with aspirin and caffeine, acid secretion increased approximately as strongly as after caffeine alone. Caffeine potentiates aspirin-induced erosions by its stimulatory effect on acid secretion whereas paracetamol inhibits these erosions by preventing their growth.
The photochemical stability of cis- and trans- isomers of tricyclic neuroleptic drugs
Authors: wan Po A Li , Irwin W J
Published: April 2011

The irradiation of the tranquillizers flupenthixol, clopenthixol and chlorprothixene has been found to induce rapid cis-trans isomerization. The composition of the photostationary mixture is not that of the batch drug and hence this process may affect the activity. Further decomposition to a thioxanthone derivative occurs rapidly in the presence of air. Exclusion of oxygen, however, does not prevent further degradation and a slower secondary isomerization is observed on prolonged irradiation. Doxepin and dothiepin also undergo analogous reactions but the isomerizations are much slower and the oxidative degradation yields many products.
Stereoselective actions of substituted benzamide drugs on cerebral dopamine mechanisms
Authors: Jenner P , Clow A , Reavill C , Theodorou A , Marsden C D
Published: April 2011

Apomorphine-induced locomotor activity in reserpine-pretreated mice was antagonized by pretreatment with (-)-sulpiride and (-)-sultopride. The (+)-enantiomers were inactive. Apomorphine- and amphetamine-induced stereotyped behaviour in rats were antagonized by (-)-sultopride but not by the (+)-enantiomer. Neither enantiomer of sulpiride prevented the onset of the stereotyped response. Both (-)-sulpiride and (-)-sultopride induced increases in striatal and mesolimbic HVA and DOPAC concentrations; (+)-sultopride elevated striatal and mesolimbic DOPAC concentrations but not HVA, while (+)-sulpiride had no effect on HVA or DOPAC in either area. Dopamine concentrations were reduced by the enantiomers of sultopride but not by sulpiride. Low concentrations (10−9 −10−66 M) of the (-)-enantiomers of both drugs displaced [3 H]spiperone from its specific binding site in rat striatal preparations, but the (+)-enantiomers were 40 and 100 times less active. However, neither enantiomer of either drug anatagonized the dopamine-induced stimulation of adenylate cyclase in rat striatal preparations. The data suggest that the central pharmacological activity of sulpiride and sultopride resides in the (-)-enantiomers and that this activity occurs at cerebral dopamine receptors not dependent on adenylate cyclase for functional activity.
Ethanol-stimulated acid secretion in the isolated whole stomach of the rat
Authors: Bunce K T , Parsons M E
Published: April 2011

The application of ethanol to the serosal surface of the isolated whole rat stomach stimulated a high rate of acid secretion, with a maximum response being obtained to 4 % v/v ethanol. This acid response to ethanol was not inhibited by high concentrations (1 mM) of atropine or cimetidine, indicating that the response was probably not mediated by either histamine, gastrin or acetylcholine. These results using the secretory antagonists were confirmed by experiments in an isolated gastric mucosa preparation. The acid response to ethanol was significantly, but not completely inhibited by 10 mM thiocyanate, indicating the existence of an acid component of non-parietal cell origin in the mucosal bathing solution. However, analysis of the mucosal solution failed to reveal the presence of an acidic metabolite of ethanol.
The Clark plot: a semi-historical case study
Authors: Stone Mervyn
Published: April 2011

A study has been made of the origins of the quantitative theory of simple competitive antagonism as manifest in the papers of Gaddum and of Clark. The classical data of Clark on the antagonism of acetylcholine by atropine were reanalysed by recently developed computer-based methods. It was seen how close Clark came to initiating a method having the following significant advantages over the Schild plot: (i) symmetrical treatment with respect to the control (zero antagonist) data; (ii) absence of difficulty with the cases where an estimated dose-ratio is less than unity; (iii) straightforward calculation of approximate standard errors for departure from overall simple competitivity at each antagonist level including control.
Metabolism of thymoxamine: identification of metabolites in rat
Authors: Feniou C , Neau B , Prat G , Cheze C , Fauran F , Roquebert J
Published: April 2011

Thymoxamine hydrochloride administered by mouth to rats at 25 or 100 mg kg−1 was excreted in the urine as the deacetyl and N-demethyl-deacetyl metabolites. These were completely sulpho- and glucuronoconjugated at 25 mg kg−1 but only partially so at the higher dose. Thymoxamine deacetylation in vitro is catalysed by plasma and hepatic cytosol esterases and the deacetyl metabolite undergoes N-demethylation catalysed by the cytochrome P 450 hepatic microsome mixed function monooxygenase system. Because of the rapidity of the deacetylation it is concluded that thymoxamine is a prodrug leading in vivo to the active deacetyl thymoxamine.
The determination of ethoxylated non-ionic surfactants in wool grease
Authors: Christoe J R , Evans D J
Published: April 2011

Surfactants in grease can be identified by dissolving the grease (5 g) in hexane-ethyl acetate (1: 1 v/v) and adding to silica gel (100–200 mesh), eluting first with solvent and then with 50% v/v aqueous ethanol, evaporating and extracting with acetone. After evaporation, the residue is heated at 130 °C for 2 h with the mixed anhydride of acetic acid and 4-toluene sulphonic acids (cleavage reagent) (3 ml) to give ethyleneglycol diacetate (EGD) and the corresponding acetate or phenolic derivatives of the hydrophobic portion of the surfactant. When cool, the mixture is diluted with water, added to Na2SO4 (anhyd.) neutralized with Na2CO3, extracted with ether, dried (Na2SO4), concentrated and a sample (3 μ1) gas chromatographed (glass column 1 m × 3 mm i.d., packed with 15% Carbowax 20M on Gas-Chrom Q, oven temp. 170 °C, inlet/outlet 210 °C, N2 carrier 30 ml min−1) and compared with g.c.s of known surfactants. Quantitatively, the grease (0·1-1·0g) is refluxed with cleavage reagent as above, cooled to 60 °C, distilled water (15 ml) added and the separated liquor centrifuged (3000 rev min−1, 5 min). The clarified liquor is added to Na2SO4 (anhyd.), neutralized and extracted with ethyl acetate and a sample (3 μl) chromatographed as above with oven temp. 150 °C. The concentration of surfactant can be determined from comparison of the height of the EGD peak (Rt 2.5 min) with heights from known amounts of the surfactant treated concurrently. The type of grease (commercial, lanolin B.P., and a methanol-soluble fraction of a commercial grease were examined) has no effect on the method.
A comparison of chemically defined and complex media for the production of Bacillus subtilis spores having reproducible resistance and germination characteristics
Authors: Hodges N A , Melling J , Parker S J
Published: April 2011

Spores of Bacillus subtilis were produced on five batches of Antibiotic Assay Medium No. 1 obtained from different suppliers, five batches obtained from a single supplier and five batches of a chemically defined liquid medium. The magnitude of the variation within each of the three groups was compared in terms of heat resistance, glutaraldehyde resistance, germination rate and sensitivity of germinated spores to neomycin. For all these parameters the degree of reproducibility achieved by using a chemically defined liquid medium was substantially better than that using batches of complex medium from a single supplier. Even larger variations in these parameters resulted when different suppliers were used. The value of defined media for the production of spore inocula to be used in sterilization control and similar procedures is discussed.
The influence of drug and diluent particle size on the in vitro release of drug from hard gelatin capsules
Authors: Newton J M , Bader F
Published: April 2011

The in vitro release of a drug from capsules containing different proportions of controlled particle size fractions of acetylsalicylic acid and lactose, has been assessed in terms of the time for 50% of the drug content of the capsule to be released into solution during a dissolution test (T50), and by a standard disintegration test. In general the two types of test gave closely related responses although some discrepancies existed with certain systems. For capsules containing only the drug, the value of T50 increased as the particle size of the drug decreased. The addition of lactose generally reduced the T50 value, the extent of the reduction showing greater dependence on the proportion of lactose added than its particle size. Capsule formulations containing 80% w/w of lactose had values of T50 which were independent of drug or diluent particle size. Capsule formulations containing lower proportions of lactose usually had an optimumcombination of particlesize fractions of drug and diluent for maximum drug release. The relationship between drug release and the porosity within the capsule was dependent on the particle size of the drug.
Assay of nicotine in biological materials: sources of contamination and their elimination
Authors: Feyerabend C , Russell M A H
Published: April 2011

A previous method for the measurement of nicotine in biological samples was subject to occasional interference from a contaminant which eluted simultaneously with the internal standard (quinoline). This has been rectified by substituting isoquinoline as the internal standard and modifying the operating conditions of gas chromatography. Other sources of contamination in nicotine assays such as the analytical reagents, the atmosphere and the sample itself are discussed in detail.
Some mechanisms which may modulate noradrenaline release in guinea-pig isolated ileum
Authors: Sanger G J , Watt A J
Published: April 2011

Guinea-pig isolated ileum pre-incubated with [3 H]noradrenaline, released 3 H-label during coaxial stimulation at 3·2-12·8 Hz. This evoked 3 H-overflow seems due to nerve stimulation, and may be frequency-dependent. The 3 H-overflow evoked by coaxial stimulation was increased with 2·6 μM phentolamine, reduced at threshold stimulation by 0·56 μM prostaglandin E1, but the tendency for 2·8 μM indomethacin to increase the evoked 3 H-overflow was not statistically significant. The results indicate that the release of noradrenaline from guinea-pig ileum may be modulated by activation of presynaptic α-adrenoceptors, whereas prostaglandins act mainly at a postsynaptic site to modulate the sympathetic response.
Evidence for a direct anti-inflammatory action of calcitonin: inhibition of histamine-induced mouse pinnal oedema by porcine calcitonin
Authors: Strettle R J , Bates R F L , Buckley G A
Published: April 2011

Porcine calcitonin (PCT) caused a potent inhibition of histamine-induced vascular leakage in the mouse pinna. These effects were observed at doses of PCT lower than those required to affect plasma calcium concentrations. In contrast PCT did not inhibit responses of the mouse pinna to 5-hydroxytryptamine despite observed falls in plasma calcium concentrations. It would appear that PCT inhibits histamine-induced oedema in the mouse by a direct action which may partially or fully explain the anti-inflammatory action of PCT, observed by other workers, in some acute inflammatory conditions.