bluuebunny/crossref_metadata_2025 huggingface dataset:
Antihypertensive and noradrenaline-depleting effects of guanethidine metabolites
Authors: MAÎTRE L , STAEHELIN M , BRUNNER H
Published: April 2011

The antihypertensive and myocardial noradrenaline-depleting activities of the three identified guanethidine metabolites were compared with those of guanethidine itself. Metabolite A (guanethidine-N-oxide) and Metabolite B [2-(6-carboxylamino)ethylguanidine] both showed approximately 1/30th of the antihypertensive effect of guanethidine in rats. Metabolite A, but not Metabolite B, caused a depletion of cardiac noradrenaline stores. The intensity of this effect was between 1/10th and 1/30th that of guanethidine. Metabolite C [(6-carboxyhexyl)-2-iminoimidazolidine] was inactive on both parameters. [3H]Noradrenaline uptake into isolated bovine nerve granules was not impaired by either guanethidine or its metabolites. It is concluded that the antihypertensive and myocardial noradrenaline depleting effects of guanethidine are produced by the unchanged drug rather than by one of the identified metabolites.
Identification in hashish of tetrahydrocannabinol, cannabidiol and cannabinol analogues with a methyl side-chain
Authors: VREE T B , BREIMER D D , VAN GINNEKEN C A M , VAN ROSSUM J M
Published: April 2011

The cannabis constituents Δ1-tetrahydrocannabinol, cannabidiol and cannabinol are accompanied by their homologues with an n-propyl and with a methyl side-chain. The identification procedure by combined gas chromatography-mass spectrometry in hashish and marihuana is described and the consequences for cannabis use are discussed.
Kinetics of dextrose degradation under autoclaving conditions
Authors: TAYLOR R B , JAPPY B M , NEIL J M
Published: April 2011

The kinetics of the decomposition of dextrose have been investigated over a temperature range of 106° to 127°. The reaction is shown to exhibit an induction period with respect to 5-hydroxymethylfurfural production which is due to the formation of an intermediate compound. A reaction mechanism is proposed which appears consistent with the experimental measurements. Rate constants are calculated for the various reaction steps and the activation energies associated with these steps are reported.
Increased release of xylocholine (TM10) from guinea-pig vas deferens treated with amphetamine sulphate
Authors: DEAN H G , HUGHES I E
Published: April 2011

Although both NN-diethyl- and NN-dimethyl-, N-methyl-[14C]-2-(2,6-xylyloxy) ethylammonium iodide (14C-1DE10 iodide and 14C-TM10 iodide; xylocholine) are taken up by guinea-pig vas deferens to a similar extent in vitro, only TM10 reduced the response of the vas deferens to electrical stimulation. Prior incubation of vas deferens with 14C-1DE10 iodide or with 14C-TM10 iodide followed by measurement of the amount of each of these compounds eliminated from the tissue by repeated washing with Krebs solution, shows both compounds to be strongly retained by the tissue. Incorporation of 10−5 g/ml amphetamine sulphate in the wash fluid failed to modify the release of 14C-1DE10 iodide but produced a short-lived increase in the amount of 14C-TM10 iodide eliminated which reached a maximum approximately 10 min after administration of amphetamine. The additional 14C-TM10 iodide eliminated by amphetamine was about 5% of the total tissue 14C-TM10 iodide content; the possible role of this fraction is discussed in relation to the adrenergic neuronblocking action of 14C-TM10 iodide.
Automatic weight-control in a rotary tabletting machine
Authors: RIDGWAY K , DEER J J , FINLAY P L , LAZAROU C
Published: April 2011

A Manesty “Betapress” 16-station high speed rotary tabletting machine has been fitted with pressure rolls containing piezoelectric transducers in the axles. The compaction force exerted at each tablet compression event produces an electrical pulse which can be fed to an integrated-circuit pulse-discriminating unit. If, for any reason, the quantity of powder in any die is such that an over- or under-pressure occurs on compaction, the resultant incorrect-magnitude pulse is used to operate a stepping motor which adjusts the feed screw of the rotary machine in the correct direction to restore the desired operating conditions and maintain weight constancy. The degree of over- or under-pressure needed to cause corrective action is readily adjustable. An electromagnetically-operated solenoid valve is also controlled by the pulse-discriminator, so that tablets of incorrect weight are deflected by an air jet as they leave the die table. The ejection force can also be monitored and the signal used to operate an alarm if the force should become too large due to punch-sticking.
X-ray analysis of Th 1165a and salbutamol
Authors: BEALE J P , STEPHENSON N C
Published: April 2011

Two drugs, Th1165a* and salbutamol,† having a promising potential as bronchodilators and producing low cardiac stimulation, have been examined for their structural features. These were found to be similar and have been noted as possibly characteristic of the particular β2-adrenoceptor site. Th1165 consists of two enantiomers possessing an (R-R) or (S-S) configuration about the two centres of asymmetry.
The effects of eserine and neostigmine on the guinea-pig ileum and on ilial longitudinal muscle strips
Authors: COX B , LOMAS D M
Published: April 2011

Eserine and neostigmine produced spasms of the guinea-pig isolated ileum that were concentration-related (4 ng-16 μg/ml). Hexamethonium (100 μg/ml) and tetrodotoxin (100 ng/ml) reduced the spasmogenic activity of both drugs. Neostigmine, but not eserine, overcame the hexamethonium antagonism. Pretreatment of the ileum with dyflos (1 μg/ml for 10 min) did not affect the action of either eserine or neostigmine, therefore the spasm was not due to inhibition of cholinesterase. The residual response to eserine or neostigmine after tetrodotoxin was abolished by hyoscine (4 ng/ml). Isolated longitudinal muscle strips were so prepared to be innervated or denervated. Both types of strip gave similar bradykinin maxima but the response of the denervated strip to eserine and neostigmine was reduced to 40% of the innervated strip and the remaining response was blocked by hyoscine (2 ng/ml). It is concluded that eserine and neostigmine have an indirect action on the smooth muscle of the ileum that is the result of acetylcholine release from cholinergic nerves. Inhibition of cholinesterase would not seem to be important for this action. A second component of the action of these two drugs appears to be a direct effect on the muscarinic receptors of the smooth muscle.
The recovery of the capacity for uptake-retention of [3H]noradrenaline in rat adrenergic nerves after reserpine
Authors: HÄGGENDAL JAN , DAHLSTRÖM ANNICA
Published: April 2011

The uptake retention of [3H]noradrenaline (2.5 μg/kg, i.v., 30 min before death) in rat salivary glands was studied at different times after reserpine treatment (10 mg/kg, i.p.). The effect of removing the cervical superior ganglion 12 h before death on the recovery of the [3H]noradrenaline uptake-retention capacity after reserpine was also investigated. The ganglionectomy was unilateral, and the contralateral side was always preganglionically denervated. In glands with uninterrupted postganglionic adrenergic nerves the onset of recovery of the [3H]noradrenaline retention capacity occurred 24–36 h after reserpine. Normal contents were found on the second to third days. Between day 3 and 6 a possible overshoot of [3H]nor- adrenaline content, followed by normal and subnormal contents (7–21 days) were recorded. Ganglionectomy, 12 h before death, markedly delayed the recovery of [3H]noradrenaline retention capacity. Both the recovery curve for [3H]noradrenaline retention in glands with intact postganglionic nerves, and the effect of ganglionectomy on the [3H]noradrenaline retention capacity, were clearly related to the relative number of new functioning amine granules that are transported via the axons to the nerve terminals at different times after the reserpine-pretreatment. The results indicate that young amine granules, recently transported to the nerve terminals via the axons, have the greatest capacity to take up and retain [3H]noradrenaline. The half-life of this capacity in the young granules appears to be about 12 h. Since published results indicate that [3H]noradrenaline is initially taken up in the “small easily releasable pool” of transmitter, we suggest that young amine granules are of the greatest importance for adrenergic function, i.e. that they are particularly active in taking up recaptured noradrenaline, in the synthesis, and in the release of this transmitter.
Relations between particle shape, particle interaction and some rheological properties of hectorite dispersions
Authors: CARLESS J E , OCRAN J
Published: April 2011

The relation between viscosity and concentration of dilute aqueous hectorite (<0·2% hectorite) follows the Schulz-Blaschke equation, from which the intrinsic viscosity and particle interaction index (K) was calculated. More concentrated (up to 5·5% hectorite) dispersions possessed plastic flow properties, and a modified Schulz-Blaschke equation was used to calculate an interaction factor (K̄). A correlation was established of (K̄) and the static yield of the gels assessed by a cone and plate viscometer. The static yield value of gels was increased by the addition of sodium chloride over the range 0·001–0·005m. In the presence of 0·01m uni-univalent electrolytes the gelling power of the cations was in the order NH4 > K > Na > Li. A relation between sodium chloride concentration, hectorite concentration and static yield value of the gel was derived.
The composition of phytosterols in first and second year Digitalis purpurea L
Authors: EVANS F J
Published: April 2011

The phytosterols of Digitalis purpurea occur as lipids and as glucosides. Gas-liquid chromatography and mass-spectrometry indicated that both fractions contained sitosterol as the major component, and also varying proportions of stigmasterol, campesterol and cholesterol. Certain of the lipid fractions contained 24-methylenecholesterol. The phytosterol concentrations and relative proportions were determined at monthly intervals during the first year of growth, and also in various morphological units of second year plants. The composition of the phytosterol fractions depended upon the plant organ examined and also upon the phase of growth of the plant.
Haemodynamic and coronary effects of quazodine in cats with developing myocardial infarcts
Authors: PARRATT J R , WINSLOW EILEEN
Published: April 2011

Acute ligation of the descending branch of the left coronary artery in anaesthetized cats resulted, within 1–2 h, in a 30% decrease in local blood flow in the region mainly supplied by the ligated vessel, a fall in systemic blood pressure, in cardiac output, and in left ventricular dP/dt max (LVdP/dt). There was electrocardiographic evidence of myocardial ischaemia (pronounced ST elevation). In these animals with developing myocardial infarcts, intravenous infusions of quazodine (MJ1988; 6,7-dimethoxy-4-ethyl-quinazoline) markedly increased myocardial contractility and local myocardial blood flow in the developing infarct, and decreased systemic arterial pressure, peripheral vascular resistance and left ventricular end-diastolic pressure, effects similar to those observed in normal cats. The increase in cardiac contractility (cardiac output and LVdP/dt) occurred without a concomitant increase in myocardial metabolic heat production. This ‘oxygen sparing effect’ probably results from a decrease in left ventricular wall tension. It is suggested that quazodine warrants further investigation as a cardiac stimulant in power failure following myocardial infarction in man.
Effects of l-dopa and inhibitors of decarboxylase and monoamine oxidase on brain noradrenaline levels and blood pressure in spontaneously hypertensive rats
Authors: YAMORI YUKIO , DE JONG WYBREN , YAMABE HIROHIKO , LOVENBERG WALTER , SJOERDSMA ALBERT
Published: April 2011

Acute administration of l-dopa (200 mg/kg) resulted in a significant decrease in blood pressure of the spontaneously hypertensive (SH) rat. Simultaneous treatment with a peripheral decarboxylase inhibitor (3,4-dihydroxyphenyl-2-hydrazino-2-methylpropionic acid; MK 485) potentiated this effect while treatment with a decarboxylase inhibitor that penetrates the central nervous system (4-bromo-3-hydroxybenzyloxyamine; NSD 1055) tended to block the effect of l-dopa. In general, only treatments that increased brainstem noradrenaline were effective in reducing blood pressure. In young SH rats chronic treatment with l-dopa and a peripheral decarboxylase inhibitor significantly retarded the development of hypertension over four weeks. Treatment of SH rats with 3 daily doses (100 mg/kg each) of p-chlorophenylalanine resulted in a complete loss of 5-hydroxy-tryptamine and a slight reduction of noradrenaline in the brainstem. The blood pressure of these animals was slightly increased over that of the control SH rats. Treatment of several groups of SH rats with a monoamine oxidase inhibitor (pargyline) in various combinations with l-dopa and a peripheral decarboxylase inhibitor resulted in a wide range of noradrenaline levels in the brainstem. There appeared to be a highly significant inverse correlation between brainstem noradrenaline and blood pressure. The findings are consistent with central noradrenergic modulation of blood pressure in the rat.
The effect of pore size of the inhaler support upon the concentration of volatile drug emerging in the air stream from a nasal inhaler
Authors: Armstrong P A M , Carless J E , Enever R P
Published: April 2011

The effect that the pore size of the inhaler support has upon the concentration of methylamphetamine emerging in the airstream from a nasal inhaler has been investigated over a range of temperatures using a series of sintered glass plugs of differing porosity. The results showed that there was a reduction in the drug concentration with decrease in pore size of the plugs. An attempt was made to correlate these findings with the Kelvin equation. It was concluded that the degree of lowering of drug concentration was much greater than could be explained on the basis of this equation; and that this was due to the fact that the airstream was not saturated with the drug vapour. The degree of undersaturation appeared to be related to the porosity of the plugs.
Effect of inosine on guinea-pig bronchial muscle
Authors: Bertelli A , Bianchi C , Beani L
Published: April 2011

Inosine, like other purine derivatives, shows antibronchospastic effects both in vivo and in vitro. Its activity remains in propranololor α-methyl-p-tyrosine-pretreated guinea-pigs, but is prevented by theophylline. Moreover, the interaction between 3′5AMP and inosine suggests potentiation. In view of recent findings showing that inosine inhibits phosphodiesterases, the conclusion is drawn that the antibronchospastic effect of this nucleoside depends on the increase of 3′5′AMP intracellular levels in the bronchial muscle.
Application of orthogonal functions to correct for quadratic irrelevant absorption in spectrophotometric analysis
Authors: Wahbi A M , Abdine H
Published: April 2011

The seven-point correction method of Ashton and Tootill has been examined. The method is generalized for other groups of points from n = 5 to n = 14. Glenn's method of orthogonal functions proved to be suitable for assaying cyclandelate in the presence of interference with quadratic curvature.
Effect of ethanol on the hydroxylation of tyrosine and tryptophan in rat brain in vivo
Authors: Carlsson Arvid , Lindqvist Margit
Published: April 2011

Various doses of ethanol were injected intraperitoneally into rats. After 20 min, 3-hydroxybenzylhydrazine (NSD 1015), an inhibitor of aromatic amino-acid decarboxylase was injected and 30 min later the animals were killed. The amount of dopa accumulating in brain as a consequence of decarboxylase inhibition was significantly increased by moderate doses of ethanol (up to 4 g kg−1). There was no corresponding effect on 5-hydroxytryptophan. The effect on dopa was found both in a dopamine- and a noradrenaline-dominated area of the brain, suggesting that catecholamine synthesis is stimulated by ethanol in both types of neuron. The data lend support to the hypothesis of Carlsson, Engel & Svensson (1972) that cerebral catecholamines are involved in the central stimulation induced by ethanol.
Plasma half-lives, plasma metabolites and anticoagulant efficacies of the enantiomers of warfarin in man
Authors: Hewick David S , McEwen John
Published: April 2011

S-(-)-Warfarin was found to be a more potent anticoagulant than R-(+)-warfarin in man. However, S-warfarin was cleared more rapidly from the plasma; respective mean plasma half-lives (from four subjects) for R and S-warfarin were 45ṁ4 and 33ṁ0h. Unlike the assay of Lewis, Ilnicki & Carlstrom (1970), the assay of Corn & Berberich (1967) for measuring plasma warfarin gave spuriously long half-life values, particularly with R-warfarin. The apparent volumes of distribution of the enantiomers were not significantly different. A major plasma metabolite detected was warfarin alcohol1, which was seen in much greater quantities after giving R-warfarin than after S-warfarin. The corresponding diastereoisomer, warfarin alcohol2, was seen in trace amounts after S-warfarin only.
Kinetics of hydrolysis of polyoxyethylene (20) sorbitan fatty acid ester surfactants
Authors: Bates Theodore R , Nightingale Charles H , Dixon Edward
Published: April 2011

The kinetics of the hydrolysis of the oleate ester of polyoxyethylene (20) sorbitan (Tween 80) in aqueous buffers were studied at an initial concentration of 0ṁ020% (w/v) and over the pH range of 1ṁ10 to 10ṁ28. The hydrolysis appears to be specific acid-catalysed at pH values below 3 and specific base-catalysed at pH values greater than 7ṁ6. The pseudo first-order rate constants for hydrogen and hydroxyl ion catalysis were determined, and the temperature and ionic strength dependence of the acid-catalysed reaction was studied. Both the initial, acid- and base-catalysed hydrolysis of Tween 80 exhibited an unusual initial, micellar surfactant concentration-rate dependence, opposite to that previously reported for the hydrolysis of anionic surfactants of the n-alkyl sulphate-type. Specifically, as the initial concentration of Tween 80 was increased above its reported critical micellar concentration, there was a progressive, marked decrease in the rate of the reaction, with the rate eventually reaching a plateau value between 0ṁ100 and 1ṁ00% (w/v). It is suggested that this behaviour is due to alterations in the micellar state of the surfactant as its concentration is increased. The influence of the chemical structure of the Tween surfactant on the acid-catalysed hydrolysis reaction at 80° was also examined using the oléate (Tween 80), stéarate (Tween 60), and palmitate (Tween 40) esters of polyoxyethylene (20) sorbitan.
The reflection of ejecting and retaining currents in the time-course of neuronal responses to microelectrophoretically applied drugs
Authors: Bradshaw C M , Szabadi E , Roberts M H T
Published: April 2011

The role of ejecting and retaining currents in determining the time-course of neuronal responses to microelectrophoretically applied drugs (acetylcholine, glutamate, noradrenaline, 5-hydroxytryptamine, and mescaline) was investigated. Comparing the parameters of excitatory responses to ejecting currents of successively increasing intensity, the following changes were observed: the response latency became progressively shorter, the plateau became higher, and the recovery time was prolonged. An increase in the intensity or duration of the pre-ejection retaining current resulted in the prolongation of the response latency and the latency to plateau, but did not alter the plateau itself. An increase in the intensity of the post-ejection retaining current reduced the recovery time of the response.
Quantitation of Δ1-tetrahydrocannabinol in plasma from cannabis smokers
Authors: Agurell Stig , Gustafsson Bertil , Holmstedt Bo , Leander Kurt , Lindgren Jan-Erik , Nilsson Inger , Sandberg Finn , Asberg Marie
Published: April 2011

A method to identify and accurately measure non-labelled Δ1-tetrahydrocannabinol (Δ1-THC) in blood of cannabis smokers has been developed. It consists of the following steps: To a 5 ml plasma sample is added deuterated Δ1-THC (Δ1-THC-d2) as internal standard. After extraction with light petroleum and evaporation, the Δ1-THC containing fraction is separated by chromatography on Sephadex LH-20 (1 times 40 cm) using light petroleum-chloroform-ethanol (10:10:1) as eluant. A fraction containing Δ1-THC is collected and subjected to mass fragmentography (LKB 9000; 3% OV-17/Gas-Chrom Q; 230°). The mass spectrometer was adjusted to record the intensities of m/e 299 and 314 of Δ1-THC and m/e 301 and 316 of Δ1-THC-d2. The standard curve was made by plotting peak height m/e 299/m/e 301. Peak levels of 19–26 ng ml−1 were reached within 10 min after smoking a cigarette containing 10 mg Δ1-THC.
Differential effects of amphetamine, fenfluramine and norfenfluramine stereoisomers on the increase of striatum homovanillic acid in rats
Authors: Jori A , Dolfini E , Tognoni G , Garattini S
Published: April 2011

(+)-Amphetamine is more effective in increasing the concentration of striatum homovanillic acid (HVA) in rats than the (-)-isomer while the (-)-isomers of fenfluramine and norfenfluramine are more active than their (+)-isomers. The concentrations of the drugs in the striatum do not explain the difference observed between the isomers on striatum HVA. Fenfluramine does not appear to act on striatum HVA through the formation of norfenfluramine.
The effect of oral administration of various sugars on blood ethanol concentrations in man
Authors: Clark E R , Hughes I E , Letley E
Published: April 2011

Urine output and blood ethanol concentrations have been measured in volunteers for 2 h after the administration of a standard oral dose of ethanol (0.798 g kg−1) given 30 min after a large oral dose of one of several sugars in 200 ml water. Both fructose (125 g) and sorbitol (125 g) produced large reductions in urine output and blood-ethanol concentrations for the duration of the experiment when compared with controls. Galactose (125 g) had a similar but transient effect and smaller doses of fructose (62.5 g) were without these actions. It is concluded that the effects observed can be explained in terms of alterations in absorption of ethanol and water from the gastrointestinal tract.
Oscillatory testing of o/w emulsions containing mixed emulsifiers of the surfactant/long chain alcohol type: Influence of surfactant chain length
Authors: Barry B W , Eccleston G M
Published: April 2011

A Weissenberg Rheogoniometer with parallel plates coupled to a Solartron Digital Transfer Function Analyser was used at 25° in oscillatory mode to investigate liquid paraffin-in-water emulsions stabilized by alkyltrimethylammonium bromides (of C12-C18 chain lengths) and cetostearyl alcohol. Ternary systems, formed by dispersing the quaternary surfactants and cetostearyl alcohol in water, were similarly examined. Each preparation was tested in the linear viscoelastic region and fundamental rheological parameters, the storage modulus (G') and the dynamic viscosity (η′), were derived as functions of frequency over the range 7.91 × 10−4 to 25 Hz. The rheological properties of the emulsions were related to viscoelastic gel networks present in the continuous phases. The corresponding ternary system parameters implied that these networks were formed by the interaction of cetostearyl alcohol and aqueous surfactant solution. Ternary systems and emulsions behaved similarly with respect to frequency. As this increased, G' rose and η′ fell, the latter through several logarithmic decades. At low frequencies, G' and η′ rose as the quaternary alkyl chain length increased. Formulations containing quaternary surfactants of medium chain lengths (C14 and C16) formed strong viscoelastic networks. The C12 systems contained tenuous networks, and networks formed from the C18 surfactant were not as rigid as predicted by the trend of the lower homologues. The oscillatory data were compared and correlated with creep data described previously.
Biliary excretion kinetics of Phenolphthalein glucuronide after intravenous and retrograde biliary administration
Authors: Gustafson J H , Benet L Z
Published: April 2011

Several organic compounds of large molecular weight have previously been shown to be rapidly and primarily excreted via the biliary system of the rat after intravenous or retrograde biliary infusion. Poor biliary reabsorption has been suggested to explain these findings. The kinetics of the biliary excretion of Phenolphthalein glucuronide have been examined with concurrent plasma data. A spectrophotometric method, capable of measuring Phenolphthalein glucuronide in amounts as small as 4 nmol per 100 μl of plasma, was developed. The glucuronide (20–40 μmol kg−1) was administered to 14 rats intravenously and to 12 rats by retrograde biliary infusion. There was a significant concentration of Phenolphthalein glucuronide in the systemic blood after glucuronide administration by either route and the kinetics of elimination of the glucuronide were similar. The plasma availability of biliary infused doses was over 45 % of the availability from the intravenous doses based on area under the curve calculations for the average plasma level-time curves. The results demonstrate the need to sample the plasma as well as the bile before any conclusion can be made about reabsorption of a compound from the biliary ducts.
A comparative study of the effect of some centrally acting skeletal muscle relaxants in mice
Authors: Cymbalist M A , Shapero M
Published: April 2011

The possibility of differentiating between sedative-hypnotics and centrally acting muscle relaxants has been investigated in mice. The ED50 values for loss of muscle tone and loss of righting reflex were determined for 2-(3î,6î-dioxaheptyl) aminomethyl-1,4-benzodioxane (ambenoxan), 2-(4î,7î-dioxaoctyl) aminomethyl-1,4-benzodioxane (WB 4123) and compared with mephenesin, meprobamate, methocarbamol and the sedative-hypnotic, sodium pentobarbitone. Comparison of the slopes of the regression lines for hypotonia and loss of the righting reflex for the compounds suggests that ambenoxan offers a greater separation between the two responses than clinically used muscle relaxants.
A study of the interaction of tetracycline with human serum lipoproteins and albumin
Authors: Powis G
Published: April 2011

The interaction of 7-[3H]tetracycline at therapeutic concentrations with human serum proteins has been studied by dialysis and by molecular exclusion chromatography. In serum, 53% of tetracycline is in the form of complexes with protein: 54% with albumin; 13% with low density lipoprotein; 19% with high density lipoprotein; 6% with very high density lipoprotein and 8% with other serum proteins. Albumin possesses two binding sites for tetracycline, one a high affinity, low capacity site and the other a low affinity, high capacity site. At therapeutic concentrations three quarters of the tetracycline bound to albumin is associated with the low affinity site. Tetracycline appears to dissolve in the lipophilic portion of the lipoprotein molecule, rather than to be associated with specific binding sites.
Metabolism of heptabarbitone
Authors: Gilbert J N T , Millard B J , Powell J W , Whalley W B
Published: April 2011

The human metabolism of 5-ethyl-5-cycloheptenylbarbituric acid, heptabarbitone, Medomin, taken orally, has been studied. Comparison of g.c., and g.c.-m.s. data, from derivatized urine extracts, with data from authentic synthetic samples, has shown that 5-(3î-oxocycloheptenyl)-5-ethylbarbituric acid (II) and 5-(3î-hydroxycycloheptenyl)-5-ethylbarbituric acid (III) are major metabolites of heptabarbitone. In addition, similar data have been obtained for a third metabolite. There was no evidence for the presence of the parent drug in the urine of the two volunteers. The rate of urinary excretion of the three metabolites is briefly discussed.
The sorption of benzocaine from aqueous solution by nylon 6 powder
Authors: Richardson N E , Meakin B J
Published: April 2011

The sorption of benzocaine by nylon 6 powder from aqueous solution has been examined under varying environmental conditions. The extent of sorption increases with increase in electrolyte concentration, and with pH up to about pH 4. Increasing temperature reduces the amount of drug sorbed. In all cases, the sorption isotherms were linear over the concentration ranges studied, and can be described by a simple distribution law which allows the effects of ionic strength and pH to be predicted. The interaction is believed to involve hydrogen bond formation between benzocaine and the amide groups of the nylon after penetration of the polymer matrix by the drug.
In vivo estimation of tyrosine hydroxylation in the dopaminergic terminals of the rat neostriatum
Authors: Javoy F , Agid Y , Bouvet D , Glowinski J
Published: April 2011

An approach has been developed to distinguish dopamine synthesis from its release and utilization in dopamine terminals of the rat neostriatum (NCP). It enables a direct in vivo estimation of tyrosine hydroxylation, a rate limiting step in dopamine synthesis. Locally injected l-3,5[3H]tyrosine is converted to [3H]dopamine in the NCP. The conversion of the labelled tyrosine into [3H]dopa leads to local accumulation of [3H]water (3H-H2O). The initial accumulation (3 min) of the 3H-H2O levels in tissues gives a good reflection of the rate of tyrosine hydroxylation occurring in the dopamine terminals of the nigro-striatal pathway. In effect, 3H-H2O formation (1) disappeared after elective degeneration of the nigro-neostriatal dopamine neurons, (2) was inhibited by α-methyl-p-tyrosine, (3) was not affected by intraperitoneal injection of urea, which is known to reduce brain water content, (4) moreover, 3H-H2O accumulation was enhanced by various neuroleptic drugs and inhibited by (+)-amphetamine. Finally, Ro 4–4602 an inhibitor of dopa-decarboxylase reduced 3H-H2O formation 30 min after its injection.
Measurement of the ‘spontaneity’ of self-emulsifiable oils
Authors: Groves M J , Mustafa R M A
Published: April 2011

Self-emulsifiable oils are solutions of surfactants in non-polar solvents which spontaneously form emulsions when added to water. Measurement of the degree of spontaneity has remained subjective. Accordingly, a method has been devised in which a small volume of the oil solution is injected into a flowing stream of water and carried across an intense beam of parallel light from a helium-neon laser. Light scattered from the beam by the dispersed oil droplets is collected by means of fibre optics onto an array of silicon photodiodes and the amplified output is integrated as a function of time. By varying the flow rate of the water stream it is possible to estimate the time required for an emulsifying system to come to its equilibrium state of dispersion under the conditions of the experiment, the ‘spontaneity’ of emulsion formation. Under the experimental conditions employed, systems comprising solutions of phosphated nonylphenolethoxylate (PNE) and phosphated fatty alcohol ethoxylate (PFE) in n-hexane came to equilibrium between 5 and 12 s, depending on the constitution. These times could be approximately correlated with the values for spontaneity estimated by the CPAC dilution test, although this latter test is somewhat subjective. The spontaneity appears to depend on the nature of the material existing within the phase diagram and the anomalous results obtained may be accounted for by the likely presence of a complex formed at the emulsion interface between the PNE, PFE and water during the dispersion process.
Prostaglandins and the anti-inflammatory activity of a human plasma fraction in carrageenan-induced paw oedema in the rat
Authors: Smith M J H , Ford-Hutchinson A W , Elliott P N C , Bolam J P
Published: April 2011

A fraction prepared from normal human plasma inhibits the swelling of the acute carrageenan-induced paw oedema in the rat. Treatment of the animals with prostaglandin E1, arachidonic acid or with substances which either block the formation of prostaglandins or antagonize their action showed that these mediators are concerned in the development of the paw oedema. The anti-inflammatory effect of the plasma fraction in the carrageenan reaction does not involve a specific interference with the prostaglandin system. The plasma fraction is not an inhibitor of the action of SRS-A on the guinea-pig ileum.
An automated sedimentation balance
Authors: Topham John D
Published: April 2011

A method of size grading powders using an automated sedimentation balance is described. The results are recorded as percentages of the total powder present in 1 or 5 μm (intervals) of particle size, after they have been multiplied by a simple correction factor. Analyses of calcium carbonate powder using this balance and the Gallenkamp balance have been compared.
Comparison of the β-adrenoceptors in the myocardium and coronary vasculature of the kitten heart
Authors: Cornish E J , Miller R C
Published: April 2011

The relative potencies of (–)-noradrenaline, (–)-adrenaline, (±)-isoprenaline and (±)-salbutamol have been assessed for their positive inotropic and chronotropic actions on kitten isolated atria. These relative potencies have been compared with those obtained for the relative coronary dilator potencies in two preparations. These were intact hearts perfused by Langendorff’s method and isolated perfused coronary arteries from the kitten. The relative molar potencies for inotropic effects were noradrenaline 1: adrenaline 1: iso-prenaline 7: salbutamol 0.6. The observed ratios for chronotropic effects were not significantly different from those for inotropic effects. The relative potencies of noradrenaline, adrenaline and isoprenaline as myocardial stimulants were similar to their relative potencies as coronary dilators in the intact heart. Similar relative potencies for noradrenaline and isoprenaline were also found in the isolated coronary artery but adrenaline was only one third as active as noradrenaline on this preparation. In both the intact heart and in the isolated coronary artery salbutamol was about one tenth as active as noradrenaline. It was therefore less active relative to noradrenaline as a coronary dilator than as a myocardial stimulant. In spite of these differences in relative potency ratios for myocardial and coronary dilator effects, similar dissociation constants (KB values) for practolol against isoprenaline were found in driven atria and in isolated coronary arteries. Myocardial and coronary vascular β-adrenoceptors thus can both be placed in the general classification of β1-adrenoceptors.
Construction and implantation of a cannula system for repeated injections into localized regions of the rat brain
Authors: Harvey Elizabeth A , Stephens R J
Published: April 2011

The construction and method of implantion of a brain cannula for chronic use in rats is described. All the components of the cannula system are easily made from stainless steel tubing and no machined parts are required. The use of a metal key eliminates the need for tapped holes during implantation. Although little time is required to prepare each animal the system remains firmly fixed to the skull and allows injections to be made accurately into selected brain areas.
Metabolism of quinalbarbitone
Authors: Gilbert J N T , Hetherington W L , Powell J W , Whalley W B
Published: April 2011

The human metabolism of (±)-5-allyl-5-(1′-methylbutyl) barbituric acid (I), quinalbarbitone, taken orally, has been studied. Comparison of g.c. and g.c.-m.s. data from derivatized extracts of urine with similar data from synthetic samples confirmed the presence of the two diastereoisomeric forms of 5-allyl-5-(3′-hydroxy-1′-methylbutyl) barbituric acid (II), 5-allyl-5-(3′-oxo-1′-methylbutyl) barbituric acid (III), 5-allyl-5-(1′-methyl-3′-carboxypropyl) barbituric acid (IV), and 5-(2′,3′-dihydroxypropyl)-5-(1′-methylbutyl) barbituric acid (V) in the urine. There was no evidence for the urinary excretion of unchanged drug. The rate of excretion of these metabolites has been examined in some detail, and rate-limited kinetics shown to apply for excretion of the acid (IV) and the diol (V).
Aggregation of antihistamines in aqueous solution. The effect of electrolyte on the micellar properties of some diphenylmethane derivatives
Authors: Attwood D , Udeala O K
Published: April 2011

The effect of sodium chloride on the micellar properties of the antihistamines, diphenhydramine hydrochloride, bromodiphenhydramine hydrochloride, chlorcyclizine hydrochloride and diphenylpyraline hydrochloride in aqueous solution has been investigated by light scattering and viscometric methods. The drugs behaved as typical ionic surfactants showing an increase in aggregation number and decrease in critical micelle concentration as the electrolyte concentration was increased over the range 0.05 to 0.154 mol kg−1. A linear relation between log critical micelle concentration and log counterion concentration was established, from which values of the degree of ionization and the free energy of micellization were calculated. The intrinsic viscosity was decreased by the addition of electrolyte and this has been attributed to a decrease in micellar hydration due to a removal of hydrogen-bonded water.
A rapid gas-liquid chromatographic estimation of nicotine in biological fluids
Authors: Feyerabend C , Levitt T , Russell M A H
Published: April 2011

A rapid gas-liquid chromatographic method for the estimation of nicotine in plasma is described. Nicotine is extracted from alkalinized plasma into diethyl ether. This is then concentrated by evaporation and, after an acid back extraction is re-extracted into n-heptane (nitrogen detector) or dichloromethane (flame ionization detector) before injection onto the gas chromatograph. Thirty samples a day can be analysed by this method which enables concentrations of 0.1 ng ml−1 nicotine to be measured. It is thus possible to measure nicotine in plasma and urine samples from non-smokers.
The surface activity of the alveolar lining layer of guinea-pig lung following anaphylaxis
Authors: Goadby P
Published: April 2011

The surface activity and lipid composition of alveolar extracts of guinea-pig lung following anaphylaxis have been studied. The extracts showed a reduced ability to lower surface tension on compression of the surface film which was maximal 30 min after challenge. No significant changes in the lipid content were found but there was a marked increase in the soluble solids 10 min after anaphylactic shock. The significance of these findings is discussed.
Effects of thioridazine and diazepam on the pharmacokinetics of [14C]imipramine in rat: acute study
Authors: Beaubien Arthur R , Mathieu Lise F , Coldwell Blake B
Published: April 2011

The pharmacokinetics of [14C]imipramine (10 mg kg−1) were tested in male Wistar rats for interaction with thioridazine (16 mg kg−1) or diazepam (10 mg kg−1). All drugs were administered orally with the test substances being given 40 min before [14C]imipramine dosing. Bile and urine were collected for 90 min after the radioactive drug was given. The animals were then killed and the tissues removed. Thioridazine reduced the excretion of radioactivity into the bile and urine, and increased the weight of the contents within the gastrointestinal tract. These effects were interpreted as being mainly due to a reduction in gastrointestinal motility resulting in a slower stomach emptying of [14C]imipramine. No effect on metabolism was detected. Diazepam pretreatment reduced the concentration ratio of radioactivity in the small intestinal contents to that of plasma, but did not alter the tissue distribution, metabolism or excretion of [14C]imipramine.
Dopamine receptor blockade and the neuroleptics, a crystallographic study
Authors: Horn Alan S , Post Michael L , Kennard Olga
Published: April 2011

The X-ray structures of 12 drugs of the tricyclic class having varying pharmacological profiles have been examined in detail in an attempt to rationalize the known structure-activity relations of neuroleptic drugs with respect to their ability to block dopamine receptors in the brain. Further evidence is presented in support of the theory that the neuroleptics are able to block dopamine receptors because of a conformational complementarity between certain portions of these drugs and dopamine.
Chemical reactions involved in penicillin allergy: kinetics and mechanism of penicillin aminolysis
Authors: Tsuji Akira , Yamana Tsukinaka , Miyamoto Etsuko , Kiya Emi
Published: April 2011

In view of the fundamental importance of the reaction of penicillins with amino groups of proteins to the penicillin allergy, the aminolysis of benzylpenicillin by various amines was kinetically investigated. The formation rate constants, kamide, of benzylpenicilloylamides were determined at 35°, 45° and 60° (μ = 0·5), and found to obey the general rate law: kamide = k1[amine] + k2[amine H+] [amine] + k3[amine]2 + k4[amine]aOH. All of the amines exhibited the unassisted nucleophilic rate constant, k1. The relative importance of the other kinetic terms depends on the basicity and the chemical structure of amines. The reaction mechanism of penicillin aminolysis was discussed. Brønsted relations for k1, k2 and k3, except for hydrazines, were satisfactory.
A comparison of the effects of morphine and pethidine upon body temperature and the reversal of reserpine's effects upon body temperature in the mouse
Authors: Menon Alexandra M , Pleuvry Barbara J
Published: April 2011

The effects of morphine and pethidine upon body temperature and upon the reversal of reserpine hypothermia in the mouse were investigated. Both morphine and pethidine produced a dose-dependent fall in body temperature, that of morphine being totally antagonized by nalorphine and partially by naloxone, while that of pethidine was antagonised by naloxone and enhanced by nalorphine. Both drugs reversed reserpine-induced hypothermia. The reversal by morphine, but not by pethidine, was partially antagonized by naloxone. Adrenalectomy prevented the reversal of reserpine hypothermia by pethidine but morphine produced a partial reversal. Ganglion blockade and α-and β-blockade all prevented reversal of reserpine hypothermia by both drugs. The results are discussed with regard to differences between pethidine and morphine and possible involvement of opiate receptors.
Methods for study of fluphenazine kinetics in man
Authors: Whelpton R , Curry S H
Published: April 2011

Fluphenazine and its principal metabolites, fluphenazine sulphoxide, and 7-hydroxyflu-phenazine were identified and quantified in human plasma, urine and faeces following intramuscular and oral administration of 14C-fluphenazine dihydrochloride. The presence of a conjugate fraction was also noted. Unmetabolized fluphenazine was selectively extracted into n-heptane. The metabolites were separated by solvent extraction into toluene. Conjugates were hydrolysed back to fluphenazine, fluphenazine sulphoxide and 7-hydroxyfluphenazine. Fluphenazine and fluphenazine conjugates were also measured in the urine of patients receiving long term non-radioactive fluphenazine decanoate therapy. The urinary excretion rate of the conjugate fraction was systematically related to the plasma concentration, regardless of urine flow rate or pH, providing a convenient method for the assessment of fluphenazine kinetics by urinary excretion studies not involving administration of labelled drug.
The adhesion of film coatings to tablet surfaces— instrumentation and preliminary evaluation
Authors: Fisher D G , Rowe R C
Published: April 2011

The strength of the adhesive bond between a film coating and a tablet surface has been studied using a specially designed tensile testing apparatus. The adhesion has been taken as the force require to remove the film from unit area of the tablet surface and has been shown to be dependent on the compression pressure used to prepare the tablet and on changes in the film formulation. Although plasticizers did not show any significant effect on the adhesion of a hydroxypropyl methylcellulose film, a reduction of 45 % was found on the addition of 10 % w/w titanium dioxide.
Size analysis of suspension inhalation aerosols by inertial separation methods
Authors: Hallworth G W , Andrews U G
Published: April 2011

The particle size distribution of beclomethasone dipropionate (BDP) aerosols delivered from pressurized metered dose suspension inhalers has been measured with three cascaded inertial separation instruments, the Casella Cascade Impactor, Multistage Liquid Impinger and Cascade Centripeter. Various methods for collecting the emitted aerosol before measurement have been examined. A bent glass tubular ‘throat’, used as a simulated oro-pharynx, collects 35–60 % of the emitted dose by impingement of the wet spray cone in the throat. The aerosol passing through the throat has a similar but somewhat finer size distribution to that collected by firing directly into a large flask. The three cascaded instruments give similar results which in the Multistage Liquid Impinger also resemble those given by a salbutamol inhaler. The mass fraction (35–60%) emitted from the oral adaptor which is of a size capable of deep lung penetration (<4 μm) is much higher than the fraction (10–16%) found in the lungs of dogs after inhalation of aerosol. The size distributions resemble those determined by microscopy and are expressed as aerodynamic sizes, thus showing that the particles approximate to unit density spheres. The performance of two simpler devices, Kirk's apparatus and the Harwell size selective air sampler are also assessed, the latter shows some promise for the simple evaluation of the respirable fraction of inhalation aerosols.
The influence of crystal form on the radial stress transmission characteristics of pharmaceutical materials
Authors: Summers M P , Enever R P , Carless J E
Published: April 2011

Various crystal forms of sulphathiazole, barbitone and aspirin were compressed in a single-punch tablet machine instrumented to monitor axially applied and radially transmitted forces, and upper punch movement. The changes in radial stress during the compression cycle depended upon the polymorphic form of the compressed material. The results were rationalized in terms of the degree of plastic flow/crushing that occurred with each material, and the degree to which the final compact underwent elastic compression. It is postulated that the reduction in the transition temperature of polymorphic forms of sulphathiazole and barbitone and the polymorphic transition of sulphathiazole Form II was due to the production of dislocations in the crystal and the distortion of the crystals at crystal boundaries formed in the compressed materials.
The transport of tetracyclines across the mouse ileum in vitro: the effect of cations and other agents
Authors: Banerjee Sachchidananda , Chakrabarti Kalyan
Published: April 2011

The intestinal transfer of different tetracyclines dissolved in calcium-and magnesium-free Krebs bicarbonate buffer solution, pH 7·4, was studied using the everted ileum of the mouse. The rates of transfer of chlortetracycline and demethylchlortetracycline were less than those of tetracycline and oxytetracycline, the latter compounds being transferred at the same rate. Addition of calcium and magnesium to the buffer greatly reduced the transfer of tetracycline; this inhibition could be antagonized by EDTA. The presence of iron also inhibited the transfer of tetracycline. The inhibitory effect of these ions on tetracycline transfer seemed due to chelation of the drug. Glucosamine and acetylmethionine, but not acetyl glucosamine, diminished the intestinal transfer of tetracyclines. The former two agents did not influence the uptake of tissue fluids. Tetracycline was also transferred from the serous to the mucous coat in the non-everted intestinal sac of mice. The above observations suggested that the absorption of tetracyclines was not due solely to passive diffusion.