bluuebunny/crossref_metadata_2025 huggingface dataset:
Dopamine-sensitive adenylate cyclase in canine renal artery
Authors: Murthy Vadiraja V , Gilbert Jean-Claude , Goldberg Leon I , Kuo J F
Published: April 2011

To characterize further a putative dopamine receptor in the renal artery, the effects of dopamine on canine renal artery adenylate cyclase activity were studied. Since the femoral artery is thought to be devoid of a similar dopamine receptor, the effects of dopamine on the adenylate cyclase activity of the canine femoral artery were also studied. In tissues from dogs with or without phenoxybenzamine pretreatment, renal artery adenylate cyclase was maximally stimulated by 4 μm dopamine, compared to 20 μm required for the femoral artery enzyme. The concentrations of isoprenaline required to maximally stimulate renal and femoral artery adenylate cyclase were 0·04 and 0·2 μm, respectively. In tissue from the phenoxybenzamine-pretreated dog, the stimulatory effect of dopamine on the renal artery enzyme was selectively blocked by 0·01 μm haloperidol, but not by 0·2 μm propranolol. In the femoral artery, however, the dopamine stimulation was blocked by both antagonists. Stimulation by isoprenaline of renal and femoral artery adenylate cyclase was blocked by propranolol. These data suggest the concept that dopamine interacts with a specific artery receptor apparently different from α- and β-adrenoceptors.
Dioxygenated metabolites of cannabidiol formed by rat liver
Authors: Martin Bill , Agurell Stig , Nordqvist Marianne , Lindgren And Jan-Erik
Published: April 2011

The metabolism of cannabidiol (CBD) was studied in vitro using a 10 000 g supernatant from rat liver. After removal of unchanged CBD and its monohydroxylated metabolites, a polar fraction remained from which ten dioxygenated metabolites were isolated. Mass spectrometry and nuclear magnetic resonance spectroscopy were used to identify the following metabolites: 6,7-dihydroxy-CBD, 1″,7-dihydroxy-CBD, 3″,7-dihydroxy-CBD, 4″,7-dihydroxy-CBD, 5″,7-dihydroxy-CBD, 2″,6-dihydroxy-CBD, 3″,6β-dihydroxy-CBD, 4″,6β-dihydroxy-CBD (tentative), 3″-hydroxy-6-oxo-CBD, and 4″-hydroxy-6-oxo-CBD. The abundance of isolated dihydroxy metabolites reflected the quantity of monohydroxy metabolites that was previously found. In both series, 7-hydroxylation occurred to the greatest extent. Side chain hydroxylation occurred predominantly at C-4″ and to a lesser degree at C-3″. Trace amounts of metabolites were hydroxylated at C-1″, -2″, or 5″.
Effects of various diuretic agents in the mouse
Authors: Sim M F , Hopcroft R H
Published: April 2011

Diuretic effects of seven orally-acting diuretic agents have been examined in the mouse. The following compounds, examples of various types of orally active compound available, produced their characteristic diuretic effects: bendrofluazide, frusemide, ethacrynic acid, acetazolamide, triamterene, aminophylline and Su 15049A. The diuretic effects of the various agents were demonstrated under both water and saline-loading conditions. After allowing for differences in baseline sodium excretion, all diuretics except acetazolamide caused a further enhancement of sodium excretion after saline-loading compared with water-loading tests. The mouse possesses several advantages over the more commonly used rat since the range of diuretic responsiveness is greater. These results suggest that the mouse is a suitable species for diuretic testing.
Gels in soap stabilized emulsions
Authors: Pickett J M , Ellway K A
Published: April 2011

In some soap stabilized liquid paraffin emulsions a correlation has been found between emulsion type and the contact angle of the soap gel (the stabilizing agent) at the o/w interface. Two unrelated series of emulsions have been prepared, one series being stabilized by magnesium oleate gels and the other series by ammonium oleate gels. The soap gels were prepared by double decomposition and suppression of ionization respectively. Unlike the magnesium oleate system no inversion to w/o emulsions occurred with the ammonium oleate series. This dissimilarity is predicted from differences in the contact angles of the soap gels at the o/w interface.
Effect of disintegrant type upon the relationship between compressional pressure and dissolution efficiency
Authors: Khan K A , Rooke D J
Published: April 2011

Four tablet disintegrants: a relatively insoluble sodium carboxymethyl cellulose, casein formaldehyde, calcium carboxymethyl cellulose and a cross-linked polyvinylpyrrolidone have been evaluated. Three widely used disintegrants, sodium carboxymethyl cellulose, sodium starch glycolate and a cation exchange resin were included for comparison. The effect of compressional pressure on the disintegration and dissolution behaviours of a soluble and an insoluble system containing different disintegrants was examined. The results show that disintegrant type can have a pronounced effect upon the relationship between compressional pressure and dissolution efficiency. The significance of this relationship is discussed in terms of the properties of disintegrants and the differing mechanisms by which they act.
5-Hydroxytryptamine is a substrate for both species of monoamine oxidase in beef heart mitochondria
Authors: Mantle T J , Houslay M D , Garrett N J , Tipton K F
Published: April 2011

The activity of beef heart mitochondrial monoamine oxidase towards 5-hydroxytryptamine (5-HT) is inhibited by the selective inhibitors clorgyline, PCO [5-phenyl-3-(N-cyclopropyl)-ethylamine-1,2,4-oxadiazole] and Deprenyl with a biphasic dependence on the inhibitor concentration. The activities towards tyramine, dopamine and tryptamine were also inhibited in a biphasic manner, but the apparent proportions of the two enzyme species active on dopamine and tryptamine depended on the inhibitor used. Phenethylamine oxidation was inhibited in a monophasic manner suggesting that only a single enzyme species was responsible for the oxidation of this substrate. The biphasic response of 5-HT oxidation to inhibition by clorgyline persisted when functionally competent mitochondria were used and was unaffected by the soluble amine oxidase inhibitors semicarbazide and amino-guanidine. These results indicate that the behaviour of the beef heart enzyme towards selective inhibitors is considerably different from that of any preparations previously studied and suggest that the classification of monoamine oxidase activities into A and B types may be only of limited usefulness.
Bioanalysis of picomole amounts of acetylcholine by ion-pair partition chromatography applied to rat sciatic nerve
Authors: Ulin Birgitta , Gustavii K , Persson B-A
Published: April 2011

A method for determination of acetylcholine in small, discrete biological objects by use of ion-pair technique has been developed. Acetylcholine is extracted as an ion pair with 3,5-di-t-butyl-2-hydroxybenzenesulphonate and separated from co-extracted components by ion-pair partition chromatography with picrate as the counter ion and porous cellulose as support. The quantitative evaluation is made from the acetylcholine peak in the chromatogram obtained by ultraviolet detection. Acetylcholine has been analysed in 1 cm large pieces of rat sciatic nerve containing about 60 pmol (10 ng). The overall recovery of the method is 100 ± 10% at the 120 pmol level of acetylcholine in a sample.
Influence of various substances on prostaglandin biosynthesis by guinea-pig chopped lung
Authors: Fjalland B
Published: April 2011

Guinea-pig chopped lung tissue was used to investigate the inhibitory effect of various steroidal and non-steroidal anti-inflammatory agents, antipyretics, analgesics, local anaesthetics and psychotropic drugs on mechanically induced release of prostaglandin-like material. Low concentrations of non-steroidal anti-inflammatory agents inhibited synthesis, but other antipyretics and analgesics, and the local anaesthetics had little effect. Thymoleptics, neuroleptics and monoamine oxidase inhibitors except phenelzine exhibited weak activity. It is concluded that the method is a useful pharmacological model to study prostaglandin biosynthesis. The weak effects of the psychotropic drugs suggest that they do not exert their clinical effect by inhibiting PG biosynthesis.
Metabolic TV-oxidation of atropine, hyoscine and the corresponding nor-alkaloids by guinea-pig liver microsomal preparations
Authors: Phillipson J D , Handa S S , Gorrod J W
Published: April 2011

Incubation of guinea-pig liver microsomal preparations with atropine or hyoscine resulted in the formation of the corresponding nor-alkaloids and both isomers of atropine N-oxide from atropine and one isomer of hyoscine N-oxide from hyoscine. Separate incubations of guinea-pig liver microsomal preparations with nor-atropine and nor-hyoscine yielded the corresponding hydroxylamines. The N-oxide and hydroxylamine metabolites were identified by comparison of their t.l.c. behaviour and m.s. with prepared compounds and also by their reduction to the corresponding tertiary or secondary amines.
The microsomal N-oxidation of phentermine
Authors: Beckett A H , Bélanger P M
Published: April 2011

The microsomal N-oxidation of phentermine (Ia) to N-hydroxyphentermine (Ib) and to α,α-dimethyl-α-nitroso-β-phenylethane (Ic) was investigated. Maximum activities were obtained with microsomal (9000 g supernatant and microsomes) fractions of rabbit liver in the presence of an NADPH generating system. Incubation of Ia with hepatic washed microsomes from a phenobarbitone pretreated rabbit increased the formation of Ib and decreased that of Ic but the total amount of N-oxidized metabolites (i.e. Ib + Ic) was not affected. The ratio of the metabolically produced Ic to Ib but not the total amount of N-oxygenated metabolites varied greatly depending of the liver microsomal fractions used in the incubation mixtures of Ia; more Ib was produced from Ia using 9000 g supernatant and conversely, more Ic was formed using the washed microsomes of the same liver. The nitroso compound (Ic) was metabolically reduced to Ib and Ib to Ia by the hepatic 9000 g supernatant and soluble fraction; under the same conditions, washed microsomes had only limited reductive properties towards Ic and Ib. N-Hydroxyphentermine (Ib) was not metabolically oxidized to Ic when incubated with washed microsomes from rabbit liver. The use of known carbon-oxidation inhibitors showed that cytochrome P-450 is not involved in the incorporation of oxygen at the nitrogen centre of Ia. The metabolic characteristics and kinetic behaviour of the microsomal N-oxidation of Ia supported a recently proposed mechanism explaining the independent formation of Ib and Ic from a common precursor resulting from metabolic N-oxidation of Ia.
A new class of irreversible muscarinic antagonists: β-haloethylamine furoates
Authors: Rosen Gerald M , Rauckman Elmer J
Published: April 2011

The synthesis of a new class of ultra-long acting muscarinic antagonists is described. Furthermore, it is noted that the stability of the, in situ, aziridinium ion is sufficiently great so that these agents can be used to study the effect of temperature upon the conformation of the muscarinic cholinoceptor. The inactivation kinetics of these receptors as well as the dissociation constants, Kd, for all probes are presented.
The influence of polyvinylpyrrolidone on the dissolution and bioavailability of hydrochlorothiazide
Authors: Corrigan O I , Timoney R F , Whelan M J
Published: April 2011

The dissolution properties of hydrochlorothiazide - PVP 10 000 mechanical mix and co-precipitate systems were qualitatively similar to those previously reported using hydroflumethiazide. Quantitative differences were dependent on the proportion of PVP present, its molecular weight and method of incorporation. Cumulative urinary excretion data from test capsule preparations showed that bioavailability was enhanced by the presence of PVP. However, the degree of enhancement was less than that expected from constant surface area disc rate studies. Dissolution tests on the capsule formulations, using the U.S.P. basket stirrer assembly, did not correlate with in vivo results. Using the Levy beaker method and a stirring speed of 40 rev min−1, good correlation between amount dissolved in 30 min and amount excreted in urine after 24 h was obtained. The dissolution tests revealed that PVP retards the initial dissolution from capsule dosage forms, probably by retarding deaggregation and dispersion of drug particles.
Release of a drug from homogeneous ointments containing the drug in solution
Authors: Spang-Brunner Beatrice H , Speiser Peter P
Published: April 2011

The rate of release of resorcinol (5 %) from hydrogels (Carbopol, sodium carboxymethylcellulose, starch), lipogels (alcoholic-base, esteric-bases containing different amounts of beeswax with and without a spreading additive, respectively) and Labrafils has been examined. For the experimental design adopted the release of the drug is linear between 10 and 70% of the amount of drug released. The results agree well with the mathematical model postulated by Higuchi (1962) for the release of a drug from homogeneous ointments containing the drug in solution.
The absorption and elimination of metoclopramide in three animal species
Authors: Bakke O M , Segura J
Published: April 2011

The absorption and elimination of metoclopramide have been studied in the rat, rabbit and dog. Thin-layer chromatography followed by photodensitometry was used for the analysis of the unchanged drug and its metabolites. N-De-ethylation is an important Phase I metabolic reaction and conjugation with glucuronic acid and sulphate is a major route of metabolism, particularly in the rabbit. The pharmacokinetic parameters after intravenous administration showed little interspecies variation. First order elimination kinetics with short half-lives and high apparent volumes of distribution (>1·1 kg−1) were observed. Major interspecies variations were seen after oral administration of high doses of the drug. Metoclopramide was eliminated slowly after oral administration to rats. The findings in the rabbit and in the dog suggest that the liver plays an active role reducing the systemic availability of unchanged metoclopramide after oral administration.
Kininogen and kininogenase synthesis by the liver of normal and injured rats
Authors: Borges D R , Gordon A H
Published: April 2011

Isolated livers from normal rats or from others at 2 days after subcutaneous injection of turpentine have been perfused with a simplified medium. Estimation of kininogen, kininogenase and 2 plasma proteins in the perfusates thus obtained indicate that both kininogen and kininogenase are synthesized in the liver. Furthermore, because twice as much kininogen and kininogenase was synthesized by the livers from the rats which had been injected with turpentine as by those from the normal rats, these two proteins must be considered to be members of the group of plasma proteins known as acute phase reactants.
An assessment of the cardiovascular sympathectomy induced by guanethidine
Authors: Blythe T H , Hall R C , Hughes I E
Published: April 2011

Guanethidine treatment of rats (30 mg kg−1, i.p. daily for 6 weeks) produced a profound reduction in the catecholamine present (as indicated by fluorescence histochemistry and catecholamine determinations) in tissues taken from the cardiovascular system, but there was evidence of the return of catecholamines within 8 weeks. While these changes are consistent with a sympathectomy, the unaltered pressor responses to physostigmine (100 μg kg−1, i.v.) and to carotid occlusion indicate an unimpaired functional capacity of noradrenergic nerves supplying the cardiovascular system. Although part of the response may be attributed to the unaffected adrenal medulla enhanced by the presence of considerable supersensitivity as shown to exogenous noradrenaline, there would appear to be a dissociation between the results obtained from physical and functional tests of the sympathectomy induced by guanethidine.
Pharmacological studies with adenine, adenosine and some phosphorylated derivatives on guinea-pig tracheal muscle
Authors: Farmer J B , Farrar D G
Published: April 2011

Adenine, adenosine and three adenine nucleotides all caused relaxation of the guinea-pig trachea. The relaxation to the nucleotides was often preceded by a contraction. The response to adenosine and the nucleotides, but not adenine, was potentiated by dipyridamole. Imidazole inhibited the response to adenine alone. Propranolol had no effect on the response to any of the compounds. It is concluded that the guinea-pig trachea does not possess a nucleotide-specific receptor as has been postulated for some other smooth muscle preparations. An alternative hypothesis postulating an adenosine-specific receptor is presented.
Interactions of bradykinin, prostaglandin E1, 5-hydroxytryptamine, histamine and adenosine-5′-triphosphate on the dye leakage response in rat skin
Authors: Chahl Loris A
Published: April 2011

Dye leakage in rats produced by intracutaneous injections of irritants was quantitated using an azovan blue technique. Concentration-response lines were obtained for irritants alone and in presence of constant concentrations of other irritants. 5-Hydroxytryptamine (5-HT) (10−7m) potentiated histamine, bradykinin and prostaglandin E1 (PGE1), but inhibited adenosine-5′-triphosphate (ATP). Histamine (10−5m) potentiated bradykinin, PGE1 and ATP. Bradykinin (10−6m) potentiated PGE1 only, but PGE1 (10−6m) potentiated bradykinin, 5-HT and histamine. ATP (10−4m) potentiated 5-HT, histamine and PGE1. Release of ATP during stimulation of sensory nerves might explain enhanced neurogenic oedema observed in skin surrounding an area pretreated with compound 48/80.
Polymorphism of disopyramide
Authors: Gunning S R , Freeman M , Stead J A
Published: April 2011

Two crystal forms of disopyramide have been characterized using X-ray diffraction, differential scanning calorimetry and infrared spectroscopy. The kinetics of the solid state transformation of Form I to Form II has been analysed using the Prout-Tompkins theory. An activation energy of 144 kJ mol−1 is calculated for the system. Dissolution and plasma concentrations show no significant differences in bioavailability between the two polymorphs.
Brain areas involved in the catecholamine mediated regulation of electroshock seizure intensity
Authors: Stull Richard E , Jobe Phillip C , Geiger Paul F
Published: April 2011

Selective treatments which alter the catecholamine content of discrete areas of the brain were tested for their effect on electroshock seizure intensity in the rat. The data indicate that depletion of noradrenaline and dopamine in near ventricular areas by the intracerebroventricular administration of the benzoquinolizine, Ro 4–1284, enhances electroshock seizure intensity. The enhancement of seizure produced by systemic Ro 4–1284 was antagonized by the intracerebroventricular injection of noradrenaline or dopamine which do not appear to penetrate more than 1 mm into the brain. Further, pretreatment with systemic iproniazid and l-dopa completely antagonized the increased seizure intensity produced by intracerebroventricular Ro 4–1284 and repleted brain catecholamines in both near and far ventricular areas. Thus, the effects of both noradrenaline and dopamine in attenuating electroshock seizure intensity appear to be exerted principally through periventricular structures.
The properties of tablets containing microcrystalline cellulose
Authors: Sixsmith David
Published: April 2011

Tablets have been prepared from mixtures of microcrystalline cellulose (Avicel) and spray dried lactose. Tests on these showed that a maximum value of dissolution rate occurred as the percentage of the cellulose increased. This maximum was at 4% w/w for mixtures containing Avicel PH 101 and coincided with the point of maximum liquid penetration rate. With grade PH 105 this maximum was at 2% w/w and corresponded to the optimum balance between the opposing factors of disintegration and liquid penetration rate. Addition of up to 2% w/w magnesium stearate to the formulation containing 4% w/w PH 101 grade had little effect on pore structure, but decreased the dissolution rate by retarding water penetration. Similar concentrations of Carbowax 4000 caused no such decrease.
Effect of oxotremorine and sodium pentobarbitone on the pharmacokinetics of intravenous tracer doses of radioactive choline
Authors: Nordberg Agneta
Published: April 2011

The present study explains for the previous findings that oxotremorine increases and sodium pentobarbitone decreases the initial brain uptake of intravenously injected radioactive choline (3H—Ch). The effects are explained by haemodynamic changes since a corresponding increase and decrease in the plasma concentrations of 3H—Ch were found. This is important to know when 3H—Ch is used for estimation of acetylcholine turnover in the brain. The drugs did not affect the distribution of radioactivity (3H) between plasma and erythrocytes.
Possible subdivisions among α-adrenoceptors in various isolated tissues
Authors: Barker Kathryn A , Harper Barbara , Hughes I E
Published: April 2011

The ratio (expressed in log10 units) of the equieffective concentrations of (+)- and (—)-noradrenaline has been measured in a variety of isolated tissues in the presence of cocaine (1 times 10−5m), tropolone (3 times 10−5m) and (±)-propranolol (5 times 10−7 to 5 times 10−5m). The values obtained fall into 3 distinct and statistically different groups. Firstly, a high group comprising (mean ± s.e.) mouse vas deferens (2·78 ± 0·04), rabbit duodenum (2·91 ± 0·07) and ileum (2·86 ± 0·05). Secondly a middle group comprising rabbit vas deferens (2·54 ± 0·04), bladder neck muscle (2·56 ± 0·07) and spleen (2·50 ± 0·02), guinea-pig vas deferens (2·55 ± 0·10) and bladder neck muscle (2·48 ± 0·13) and rat deferens (2·40 ± 0·08) and thirdly, a low group comprising the bladder detrusor muscle from both the rabbit (2·08 ± 0·08) and the guinea-pig (2·07 ± 0·04). Under the same conditions measurement of pA2 values for phentolamine and piperoxan against noradrenaline gave the following values in rat vas deferens (8·22 ± 0·07 and 6·72 ± 0·03 respectively) and mouse vas deferens (8·31 ± 0·05 and 6·53 ± 0·07 respectively). The results are discussed in relation to other findings concerning the nature of the α-adrenoceptor in these tissues. In spite of the absence of any significant difference between the potency of the α-adrenoceptor blocking agents in the two species it is suggested that α-adrenoceptors may not belong to a single homogeneous population but may vary in their characteristics from tissue to tissue.
Effect of butaclamol, a new neuroleptic, on serotoninergic mechanisms
Authors: Pugsley T A , Lippmann W
Published: April 2011

Butaclamol (1·0–0·1 mg kg−1, i.p.) and spiroperidol (1·0–0·5 mg kg−1, i.p.), but not (—)-butaclamol (15 mg kg−1, i.p.), blocked the hyperactivity induced in rats by tranylcypromine-l-tryptophan pretreatment. Neither butaclamol nor spiroperidol altered the accumulation of brain 5-HT following pargyline or the decline of brain 5-HT following inhibition with the tryptophan hydroxylase inhibitor α-propyldopacetamide thus indicating that butaclamol and spiroperidol do not affect either the synthesis or the turnover of brain 5-HT. It is concluded that the antagonism of the tranylcypromine-l-tryptophan-induced hyperactivity by butaclamol and spiroperidol is due to their blockade of dopaminergic receptors rather than an action on neuronal serotoninergic mechanisms.
Hyperpyrexic interaction between debrisoquine and pethidine in rabbits
Authors: Osman O H , Eltayeb I B
Published: April 2011

Pethidine injection into rabbits treated with debrisoquine either acutely or chronically resulted in severe interaction and fatal hyperpyrexia. Pretreatment of rabbits with p-chloro-phenylalanine, chlorpromazine, or cyproheptadine protected them against the interaction, while α-methyl-p-tyrosine was ineffective. In addition the administration of debrisoquine into 5-HTP pretreated rabbits produced a severe interaction and hyperpyrexia. The hepatic N-demethylation of pethidine was significantly inhibited by debrisoquine pretreatment both in vivo and in vitro. The debrisoquine-pethidine interaction could be due to 5-HT potentiation or prevention of uptake. Alternatively it could be due to inhibition of biotransformation of pethidine by debrisoquine. However, neither mechanism by itself alone could be held responsible as the sole explanation of the interaction.
Synthesis and pharmacological properties of a series of antidopaminergic piperidyl benzamides
Authors: Prieto J , Moragues J , Spickett R G , Vega A , Colombo M , Salazar W , Roberts D J
Published: April 2011

The synthesis and pharmacological screening for anti-apomorphine, stomach emptying and local anaesthetic activities of some new piperidylbenzamides is described. One of these, N-(1′-benzyl-4′-piperidyl)-2-methoxy-4-amino-5-chlorobenzamide (clebopride) is more potent than metoclopramide in tests related to blockade of cerebral dopamine receptors.
Structure and rheology of cetomacrogol creams: the influence of alcohol chain length and homologue composition
Authors: Eccleston G M
Published: April 2011

Liquid paraffin-in-water emulsions prepared with cetomacrogol 1000 and alcohols cetostearyl (A), cetyl (B), stearyl (C) and myristyl (D) were examined by microscopical, particle size analytical and rheological (continuous shear, small strain creep and oscillation) techniques at 25° as they aged over 30 days. The particle sizes of the emulsions were similar and did not increase significantly with age. Thus the rheological stabilities were not correlated with particle size distributions, but rather with viscoelastic networks formed in the continuous phases when the non-ionic mixed emulsifiers interacted with water. The rheological properties of emulsions B and D differed from those of emulsion C. Emulsion A, of mixed homologue composition, showed some properties similar to each of the pure alcohol emulsions. Emulsions B and D were semi-solid immediately after preparation whereas emulsion C was so mobile initially that small strain data were not derived. On ageing, the consistencies of B and D changed slightly initially, and then remained essentially constant. In contrast, the consistency of emulsion C increased on ageing, especially over the first few days when there was a change from mobile liquid to semisolid. Emulsion A was a semisolid initially but like emulsion C increased in consistency especially over the first 24 h. Continuous shear data indicated that this emulsion was the most resistant to structure breakdown. Microscopical examinations supported the view that the networks formed in emulsion A were the most extensive and that stearyl alcohol networks in C formed comparatively slowly. Although the cetomacrogol/pure alcohol networks were diffuse and sometimes crystallized, they did not rapidly disintegrate on storage as did the ionic surfactant/pure alcohol networks examined previously.
Pharmaceutical suspensions: relation between zeta potential, sedimentation volume and suspension stability
Authors: Kayes J B
Published: April 2011

The effect of added surface-active agents of various ionic types on the sedimentation volume of drug suspensions of betamethasone, griseofulvin, nalidixic acid and thiabendazole has been investigated, and the results correlated with previously measured zeta potentials. Study of the zeta potential/sedimentation volumes versus concentration plots showed that apparently only coagulated, deflocculated or sterically stabilized systems were formed. In most cases the sterically stabilized systems were produced from mixtures of ionic/non-ionic surfactants. These are examples of controlled coagulation, although non-ionic surfactant alone conferred stability against caking. Secondary minimum flocculation was not apparent but this may have been due to the method of examination of suspensions. The work confirmed that the DLVO theory of colloid stability and its modification to include a steric term can be applied to coarse suspension systems.
The in vitro bioavailability of various drugs formulated as hard gelatin capsules
Authors: Newton J M , Razzo F N
Published: April 2011

A factorially designed experiment has been carried out to study the influence of various additives on the in vitro release of drug from hard gelatin capsules. Analysis of variance confirms previous findings that, although the main factors of diluent type, diluent concentration, the absence and presence of both magnesium stearate and sodium lauryl sulphate, were highly significant, the existence of interactions between the factors prevented exact quantitative prediction of the influence of each factor. There appears however, to be a strong indication that the in vitro drug release of capsule formulations (y), expressed as the % of the drug content of the capsule which dissolves, can be related to the solubility of the drug (cs) by the expression y = 21·2 log cs + 31.2.
Phase equilibria and stability characteristics of chlorpropamide-urea solid dispersions
Authors: Ford James L , Rubinstein Michael H
Published: April 2011

Physical mixtures and melts of various compositions of chlorpropamide and urea have been prepared. The phase diagrams and the effects of ageing of the systems have been measured by differential scanning calorimetry. The eutectic composition was found to contain 89% w/w chlorpropamide. Greater concentrations of chlorpropamide produced solid solutions of urea in chlorpropamide, whereas solid solution formation did not occur at compositions less than 89%. Melts in the range 50–100% chlorpropamide, which included the eutectic, existed as glass solids. The effect of ageing produced generally an increase in the liquidus peak temperature which was considered to be due to a gradual increase in crystal size.
Carrageenan and thrombin trigger prostaglandin synthetase-independent aggregation of rabbit platelets: inhibition by phospholipase A2 inhibitors
Authors: Vargaftig Bernardo B
Published: April 2011

Acetylsalicylic acid, salicylic acid and indomethacin were equally effective in inhibiting aggregation of plasma-free rabbit platelets induced by carrageenan and by thrombin. In contrast, only acetylsalicylic acid and indomethacin suppressed the accompanying formation of prostaglandin-like activities. Blockade of aggregation required the presence of the inhibitors in the platelet preparation, whereas blockade of prostaglandin synthetase remained even when the inhibitors were washed out. Prostaglandin synthetase-derived products appear not to be involved in the development of aggregation by carrageenan or by thrombin. Such aggregation was inhibited by two phospholipase A2 inhibitors, bromophenacyl bromide and mepacrine. It is suggested that carrageenan and thrombin-induced aggregation are mediated by non-prostaglandin, phospholipase A2-derived products.
The decomposition of acidic and neutral cannabinoids in organic solvents
Authors: Smith R N , Vaughan C G
Published: April 2011

High-pressure liquid chromatography was used to study (a) the relative efficiencies of methanol, chloroform, light petroleum (B.P. 40–60°) and methanol-chloroform (9:1) for extracting neutral and acidic cannabinoids from cannabis resin; (b) the decomposition patterns of the resulting solutions under various storage conditions, and (c) the cannabinoid profile of a cross section through a block of cannabis resin. The results show that (a) methanol is the most effective extracting solvent of those tested; (b) acidic cannabinoids in solution decompose in darkness by varying amounts depending on the temperature, solvent, storage time and particular cannabinoid; (c) neutral cannabinoids in solution are relatively stable in darkness; (d) daylight causes appreciable decomposition of both acidic and neutral cannabinoids in solution, and (e) the cannabinoid profile of a resin is complex with lower levels of acidic material in the outer layers.
The distribution of components in the different size fractions of granules prepared from binary mixtures
Authors: Opakunle W O , Spring M S
Published: April 2011

Boric acid, sulphanilamide and citric acid have been mixed separately with lactose and then granulated by massing and screening. The granules have been fractionated by sieving and each fraction has been analysed for lactose content. The effect of premixing time, massing time, binder volume and ratio of components on the distribution of lactose between size fractions of granules prepared from lactose: boric acid mixtures has been investigated. Uneven distribution of lactose has been found for all blends examined. There is a premixing time and massing time that gives the optimum distribution of lactose for any given blend and binder volume. Increased binder volume in some cases improves granule uniformity. The proportion of lactose in the blend has a major effect on the distribution of this component in the granules, as does the particle size of the lactose. Granules prepared from blends of lactose with sulphanilamide and with citric acid were also examined for lactose distribution.
The pharmacology of benoxaprofen (2-[4-chlorophenyl]-α-methyl-5-benzoxazole acetic acid), LRCL 3794, a new compound with anti-inflammatory activity apparently unrelated to inhibition of prostaglandin synthesis
Authors: Cashin C H , Dawson W , Kitchen E Ann
Published: April 2011

Benoxaprofen is a potent and long-acting anti-inflammatory and antipyretic compound. Its anti-inflammatory activity has been demonstrated in carrageenan-induced oedema, in cellulose pellet granuloma and in both developing and established adjuvant arthritis tests in rats. Its antipyretic activity is greater than either aspirin or paracetamol in tests inducing pyrexia with yeast or ‘E’ pyrogen in rats and rabbits. Benoxaprofen has analgesic activity in tests where pain is accompanied by inflammation but not in other experimental models of pain. The weak prostaglandin synthetase inhibiting properties of this compound differentiate it from other acid anti-inflammatory compounds. The low ulcerogenic potential of benoxaprofen seen in animal models may be related to its relative inability to inhibit PG synthetase.
Differentiation of the dopamine mechanisms mediating stereotyped behaviour and hyperactivity in the nucleus accumbens and caudate-putamen
Authors: Costall Brenda , Naylor Robert J , Cannon Joseph G , Lee Theresa
Published: April 2011

A number of dopamine agonists were applied intracerebrally to the nucleus accumbens and caudate-putamen of rat in an attempt to differentiate the dopamine mechanisms in these nuclei which mediate hyperactivity and stereotyped behaviour. The major effect of dopamine was to induce hyperactivity from the nucleus accumbens and stereotypy from the caudate-putamen; N-n-propyl-norapomorphine induced hyperactivity and stereotypy from the nucleus accumbens whilst apomorphine induced a marked stereotypy from the caudate-putamen, modest stereotypy from the nucleus accumbens and no hyperactivity. In contrast to apomorphine, 2-(NN-dipropyl)amino-5,6-dihydroxy TN‡ induced a more marked stereotypy from the nucleus accumbens and, again, no hyperactivity. The major effect of 2-(NN-diethyl)amino-5,6-dihydroxy TN was to cause an intense hyperactivity from the nucleus accumbens and marked stereotypy from the caudate-putamen whilst the primary amine, 2-amino-5,6-dihydroxy TN induced hyperactivity and stereotypy from both areas. The marked hyperactivity and stereotyped responses were inhibited by haloperidol, but not by α- or β-blockers. These data would indicate that there may be different dopamine mechanisms in the nucleus accumbens and caudate-putamen for the mediation of hyperactivity and stereotyped behaviour.
Studies on the ethanol-induced changes in glycerolipid synthesis in rats and their partial reversal by N-(2-benzoyloxyethyl)norfenfluramine (benfluorex)
Authors: Pritchard P Haydn , Brindley David N
Published: April 2011

Rats were treated daily for 5 days with benfluorex (S-780) 50 mg kg−1 and 2 h after the fifth treatment were intubated with ethanol 5 g kg−1 or with isocaloric glucose. S-780 did not alter the absorption or oxidation of [1-14C]ethanol nor did it decrease the concentration of ethanol and its water soluble metabolites in the tissues examined. The rate of hepatic glycerolipid synthesis was measured in vivo using [14C]palmitate and [3H]glycerol and the accumulation of [14C]palmitate in various tissues was determined 4 h after intravenous injection. Ethanol treatment increased the relative rate of TG† synthesis in the liver and decreased the synthesis of PC, PE and PS + PI. The relative flux from PA to DG and TG was increased. These changes were reflected in the accumulation of [14C]palmitate in hepatic lipids and were obtained under conditions where the net rate of [14C]palmitate oxidation to 14CO2 was greater in those rats treated with ethanol instead of glucose. S-780 did not alter the oxidation rates over a 4 h period. Ethanol treatment increased the accumulation of [14C]palmitate in the PS + PI fraction of lung and decreased the proportion in PE. In kidney it increased the concentration of [14C]palmitate in TG, DG and PE and decreased the concentration in PC and PS + PI. Pretreatment of the rats with S-780 partially reversed the changes in palmitate accumulation in glycerolipids which were caused by ethanol. S-780 treatment also decreased the rate of hepatic TG synthesis from glycerol in the rats fed glucose. It increased the percentage recovery of [14C]palmitate in the livers and kidneys of glucose fed rats and decreased that in adipose tissue. This treatment decreased the proportion of [14C]palmitate recovered in the TG of the kidneys and lungs of these rats and increased the proportion in PI + PS. The results are discussed in relation to the mechanisms by which ethanol and S-780 are thought to interfere with glycerolipid synthesis.
The in vitro metabolism of 2-nitroso-1-phenylpropane dimer by fortified 9000g supernatants from rabbit liver
Authors: Beckett A H , Jones G R
Published: April 2011

2-Nitroso-1-phenylpropane dimer, a postulated metabolic product of amphetamine, was metabolized by fortified 9000 g supernatants from rabbit liver, mainly by oxidation on the carbon beta to the nitrogen to form a ‘β-hydroxylated nitroso dimer’. The corresponding nitro compound, ketone and alcohol were also products, the latter two but not the former being cofactor dependant. The nitroso compound was not metabolically reduced under the conditions used.
Application of orthogonal functions to the spectrophotometric determination of phenytoin and phenobarbitone in pharmaceutical preparations
Authors: Amer M M , Ahmad A K S , Hassan S M
Published: April 2011

Orthogonal polynomial functions have been used in the simultaneous determination of mixtures of phenytoin and phenobarbitone in pharmaceutical preparations. The mean recovery (9 determinations) and coefficient of variation were 100·0 ± 1·4% for phenobarbitone and 100·0 ± 1·3% for phenytoin. Neither the ΔA method of Pannerden & Fontein nor a ΔA modification of Vierordt's method of two-component analysis gave results of the same accuracy and precision as the proposed method.
Generated surface area measurement of disintegrating tablets
Authors: Rubinstein Michael H , Wells James I
Published: April 2011

The surface areas generated by the disintegration and dissolution of six commercial brands of phenylbutazone tablets B.P. 100 mg have been measured using a Model Ta Coulter Counter. The graphs of surface area generated against time were all of the same shape and always reached a maximum value. The initial surface area increase was due to tablet disintegration and deaggregation and followed first order kinetics. A good correlation between the slope of this initial increase and disintegration time was found. The maximum surface area generated correlated at the probability level of better than 99·9% with the dissolution rate measured as t60. The subsequent decrease in surface area, after this maximum, was considered to be due to phenylbutazone dissolution and was also first order rate controlled.
Effect of a second solubilizate on the partition coefficient of drugs in micellar solution and their permeation rate across an artificial membrane
Authors: Alhaique F , Giacchetti D , Marchetti M , Riccieri F M
Published: April 2011

The distribution of a solubilizate between micelles and the aqueous phase does not obey a simple partition law when a second solubilizate species is present. Alterations of the apparent partition coefficient cannot be explained in terms of a simple displacement mechanism, following the interaction of both solubilizates with the same site of the micelle. A non linear increase in solubilizate association to micelles following an increase in surfactant concentration is observed in the presence of a second solubilizate. A depression in the cloud point temperature follows the addition of a second species and is such that cannot be interpreted as a simple additive effect. Alteration of the apparent partition coefficient in a micellar solution has an effect on the permeation rate of the solubilizate across an artificial membrane. Bio-pharmaceutical implications are discussed.
Metabolic oxidation of aralkyl oximes to nitro compounds by fortified 9000g liver supernatants from various species
Authors: Beckett A H , Jones G R
Published: April 2011

Incubation of ‘amphetamine oxime’ (IIa, anti-benzyl methyl ketoxime) with fortified rabbit liver 9000 g supernatants gave the nitro compound (Ie) and the β-hydroxylated oxime (IIc) in addition to the previously reported ketone (IIb) and alcohol (Ic) metabolites. Formation of the products was cofactor dependent. The nitro compound was also formed using mouse, hamster and guinea-pig 9000 g liver supernatants and to a minor extent by rat liver. The oximes of 2-phenethylamine (IIe) and norfenfluramine (IIg) were also metabolized to the corresponding nitro compounds, ketones and alcohols with rabbit 9000 g liver supernatants; however, no nitro compound (IIIb) was detected after the incubation of ‘mexiletine oxime’ (IVa). The metabolic products were identified and characterized by g.l.c., t.l.c. and g.l.c. linked mass spectrometry by comparison with synthetic materials.
Dopamine receptors in rat striatum and nucleus accumbens; conformational studies using rigid analogues of dopamine
Authors: Woodruff G N , Watling K J , Andrews C D , Poat Judith A , McDermed J D
Published: April 2011

A study was made of the actions of dopamine and of some 2-amino-1,2,3,4-tetrahydronaphthalenes on dopamine-sensitive adenylate cyclase in homogenates of rat striatum and nucleus accumbens. The compounds were also tested for their ability to stimulate motor activity following bilateral injection into the nucleus accumbens of conscious rats. The most active compounds on adenylate cyclase from both striatum and nucleus accumbens were dopamine and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene(6,7-diOHATN). The 5,6-dihydroxy analogue (5,6-diOHATN) was 50 times less active than 6,7-diOHATN in striatal homogenates and 350 times less active in homogenates of nucleus accumbens. All dihydroxy compounds tested were active in causing stimulation of motor activity, the most active compounds being 6,7- and 5,6-diOHATN. Both dimethoxy derivatives tested were inactive on the adenylate cyclase and as locomotor stimulants.
Interpretation of dissolution rate data from in vitro testing of compressed tablets
Authors: Kitazawa Shikifumi , Johno Ikuo , Minouchi Tokuzo , Okada Jutaro
Published: April 2011

To find if theoretically and experimentally a relation existed between the dissolution rate theory of Kitazawa, Johno & others (1975) and that of Wagner (1969), a study was undertaken with uncoated caffeine, aspirin and proxyphylline tablets using two dissolution methods. Although the original treatment for surface area of drug available for dissolution was quite different between the two dissolution theories, the dissolution rate constants obtained were in fair agreement. Hence it might not be always necessary to take into consideration changes in the surface area as a function of dissolution rate, and the 1n W∞/ (W∞ - W) versus time plot devised by Kitazawa & others might be a useful and simple means of obtaining the dissolution rate constant of an active ingredient from a dosage form such as compressed tablet.
Cannabinoid patterns in seedlings of Cannabis sativa L. and their use in the determination of chemical race
Authors: Rowan M G , Fairbairn J W
Published: April 2011

We have examined the cannabinoid contents of seedlings from twelve strains of Cannabis of known chemical race. Fourteen days after emergence of the shoot those of the tetrahydrocannabinol (THC) type could be distinguished from those of the cannabidiol (CBD) type. The true leaves of the THC type contained a relatively high content of THC and also contained cannabichromene (CBC), sometimes as the major cannabinoid, whereas the CBD type had much lower amounts of THC and no CBC; CBD being the major component. A strain from China corresponded to the THC type but showed some unusual features. Seeds purchased at seven outlets in Britain were also examined. Only two batches germinated but these proved to be of a THC type and resembled the Chinese strain.
Increasing the probability of sterility of medicinal products
Authors: Brown M R W , Gilbert P
Published: April 2011

Calculations show that official tests for sterility offer unacceptably low degrees of assurance of sterility. Some batches of heat treated articles with 10% contamination can pass the E.P. test on about 92% of occasions. It is proposed that viable counts be made on products immediately before the terminal inactivation procedure and that upper limits be set for the level of contamination. Samples of the product should be inoculated with spores of known resistance characteristics and also with samples of swabs from the production area. Such inoculated products should then be tested for absence of viable organisms, after being subjected to the terminal inactivation procedure. This test should be coupled with close environmental and process control and personnel education. It is recommended that these procedures replace the conventional test for sterility. The use of spores as direct and independent indicators of sterility, especially where the lethal conditions cannot be monitored instrumentally is recommended. A flexible approach is proposed for the use of the ‘lethality factor’ suitable for a terminal heat inactivation procedure; this would depend on the nature of the product and the standard of monitoring facilities and personnel. A change in the language is proposed. A medicinal product processed such that an acceptable probability of sterility exists, should be designated not as sterile but as safe.
The dissolution mechanism in a system undergoing complexation: salicylamide in caffeine solution
Authors: Donbrow M , Touitou Elka
Published: April 2011

The dissolution rate of compressed salicylamide discs has been measured in water and in caffeine solutions of increasing concentration at 15, 25, 37 and 45° in an apparatus rotating at 48 rev min−1 or more. Dissolution rate profiles showed breaks indicative of a shift in the mechanism of dissolution from interfacial towards transport control. The shifts occurred at higher caffeine concentrations on increasing the agitation rate or temperature. The dependencies of dissolution rates on agitation rates typified the intermediate type of dissolution and Arrhenius plots indicated that interfacial and transport processes participated in salicylamide dissolution.
Relaxations mediated by adrenergic and non-adrenergic nerves in human isolated taenia coli
Authors: Stockley Helen L , Bennett Alan
Published: April 2011

In human taenia coli electrical field stimulation after cholinergic blockade excited mainly non-adrenergic inhibitory nerves. Adrenergic relaxations during stimulation were demonstrated only with short electrical pulses at high frequencies or with ganglion stimulants. Reduction by tetrodotoxin of relaxations to indirectly acting sympathomimetics supports the histochemical finding that colonic adrenergic nerves are mainly preganglionic, and possibly synapse with non-adrenergic inhibitory nerves. When the latter undergo direct maximal stimulation, responses to adrenergic nerve excitation are masked.