bluuebunny/crossref_metadata_2025 huggingface dataset:
The evaluation of the force to expel oily injection vehicles from syringes
Authors: Dexter M B , Shott M J
Published: April 2011

Measurement of the force needed to expel oily injection vehicles from all-glass syringes through hypodermic needles has shown that the force required to maintain various rates of expulsion is in agreement with a modified form of the Poiseuille equation. The flow from disposable plastic syringes with rubber plunger tips fits this equation only if a correction is made to take account of the resistance to movement of the plunger (which is effectively zero for all-glass syringes). This resistance or binding force was shown to be increased by exposure to vegetable oils, and its magnitude was inversely dependent on vehicle viscosity. This increase was caused by swelling of the rubber plunger tips due to uptake of the oily vehicles by the rubber. No such increase in binding force was observed with a viscous aqueous vehicle.
A high performance liquid chromatographic assay of cis- and trans- isomers of tricyclic neuroleptic drugs
Authors: Po A Li Wan , Irwin W J
Published: April 2011

Tricyclic neuroleptics based upon the thioxanthene nucleus exhibit geometrical isomerism and the major pharmacological activity resides in the Z-component. An h.p.l.c. procedure which enables the separation detection and quantification of these isomers is described. The method is applicable to the analysis of flupenthixol, clopenthixol, chlorprothixene, doxepin and dothiepin. Measurement of the isomer-ratios in various samples of flupenthixol has shown that small batch to batch variations are apparent. The determination of the isomer-ratio in formulations has been shown to rely upon the complete extraction of the medicament. This is due to the differential release of the components from the tablet matrix with the cis-isomer being favoured. There is little difference observed between the adsorption isotherms of the two components (onto charcoal) but in competition experiments differential adsorption may be demonstrated. This has clear implications for the pharmacokinetics of these drugs.
The effects of dihydrochandonium and other chandonium analogues on neuromuscular and autonomic transmission
Authors: Apong P Teer , Marshall I G , Harvey A L , Singh Harkishan , Paul Dharam , Bhardwaj T R , Ahuja N K
Published: April 2011

The muscle relaxant chandonium and four of its analogues have been assessed for neuromuscular, ganglion blocking and vagolytic activity in the chloralose-anaesthetized cat, for neuromuscular blocking activity in the chick isolated biventer cervicis and rat phrenic nerve-hemidiaphragm preparations, for muscarinic and histamine blocking activity in the guinea-pig isolated ileum preparation and for effects on adrenergic responses in the rat isolated vas deferens preparation. All five compounds produced neuromuscular block of rapid onset and short duration when given to cats in doses of 5–500 μg kg−1 and produced non-depolarizing competitive neuromuscular blockade in the isolated skeletal muscle preparations. Saturation of the 5–6 androstene bond to produce dihydrochandonium (HS692) resulted in a loss of potency by a factor of 0·5. The NN-diethyl analogue of dihydrochandonium (HS693) was about half as potent as HS692. The triethyl (HS704) and NN-diethyl (HS705) analogues of chandonium possessed one-tenth and one-fifth respectively of the muscle relaxant activity of chandonium. In cats, all compounds inhibited the bradycardia produced by vagal stimulation and by methacholine, the vagolytic effect of HS693 being particularly powerful and long-lasting. Although the compounds did not block the depressor response to methacholine in vivo, all the compounds inhibited responses to carbachol in the guinea-pig isolated ileum. However, from pA2 values the compounds were found to be 10–100 times more active at nicotinic than at muscarinic receptors. None of the compounds had histamine-blocking activity, ganglion-blocking activity, or actions on adrenergic responses.
Elimination of prostacyclin (PGI2) and 6-oxo-PGF1α in anaesthetized dogs
Authors: Salmon John A , Mullane Kevin M , Dusting Gregory J , Moncada Salvador , Vane John R
Published: April 2011

The plasma concentration of 6-oxo-PGF1α was measured by radioimmunoassay after constant rate infusion of 6-oxo-PGF1α or prostacyclin (PGI2) into anaesthetized dogs. A steady-state plasma concentration was rapidly attained with both compounds. After termination of the infusions, the concentration of 6-oxo-PGF1α declined according to a bi-exponential process. The steady-state plasma concentrations of 6-oxo-PGF1α obtained after infusion of 6-oxo-PGF1α and PGI2 were approximately 10 times higher than the corresponding steady-state level of PGF2α measured after infusion of PGF2α into the same dogs. The data presented suggest that PGI2 and 6-oxo-PGF1α are eliminated more slowly than PGF2α, probably because they are not taken up and metabolized in the lungs as rapidly as PGF2α.
Factors underlying the variable inotropic effect of ouabain on isolated rat atria. Changes in contractile frequency and adrenergic mechanisms
Authors: Gimeno Alvaro L , Sterin-Borda Leonor , Borda Enri S , Gimeno Martha F
Published: April 2011

The effects of concentrations of ouabain on the isometric developed tension (IDT) of isolated left auricles driven at 0·4, 0·8 and 3·3 Hz, were explored. With 0·4 or 0·8 Hz, increasing concentrations of ouabain (3·4 or 6·8 times 10−6; 1·0; 3·4 or 6·8 times 10−6M) elicited a decreasing enhancement of atrial contractile peak tension, whereas with 3·3 Hz the effect was augmented with concentration. Ouabain (3·4 times 10−6 M) enhanced comparably the IDT at all the driving rates, but at higher concentrations the effect varied with the frequency. The positive inotropic action of ouabain at 3·4 times 10−6 M on preparations driven at faster frequencies was antagonized by Sotalol (MJ-1999) and also after catecholamine depletion by in vivo reserpinization followed by addition of tyramine in vitro. Cocaine or U-0521 significantly enhanced the positive inotropic effect of ouabain (3·4 times 10−5 M) in atria stimulated at low rates. On the contrary, Sotalol, cocaine, U-0521 or catecholamine depletion did not alter the positive inotropic influence of ouabain at 3·4 times 10−6 M at any of the frequencies used. It is suggested that ouabain influenced contractile peak tension of rat isolated atria through two mechanisms: one, seen after higher concentrations, which appeared to be associated with adrenergic factors and dependent on the frequency of stimulation; the other, observable with the lower concentrations, which did not appear to have a direct relationship with adrenergic processes and which was independent of the frequency of stimulation.
Cardiovascular studies with impromidine (SK&F 92676), a new very potent and specific histamine H2-receptor agonist
Authors: Owen D A A , Harvey Carol A , Gristwood R W
Published: April 2011

Impromidine (SK & F 92676) has recently been identified as a potent and specific histamine H2-receptor agonist. The present paper describes some cardiovascular studies with the drug. Impromidine lowers blood pressure in cats and rats by interaction with H2-receptors. During continuous intravenous infusions of impromidine, the fall in blood pressure is due to a reduction in total peripheral resistance; cardiac output increases during hypotension. The responses to impromidine are similar to responses to histamine in mepyramine-treated cats. Impromidine administered intra-arterially also causes vasodilatation in the femoral and mesenteric vasculature by interaction with H2-receptors. Impromidine stimulates all measured parameters including coronary flow in the isolated working heart of the guinea-pig. Dose-response curves to impromidine were displaced to the right in the presence of cimetidine.
Anti-inflammatory and platelet anti-aggregant activity of phospholipase-A2 inhibitors
Authors: Vallee E , Gougat J , Navarro J , Delahayes J F
Published: April 2011

Mepacrine, papaverine, p-bromophenacyl bromide and 2,3-dibromo(4′-cyclohexyl-3′-chloro)-phenyl-4-oxo-butyric acid (CB 874) inhibit the hydrolysis of phospholipids induced by thrombin in dog platelets. They also exhibit anti-inflammatory and anti-aggregant properties. These biological activities may be explained by a direct or indirect inhibitory action on phospholipase A2. Phospholipase A2 inhibitors may block not only the release of arachidonic acid and its subsequent conversion into prostaglandins but also the formation of lysophospholipids involved in inflammation and/or platelet aggregation.
The rapid development of functional tolerance to ethanol by mice
Authors: Grieve Susan J , Littleton John M
Published: April 2011

A method is described in which the development of tolerance to ethanol in individual mice can be measured during the inhalation of ethanol vapour. This method has been used with two behavioural end-points, loss of righting reflex and loss of rotarod performance. It demonstrates that, in the adult male, TO Swiss mouse, peak tolerance, in which approximately 2 × the original effective blood ethanol concentration is required to produce the behavioural end-point, can develop in 3–5 h. After this time the ability of the animals to perform normally in the presence of continued high concentrations of ethanol in blood begins to fall. The results are discussed in relation to current concepts of tolerance to central nervous system depressant drugs.
Aspirin-caffeine interaction in the rat
Authors: Collins Catherine , Laird R I , Richards P T , Starmer G A , Weyrauch Solveig
Published: April 2011

Both aspirin at a high dose (400 mg kg−1) and caffeine (5 mg kg−1) induced hyperactivity in the DA rat, but lower doses of aspirin were without effect. Caffeine-induced hyperactivity was brief (2 h) but that due to aspirin was evident from 1–6 h after dosing. Co-administration of the two drugs caused long-lasting hyperactivity, even with doses of aspirin which had no stimulant effects themselves. Absorptive and metabolic effects did not appear to play a major role in the interaction. The most likely effect is that of salicylate on catecholamine utilization in the central nervous system, which is compounded in the presence of a phosphodiesterase inhibitor.
The use of phospholipid liposomes for lithium administration. Polydipsic effect and tissue distribution of lithium
Authors: Zilberman Yael , Lichtenberg Dov , Gutman Yehuda
Published: April 2011

Administration of lithium entrapped in phospholipid liposomes increased the lithium-induced polydipsia, but did not accelerate the onset of this effect. It also resulted in a larger accumulation of lithium in the liver, kidney and spleen, but not in the brain. The time course of polydipsia suggests that it depends on the intracellular lithium concentration. However, the rate of development of this effect depends on some additional factor.
The effect of 2-substitution on conformations and brain concentrations of phenothiazine-neuroleptics in relation to dopamine-antagonism
Authors: Grol Cor J , Rollema Hans , Asselbergs Hans W
Published: April 2011

Conformational energies of promazine, chlorpromazine and triflupromazine were calculated with the INDO-method and plotted as a function of two torsion angles. Distance maps were constructed for the N-S and N-2-substituent distances and compared with the N-O distances in dopamine in its preferred conformation, demonstrating the flexibility of the phenothiazine molecules, and showing that interactions with various dopamine-receptor sites, are likely. To eliminate the influence of transport and distribution on the activity, rat brain concentrations of the phenothiazines were determined simultaneously with the increase in striatal homovanillic acid (HVA) concentrations. Concentrations causing a 300% rise in HVA (taken as a measure of neuroleptic activity) were compared with i.p. doses inducing the same rise in HVA, showing that relative potencies based on brain concentrations and relative potencies obtained from i.p. doses were virtually equal. As the increase in lipophilicity does not significantly improve penetration into the brain, it is concluded that the enhancing effect of 2-substitution on the neuroleptic activity might be due to (a) the increase in the probability of conformations in which the side chain is directed towards one side of the molecule and (b) to a direct interaction with the receptor at a site corresponding with one of the dopamine oxygens.
Effects of antirheumatic drugs on protein sulphydryl reactivity of human serum
Authors: Hall Nicolas D , Gillan Anne H
Published: April 2011

The effect of a number of antirheumatic drugs on sulphydryl group reactivity in human serum has been determined using the thiol reagent, 5,5′-dithiobis (2-nitrobenzoic acid) (DTNB). Drug effects in vivo have been measured using sera from patients with rheumatoid arthritis receiving these compounds and the drugs have also been added to healthy human serum in vitro. An increased rate of sulphydryl-disulphide exchange between serum sulphydryl groups and DTNB was noted in rheumatoid disease. This finding was not associated with anti-inflammatory drug therapy. In vivo, non-steroidal anti-inflammatory drugs did not affect this reaction, but aurothiomalate, D-penicillamine and levamisole all significantly increased the rate of sulphydryl-disulphide exchange. When the drugs were added to healthy human serum in vitro, indomethacin, aurothiomalate and D-penicillamine stimulated sulphydryl reactivity with DTNB but levamisole had no effect. Aurothiomalate appeared to act in this system as a mixture of gold atoms and thiomalate molecules, the thiomalate stimulating and the gold inhibiting thiol reactivity. This study demonstrates that the stimulation of sulphydryl-disulphide exchange reactions in vivo is a property of three long-acting drugs used to treat rheumatoid arthritis, but not of non-steroidal antiinflammatory agents. This reactivity may therefore differentiate the second-line drugs showing true antirheumatic activity from ‘simple’ anti-inflammatory compounds. Comparative studies have shown that the addition of drugs to serum in vitro may give different results from those obtained with sera from rheumatoid patients receiving these agents. This may be due to in vivo metabolism of the compound, drug concentration effects or the parameters of the in vitro assay system. In view of this, caution is required in the interpretation of data obtained from in vitro studies of these compounds.
pA2 values of selective β-adrenoceptor antagonists on isolated atria demonstrate a species difference in the β-adrenoceptor populations mediating chronotropic responses in cat and guinea-pig
Authors: O'Donnell Stella R , Wanstall Janet C
Published: April 2011

pA2 values for atenolol (β1-selective) and α-methylpropranolol (β2-selective) have been determined on isolated atria of cat and guinea-pig using noradrenaline (β1-selective) and fenoterol (β2-selective) as agonists. On guinea-pig atria, the pA2 values did not vary with the agonist used. On cat atria the pA2 for atenolol was greater with noradrenaline than with fenoterol and the pA2 for α-methylpropranolol was greater with fenoterol than with noradrenaline. Fenoterol was 20 times more potent on cat than on guinea-pig atria whereas noradrenaline was approximately equipotent in the two species. The results have been interpreted as suggesting that both cat and guinea-pig atria contain one receptor type in common (β1) but that only cat atria contain β2-adrenoceptors as well.
The assay and stability of chlorpropamide in solid dispersion with urea
Authors: Ford James L , Stewart Alan F , Rubinstein Michael H
Published: April 2011

Thin layer chromatography followed by reflectance densitometry has been used to evaluate the stability of chlorpropamide-urea during the fusion process. Urea was found to decompose to biuret and chlorpropamide to p-chlorobenzenesulphonamide: several other unidentified decomposition products were detected. The energy for decomposition of chlorpropamide was 57·1 kJmol−1 for melts containing 15 and 30% chlorpropamide. Decomposition followed apparent first order kinetics.
Functional tolerance to ethanol in mice: relationship to lipid metabolism
Authors: Grieve Susan J , Littleton John M , Jones Paul , John Geryk R
Published: April 2011

The development of functional tolerance to ethanol was studied in young adult mice of the TO Swiss and C57BL strains. Ethanol administration was by intermittent inhalation for 7 h and the development of tolerance was assessed by estimating blood ethanol concentrations at successive losses of the righting reflex. The administration of (±)α-tocopherol at a dose previously shown to inhibit the effect of ethanol on peripheral phospholipid composition (750 mg kg−1 i.p.) was without effect on functional tolerance. Chronic administration of DL-carnitine, 7% w/w in diet for 10 days, a treatment previously shown to prevent ethanol-induced triglyceride accumulation, was also without effect on ethanol tolerance. Administration of the cholesterol synthesis inhibitor, diazacholesterol (30 mg kg−1 i.p.) 3 times per week for 3 weeks from weaning, markedly inhibited the subsequent development of functional tolerance. Administration of the inhibitor of protein synthesis, cycloheximide (300 μg kg−1 i.p.) greatly inhibited the development of ethanol tolerance whereas actinomycin D (100 μg kg−1 i.p.) was without effect. The results are discussed in relation to the hypothesis that ethanol cellular tolerance results from adaptation in the composition of the lipids of neuronal membranes. It is concluded that synthesis of some protein is involved in the development of cellular tolerance and also that cholesterol plays some part in the development of tolerance.
The effect of pyrogen on the in vivo metabolism and initial kinetics of chloroquine in rats
Authors: Osifo Nosakhare G
Published: April 2011

The possible contribution of hepatic metabolism impairment, caused by pyrogen, to the increased toxicity and altered pharmacokinetics of chloroquine in rats was investigated. The ratio of unchanged chloroquine (CQ) to total quinolines (TQ) was determined in the 24-h urine collection, the plasma and the liver. Pretreatment with massive doses of E. coli lipopolysaccharide pyrogen did not produce any significant change in the ratio of CQ/TQ in the urine, liver or plasma between control and pyrogen-treated rats. This finding occurred in spite of a pronounced initial behavioural effect of the pyrogen on the rats. The ratio of CQ/TQ was also preserved in the 7th day 24-h urine collection from a control and a pyrogentreated rat although the total urinary excretion of TQ had decreased by about 99·5% of the first 24-h collection. Analysis of the pharmacokinetic parameters from plasma levels in the first 24 h showed significant alterations in the apparent volume of distribution (AVD), the half-life (T 1/2) and the rate of decay constant (K) of the drug in pyrogen-treated rats. These findings were interpreted to indicate that chloroquine metabolism in vivo, which occurs mainly via a dealkylation process, may not be readily deranged by pyrogen. The changes in the pharmacokinetic parameters are discussed in relation to the known haemodynamic changes that occur in the febrile state.
Monoamine oxidase inhibition and brain amine metabolism after oral treatment with toloxatone in the rat
Authors: Keane P E , Kan J P , Sontag N , Benedetti M Strolin
Published: April 2011

Rats were administered toloxatone 100 mg kg−1 p.o., and killed 0·5 to 8 hours later. Toloxatone reversibly inhibited type A MAO, but did not affect the activity of type B MAO in whole brain. Cerebral concentrations of noradrenaline, dopamine and 5-hydroxytryptamine were increased after toloxatone, while their metabolite concentrations were reduced. Synaptosomal uptake processes of these amines were not altered by toloxatone.
Reduction in blood pressure in normal and spontaneously hypertensive rats by lergotrile mesylate
Authors: Sved Alan F , Fernstrom John D
Published: April 2011

The acute administration of lergotrile mesylate to normal or spontaneously-hypertensive rats (SHR) causes a prompt reduction in blood pressure. In SHR, doses as small as 0·05 mg kg−1 are effective; maximal reductions in blood pressure are obtained at a dose of 0·25 mg kg−1. Lergotrile may be administered intraperitoneally or orally. Its efficacy as an antihypertensive agent in rats does not diminish significantly when administered twice daily for 7 days. Although lergotrile has been reported to be a dopamine agonist, the present data do not establish the mechanism by which the drug lowers blood pressure.
Release of [3H]noradrenaline induced by 5-hydroxy-tryptamine from cat pial arteries
Authors: Marin J , Salaices M , Sánchez C F
Published: April 2011

Pial arteries of cats were used to analyse the effects of 5-hydroxytryptamine (5-HT) on the release of [3H]noradrenaline. To achieve this the vessels were preincubated with [3H]noradrenaline and the effect of different concentrations of 5-HT (10−6, 10−5, 10−4 M) on the release of tritium was studied. 5-HT elicited release of radioactivity in a dose-dependent manner. Removal of both superior cervical sympathetic ganglia 15 days before the experiment or pretreatment of the animals with reserpine (3 mg kg−1, total dose) produced a significant decrease in the outflow of tritium induced by 5-HT. In these arteries, the amount of radioactivity retained at the end of the experiment was much diminished. Cocaine (10−6 M) caused a significant decrease in the tritium efflux induced by 5-HT (10−5 M). These results show that 5-HT has an indirect adrenergic effect in the pial arteries of the cat only at high doses of 5-HT, and confirm that sympathetic innervation of these vessels mainly comes from the superior cervical ganglia.
Methysergide induces selective potentiation in cholinergic contractions of the guinea-pig vas deferens by facilitating acetylcholine release
Authors: Katsuragi Takeshi , Furukawa Tatsuo
Published: April 2011

Methysergide (3 times 10−6 M) enhanced the contractile responses of the isolated stripped vas deferens of guinea-pig to acetylcholine(ACh) and arecoline, but not those to noradrenaline, tyramine and bradykinin. Methysergide (3 times 10−5 M) suppressed the contraction elicited by noradrenaline or histamine. The methysergide-induced potentiation of the response to ACh was prevented by pre-addition of hemicholinium but not by tetrodotoxin or morphine. The augmentation of the response to ACh by physostigmine was unaffected by hemicholinium. The phasic contraction of the tissue elicited by 30 mM KCl was also enhanced by methysergide, and this enhancement was prevented by the pre-addition of atropine (1·4 times 10−7 M). In the depolarized vas deferens after exposure to 30 mM KCl, methysergide occasionally induced a sustained tonic contraction which was inhibited by atropine. These findings suggest that methysergide facilitates a release of ACh by acting on the cholinergic nerve terminals and selectively potentiates the cholinergic response.
The effects of bromocriptine on pre-synaptic and post-synaptic α-adrenoceptors in the mouse vas deferens
Authors: Gibson Alan , Samini Morteza
Published: April 2011

Noradrenaline (NA) and dopamine (DA) contracted the mouse vas deferens and reduced the responses to low frequency nerve stimulation (0·1 Hz). The relative potencies of antagonists suggested that these effects were due to stimulation of post-synaptic and pre-synaptic α-adrenoceptors respectively. Bromocriptine produced a non-competitive antagonism of contractile responses to NA (pD2′ = 7·6) and DA (pD2′ = 8·0) but had no effect on responses to carbachol. Bromocriptine also reduced single twitch responses of the vas to low frequency field stimulation (0·1 Hz), but did not affect stimulation at higher frequencies (1·20Hz). Yohimbine selectively and rapidly reversed the inhibiting effects of bromocriptine on single twitches, although they could not easily be reversed by washing. Bromocriptine produced a yohimbine-reversible reduction in the stimulated overflow of tritium from vasa previously loaded with 3H-NA. Thus the mouse vas deferens does not appear to contain specific DA receptors and the results suggest that bromocriptine acts as a pre-synaptic α-adrenoceptor agonist and post-synaptic α-adrenoceptor antagonist in this tissue.
Stereoselectivity of some oxotremorine antagonists containing two chiral centres
Authors: Ringdahl Björn , Resul Bahram , Dahlbom Richard
Published: April 2011

The stereoisomers of some analogues of oxotremorine containing two chiral centres, one in the 1-position of the butynyl chain and one in the 2-position of the pyrrolidine ring, have been prepared. The compounds are oxotremorine antagonists. They show a marked stereoselectivity, which depends mainly on the configuration of the chiral centre in the butynyl chain and to a lesser extent on the configuration of that in the pyrrolidine ring.
Effect of contaminating proteolytic activity upon insulin and insulin-protamine complex
Authors: Caygill Christine P J , Ayling Christine M
Published: April 2011

The proteolytic contamination in batches of various insulin preparations was studied using chromogenic synthetic peptide substrates, synthetic ester substrates, and a test similar to the European Pharmacopoeia test for ‘Limit of Proteolytic Activity’. In order to study the latter test, insulin-protamine complexes were prepared using salmine sulphate and samples of crystalline insulin, some of which contained peptidase activity. All insulin-protamine complexes prepared from insulin crystals in which peptidase activity had been detected using a synthetic chromogenic substrate were degraded on storage at 37 °C, whereas those prepared from insulin crystals in which no peptidase activity could be detected showed no significant loss in weight. Chromatography on Sephadex G50 revealed degradation of insulin in solutions containing traces (∼0·5 p kat mg−1 preparation) of peptidase activity and stored for 2 weeks at 37 °C at pH 7·4, but not of such insulin stored at pH 2·5 at 37 °C for up to 6 weeks. Since insulin preparations formulated at neutral pH are so susceptible to molecular degradation by traces of peptidase contamination, it is suggested that the test using a chromogenic peptide substrate could be applied to bulk crystals before vialing of insulin preparations and could also replace the current test specified in the monograph on Isophane Insulin of the European Pharmacopoeia.
Preliminary evaluation of dika fat, a new tablet lubricant
Authors: Udeala O K , Onyechi J O , Agu S I
Published: April 2011

Dika fat, a solid vegetable oil extracted from the kernels of Irvingia gabonensis var excelsia has been evaluated as a lubricant* on the basis of its effect on the flow rate of granules, disintegration time and dissolution rate of tablets. The fat shows a maximal effect on flow at a concentration of 2·5% w/w. It produces better disintegration and dissolution profiles than magnesium stearate at all concentrations tested. The indication is that there is less degradation of aspirin in tablets containing this oil than there is in tablets containing magnesium stearate. The use of Dika fat(m.p. 39–40 °C) eliminates the hydrogenation step often necessary for vegetable oils.
Effect of ethylcellulose grade and sealant treatments on the production and in vitro release of microencapsulated sodium salicylate
Authors: Deasy P B , Brophy M Regina , Ecanow B , Joy Mary M
Published: April 2011

Sodium salicylate was microencapsulated with ethylcellulose 100 cp by polymer deposition from cyclohexane by temperature change to give a finer product, with slower drug release, than that obtained with 10 cp grade of ethylcellulose. Scanning electron microscope and polymer disc swelling studies confirmed that larger microcapsules after drug release ruptured into smaller particles with swollen surfaces containing pores. Treatment of microcapsules with paraffin wax solution retarded release of core material, the release being affected by the percentage of sealant used and the particle size of the product. The mechanism of release from the sealed microcapsules was complex involving mainly diffusion, but polymer erosion and drug binding were also involved. Other sealant materials were less effective in retarding dissolution.
Cannabinoid compounds in South African Cannabis sativa L
Authors: Field B I , Arndt R R
Published: April 2011

Dagga (Cannabis sativa L.) samples were collected from various geographical regions of South Africa. These were classified into age, sex and plant part and the cannabinoids were analysed quantitatively by gas-liquid chromatography and mass spectrometry. Analytical results show that there appears to be at least three chemovariants of Cannabis sativa growing in South Africa with respect to relative cannabinoid content. One of these variants appears to be unique to Southern Africa. It also appears that South African C. sativa ranks among the world's more potent C. sativa variants in terms of its Δ9 -tetrahydrocannabinol content.
Mitomycin C-dextran conjugate: a novel high molecular weight pro-drug of mitomycin C
Authors: Kojima T , Hashida M , Muranishi S , Sezaki H
Published: April 2011

A high molecular weight derivative of mitomycin C (MMC), mitomycin C-dextran conjugate (MMC-D) has been synthesized and its biological and pharmacological properties investigated. MMC is released from MMC-D in vitro with a half-life of 24 h. After intraperitoneal injection of MMC-D, free MMC could be detected in plasma and urine of mouse for 5–8 h, while MMC administered as a free form was eliminated rapidly. After MMC-D, given to mice bearing Ehrlich ascites carcinoma or B16 melanoma there was a reduction in toxicity and an increase in survival time compared with MMC. These observations suggest that the high molecular weight MMC-dextran derivative is a kind of pro-drug which persists in the body giving a sustained release of free MMC thus significantly increasing the antitumour activity of the parent drug.
Some preliminary observations of the nephrotoxicity of the male antifertility drug (±)α-chlorohydrin
Authors: Morris I D , Williams L M
Published: April 2011

(±)α-Chlorohydrin (80 mg kg−1) given by mouth to group-housed adult male Sprague Dawley rats produced an increase in the weight of the kidneys which persisted for at least 7 days, but there were no deaths. This dose administered to Sprague Dawley rats caged singly killed 3 out of 8 animals. The toxicity was studied in more detail using Wistar rats caged singly in metabolic cages. 4 out of 9 animals died with oliguria and anuria after 120mg kg−1 (±)α-chorohydrin, 100 and 120 mg kg−1 (in the surviving animals), produced a loss in appetite and body weight, proteinuria, a dose-related diuresis and an increased water intake. Urinary glucose was dramatically elevated after 100 mg kg−1 but after 120 mg kg−1 the glucosuria was not as marked. By day 7 all parameters were returning to their pre-injection values. A dose of 80 mg kg−1 had no effect upon any of the parameters studied. The results are discussed in relation to the basic biochemical mechanism by which the drug exerts its antifertility action, which is achieved at much lower doses.
The binding of [3H] pargyline to rat liver mitochondrial monoamine oxidase
Authors: Parkinson David , Callingham Brian A
Published: April 2011

The synthesis and purification of tritium labelled N-desmethylpargyline and pargyline are described. The suitability of these irreversible suicide inhibitors of monoamine oxidase (MAO) as ligands in binding studies to rat liver mitochondrial MAO has been evaluated. [3 H] Pargyline was found to be more satisfactory than its N-desmethyl analogue because of its greater potency and lower proportion of non-specific binding. The binding of pargyline reached saturation when about 31 pmol mg protein−1 was bound. It was not possible to explain the time course of the binding by either simple first or second-order kinetics. [3 H]-Pargyline is a potentially valuable ligand for the estimation of the concentration of MAO active centres without the need to remove the enzyme from the mitochondrial membrane.
Species differences in clobazam metabolism and antileptazol effect
Authors: Caccia S , Guiso G , Samanin R , Garattini S
Published: April 2011

The antileptazol effect of clobazam lasts longer in the mouse than in the rat. After intraperitoneal injection of clobazam (10 mg kg−1) plasma and brain concentrations of the drug and its rate of disappearance were similar in both species, whereas the metabolite N demethylclobazam was present at higher concentrations and for longer in the mouse than in the rat. Although the exact contribution of the N-desmethylclobazam to the anticonvulsant effect of clobazam cannot be assessed, the longer duration in mice than in rats seems to be associated with different brain accumulations of the metabolite.
Effective intestinal absorption of insulin in diabetic rats using a new formulation approach
Authors: Touitou Elka , Donbrow Max , Rubinstein Ardon
Published: April 2011

Insulin injected intra-jejunally together with the non-ionic surfactant cetomacrogol was effective in streptozocin-induced diabetes in the rat, as measured by the hypoglycaemic effect. The reduction in blood sugar was maximal at about 2 h after administration but continued at a high level for the 4 h of the experiment. No hypoglycaemic effect was observed in controls injected with insulin or saline alone. Intestinal absorption of insulin has thus been effected by the addition of cetomacrogol, which appears to enhance membrane-permeability to insulin rather than to function as a protective agent preventing insulin degradation, as in liposome-encapsulation. In support of this, a significant hypoglycaemic action was still obtained when the insulin injection was given half-hour after that of the cetomacrogol, both intra-jejunally. Furthermore, oral administration of the surfactant followed by intra-jejunal injection of the insulin also gave a hypoglycaemic effect. The use of this agent to enhance insulin absorption offers the possibility of a new approach to oral insulin therapy.
The molecular weight and molecular weight distribution of hydroxypropyl methylcellulose used in the film coating of tablets
Authors: Rowe R C
Published: April 2011

The molecular weight and molecular weight distributions of nine grades of hydroxypropyl methylcellulose used in the film coating of tablets have been measured using gel permeation chromatography. With the exception of Pharmacoat 603, there is a high molecular (>5 times 105) component present in all grades ranging from relatively small amounts in grades with low nominal viscosity to relatively large amounts in the 50 mPas grade. The peak molecular weight taken from the distribution curve—an indication of the molecular weight of the main component—could be calculated from the nominal viscosity using the equation. Peak molecular weight = 23·54 times 103 (viscosity)0·45. The relationship could also be expressed in the standard form [η] = KMα where M is the peak molecular weight [η] is the intrinsic viscosity and K and α are constants (in this case 9·94 times 10−4 and 1096 respectively). The wide molecular weight distribution of these samples and the presence of quite high proportions of very low molecular weight (<5 times 103) components especially in samples with nominal viscosity designations of less than 15 mPas appears to affect their mechanical properties.
Cooling as a possible method for increasing the flowability of certain pharmaceutical and other powders
Authors: Onyekweli A O , Pilpel N
Published: April 2011

Measurements have been made of the rates of flow under gravity of powdered sugars and of fatty acids through circular orifices at temperatures between −25 and 110 °C. The flow rates decrease considerably as the powders are heated; conversely they increase as the powders are cooled from a high ambient temperature of 40 to −25 °C. The results are ascribed to changes in the cohesiveness of the powders caused by softening and plastic deformation of particles at elevated temperatures. Lactose, paracetamol and griseofulvin granule formulations have been reported to show similar effects and the possibility is discussed of using cooling to increase the flowability of particular powders in pharmaceutical production. The rates of flow of the powders are given by the expression

where W is the flow rate in g min−1, Do is the orifice diameter in cm, ρ is the particle density in g cm−3, g is the gravitational constant, and A and n are numerical terms which depend on temperature and particle size.
Accelerated storage tests on pharmaceutical products: effect of error structure of assay and errors in recorded temperature
Authors: Davies O L , Budgett D A
Published: April 2011

The likely error structure for accelerated shelf-life studies is discussed. How to fit the Arrhenius relationship in the presence of this structure is shown and it is concluded that test potencies between 20% and 50% are likely to provide most information. The effect of temperature errors on the estimation of shelf-life is also considered.
Photosensitization by drugs: photolysis of some chlorine-containing drugs
Authors: Moore Douglas E , Tamat Swasono R
Published: April 2011

Irradiation with ultraviolet light of chlorpromazine, prochlorperazine, frusemide or hydrochlorothiazide in either aqueous or methanol solution yielded free chloride ion. Potentiometric methods were used to detect one mol of chloride ion produced per mol of drug irradiated in deoxygenated solution, with a concomitant equimolar appearance of hydrogen ion. Saturation of the solutions with oxygen strongly inhibited the photolysis reaction in methanol but only partially inhibited the production of Cl− and H+ in aqueous solution. The oxidation of 2,5-dimethylfuran is photosensitized by these drugs more effectively in methanol compared with aqueous solution. The photochemical behaviour is consistent with a photo- dissociative process occurring predominantly in methanol while photoionization predominates in aqueous media. No chloride ion was detected after extended irradiation of Chlortetracycline, demeclocycline, chlordiazepoxide and hexachlorophane. The photolability of the chlorine in the compounds tested correlated with their ability to photosensitize oxidation by the Type I (free radical) mechanism.
Inhibitors of α-chymotrypsin derived from cephalosporins: structure-activity relationships
Authors: Hachim B , Smith H J
Published: April 2011

Cephalothin and certain other cephalosporins are irreversible inhibitors of α-chymotrypsin in near neutral media. The active inhibiting species is slowly generated in small yield from cephalothin in aqueous solution. Structure-activity studies for 37 other cephalosporins and related compounds establish that inhibitors of the enzyme require in the parent cephalosporin molecule a 7-acyl substituent containing a flat area in the form of an aromatic or heterocyclic ring together with a 3-acetoxymethyl or other substituent which is labile to water. The inhibitory species is considered to be the oxazolinone derived from the corresponding cephalossporoic acid.
Rotational behaviour elicited by 5-HT in the rat: evidence for an inhibitory role of 5-HT in the substantia nigra and corpus striatum
Authors: James Thomas A , Starr Michael S
Published: April 2011

Unilateral intranigral microinjection of 5-HT or Wy 25093, a selective inhibitor of 5-HT uptake, elicited ipsiversive circling and a fall in striatal dopamine (DA) turnover. Conversely intranigral methysergide or unilateral lesions of the raphe-nigral 5-HT pathway produced contraversive turning and/or increased DA turnover. Both types of behaviour were accentuated by nialamide and attenuated by haloperidol. Caudate injections of 5-HT or Wy 25093 provoked contraversive turning which was increased by nialamide and hyoscine, partially diminished by haloperidol and antagonized by eserine. Ipsiversive circling was induced by intracaudate methysergide, which was potentiated by nialamide and eserine, unaffected by haloperidol and depressed by hyoscine. It is proposed that 5-HT normally subserves an inhibitory function both in the substantia nigra and corpus striatum.
Comparison of the effects of the stereoisomers of fenfluramine on the acetylcholine content of rat striatum, hippocampus and nucleus accumbens
Authors: Consolo S , Ladinsky H , Forloni G L , Tirelli A S , Garattini S
Published: April 2011

The (+)- and (-)- isomeric forms of fenfluramine were compared for their effects on rat brain area acetylcholine (ACh) content. The drugs showed similar patterns in increasing ACh content in the accumbens and hippocampus and in being ineffective in the brainstem. The actions differed in the striatum where the (+)-form markedly increased ACh content while the (-)-form produced no change. Both isomer-induced increases in ACh in the accumbens were prevented when 5-HT synthesis was blocked by p-chlorophenylalanine, thus denoting 5-hydroxytryptaminergic mediation of these effects. In striatum, the increase in ACh induced by (+)-fenfluramine was summated with the increase in ACh induced by dopamine receptor stimulation with apomorphine and was not prevented by dopamine receptor blockade with pimozide. On the other hand, apomorphine's effect was blocked by (-)-fenfluramine while pimozide pretreatment unmasked an increase in ACh induced by (-)-fenfluramine. The results favour the notion that there is a population of cholinergic neurons intrinsic to the striatum which is under inhibitory 5-HT regulation and independent of inhibitory dopamine regulation.
In vitro and in vivo α-blocking activity of thymoxamine and its two metabolites
Authors: Creuzet M H , Prat G , Malek A , Fauran F , Roquebert J
Published: April 2011

The α-adrenoceptor potency of thymoxamine and its two metabolites deacetylthymoxamine and demethyldeacetylthymoxamine were determined on the contraction of rat vas deferens induced by noradrenaline, the blood pressure increase induced by noradrenaline given i.v. to dogs and the contraction of the nictitating membrane induced by electrical stimulation in cats. In vivo the three drugs were administered at 6·35 times 10−6 mol kg−1 intravenously. Deacetylthymoxamine presented nearly the same α-blocking activity as the parent drug. This was ascribed in vivo to the rapid deacetylation of thymoxamine. Demethyldeacetylthymoxamine was less active. In vitro its pA2 was 6·20 ± 0·09 compared with 6·75 ± 0·20 for thymoxamine and 6·57 ±0·13 for deacetylthymoxamine. In vivo, it was inactive in dog and less active than the other two drugs soon after its administration in the cat. The oral LD 50 values in the mouse for the three drugs were respectively 0·81, 0·71 and 1·14 mmol kg−1 for thymoxamine, deacetylthymoxamine and demethyldeacetylthymoxamine.
The availability of nitroglycerin from parenteral solutions
Authors: Roberts M S , Cossum P A , Galbraith A J , Boyd G W
Published: April 2011

The availability of nitroglycerin from solutions infused from Viaflex plastic infusion bags or glass infusion bottles through Buretrol plastic giving sets has been examined. Each of the individual components of the infusion bag/giving set system (i.e. infusion bag, burette and infusion tubing) sorbed nitroglycerin to a significant extent. It was found that the extent and rate of nitroglycerin disappearance from solutions stored in each of the components were in the rank order: tubing > burette > infusion bag. The disappearance kinetics of nitroglycerin from solutions stored in each component was more accurately described by a ‘diffusion’ model than by the ‘two compartment kinetic’ model reported previously. The dimensions of the components and the volume of solution used were determinants of the rate and extent of nitroglycerin disappearance. In simulated infusions of nitroglycerin through plastic infusion bag (or glass bottle)/giving set system the flow rate of solution through the plastic infusion tubing affected the concentration of nitroglycerin in the effluent and the extent of sorption by the components of the infusion delivery system. The loss of nitroglycerin in these studies could be accounted for solely by the sorption of nitroglycerin by the plastic components of the infusion bag/giving set system.
The effects of sodium nitroprusside and cyanide on haemoglobin function
Authors: Vesey C J , Krapez J R , Cole P V
Published: April 2011

Incubation of human blood with 0·3 mM sodium nitroprusside (SNP) or 1 mM potassium cyanide (KCN) for 180 min produced a 600-fold increase in red cell cyanide concentration, a 4% decrease in oxygen capacity and a 6% increase in oxygen affinity. These effects were not reproduced in patients receiving SNP by infusion probably because in the clinical situation much smaller amounts of the drug were used and red cell cyanide levels were lower. The in vitro observations could be explained by cyanide either combining directly with the haemoglobin or encouraging its spontaneous oxidation to methaemoglobin during the incubation. Differences in distribution of cyanide between red cell and plasma following incubation with SNP or KCN and the initial lag phase in accumulation of cyanide in the red cell with SNP provide further evidence that nitroprusside breaks down principally within the red cell.
p-Methoxyamphetamine, a potent reversible inhibitor of type-A monoamine oxidase in vitro and in vivo
Authors: Green A L , Hait Mayyada A S El
Published: April 2011

p-Methoxyamphetamine is over 20 times as potent as (+)-amphetamine as an inhibitor of 5-HT oxidation by monoamine oxidase in mouse brain in vitro, with a Ki value of 0·22 μM. It is highly selective towards A-type monoamine oxidase and possesses only weak activity against the B-type enzyme (Ki value about 500 μM with benzylamine as substrate and solubilized rat liver mitochondria as enzyme source). It is 10 times more active than (+)-amphetamine in protecting mouse brain monoamine oxidase from inhibition by phenelzine in vivo. o-Methoxy- and m-methoxyamphetamines inhibit monoamine oxidase both in vitro and in vivo with potencies comparable with, or less than that of (+)-amphetamine.
The distribution and fate of 131 I-labelled liposomes
Authors: Hardy J G , Kellaway I W , Rogers J , Wilson C G
Published: April 2011

The distribution of 131 I-labelled liposomes with sodium iodide entrapped in the aqueous core has been compared with that of a preparation containing iodinated phospholipid, following i.v. administration to rabbits. Liver uptake was observed initially with both liposomes, but the distribution of the former preparation soon became indistinguishable from that of [131 I] sodium iodide. Iodine-131 was still detectable in the liver 150 h after administration of the phospholipid labelled material. Scintigrams showing the distributions of the radionuclides following administration of 131 I-labelled liposomes and 99m Tc-DTPA liposomes indicate that there may be some biliary clearance.
Rectal absorption of insulin suppositories in rabbits
Authors: Ichikawa Kunihide , Ata Isao Oh , Mitomi Mitsuo , Kawamura Shigeo , Maeno Hiroo , Kawata Hiroitsu
Published: April 2011

When insulin solutions (100 U kg−1) at various pH values were placed in the rectum of rabbits, a large decrease in blood glucose concentration was observed except at the pH close to the iso-electric point of insulin. The effect of surface-active agents on the rectal absorption of insulin was examined by measuring the blood glucose concentration after the administration of 2 or 5 U kg−1. Non-ionic ether type, anionic, cationic and amphoteric surfactants as well as bile acids increased the absorption. The optimal effect with suppositories was reached with the addition of 1% polyoxyethylene (9) lauryl alcohol ether. Insulin suppositories containing agents enhancing rectal absorption were compared with the insulin for intravenous, intramuscular and subcutaneous injection. The changes of blood glucose and plasma immuno-reactive insulin concentration after rectal administration of insulin were similar to those after intravenous injection.