bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of chronic nicotine pretreatment on (+)-amphetamine and nicotine-induced synthesis and release of [3H]dopamine from [3H]tyrosine in rat nucleus accumbens
Authors: Fung Yiu K
Published: April 2011

The effects of chronic (14 day) administration of nicotine (1·5 mg kg−1 day−1) on the rat nucleus accumbens have been examined. Pretreatment of animals with nicotine increased the endogenous level of dopamine. The ability of (+)-amphetamine to stimulate formation and release of [3H]dopamine from [3H]tyrosine was greatly potentiated in tissue slices from the nucleus accumbens of rats pretreated with nicotine. Furthermore, nicotine was effective in stimulating the formation and release of from [3H]dopamine from [3H]tyrosine in tissue slices from chronic nicotine-treated animals.
Influence of Plasma Protein Binding on the Brain Uptake of an Antifungal Agent, Terbinafine, in Rats
Authors: Machard Brigitte , Misslin Pierrette , Lemaire Michel
Published: April 2011

The intracarotid injection technique has been used to determine the unidirectional brain uptake of an antifungal, lipophilic agent, terbinafine (Lamisil, Sandoz Basle), in the rat. Ultrafiltration showed it to be highly bound to human plasma, human serum albumin (HSA), α-acid glycoprotein (AAG) and lipoproteins (VLDL, LDL, HDL). The effect of plasma protein binding of the drug on brain uptake was also examined with the technique. The lowest brain uptake was observed in the presence of plasma (6%); it varied from 23 to 30% with physiological concentrations of VLDL, LDL and HSA and was significantly higher (43–45%) in the presence of physiological concentrations of AAG and HDL. The free fraction as determined in-vitro and the brain uptake of the drug varied inversely with the plasma protein concentrations; however, the brain uptake was higher than expected from in-vitro measurements. These data indicate that the amount of circulating Lamisil available for brain penetration exceeds its free fraction; they also show that plasma proteins differently reduce the brain transport of the drug.
The Inhibitory Effects of Cannabinoids, The Active Constituents of Cannabis sativa L. on Human and Rabbit Platelet Aggregation
Authors: Formukong E A , Evans A T , Evans F J
Published: April 2011

Olivetol, cannabigerol (CBG), cannabidiol (CBD), cannabinol (CBN) and tetrahydrocannabinol (δ1-THC) were assessed for their ability to inhibit agonist-induced platelet aggregation and [14C]5-HT release. With the exception of olivetol, (40% maximal effectiveness), none of the compounds inhibited tetradecanoylphorbolacetate (TPA)-induced aggregation of human or rabbit platelets. All of these cannabinoids partially inhibited primary aggregation and totally inhibited secondary aggregation of human platelets when adrenaline was used as the agonist. Inhibition was dose-dependent over the range 10−3–10−5 M. Both rabbit and human platelet aggregation induced by adenosine diphosphate was inhibited in a dose-dependent manner and the order of potency was CBG > CBD > olivetol > THC > CBN, the IC50 of CBG being 2·7 × 10−4M. PAF-induced aggregation of rabbit platelets was also inhibited by these compounds in a dose-dependent manner over the concentration range 10−3 to 10−4 M, however [14C]5-HT release was only partially prevented by the cannabinoids in a manner which did not correlate with inhibition of aggregation.
Solubilization of Indomethacin by Polysorbate 80 in Mixed Water-Sorbitol Solvents
Authors: Attwood D , Ktistis G , Mccormick Y , Story M J
Published: April 2011

The effect of indomethacin on the micellar properties of the non-ionic surfactant, polysorbate 80, in water-sorbitol mixtures containing up to 25% w/v sorbitol has been investigated by light scattering, photon correlation spectroscopy and viscometric techniques. The molecular weight of polysorbate 80 micelles containing solubilized indomethacin increased linearly with increase of sorbitol concentration. Solubilization of indomethacin resulted in an increase of micellar weight due not only to the incorporation of solubilizate but also to an increase in the number of polysorbate molecules per micelle. The micelles in all systems were most satisfactorily represented as oblate ellipsoids, the asymmetry and hydration of which increased with increase of sorbitol concentration. Indomethacin solubilization caused a restructuring of the micelle to produce a more symmetrical micelle of increased hydration.
The Antiemetic Profile of Zacopride
Authors: Smith William L , Alphin Reevis S , Jackson Carlotta B , Sancilio Lawrence F
Published: April 2011

The antiemetic activity of zacopride against a variety of emetogenic agents has been determined in dogs. Zacopride was highly effective in inhibiting emesis due to a wide range of cancer chemotherapeutic agents, particularly cisplatin. It was well absorbed orally since the dose of zacopride required to inhibit cisplatin-induced emesis in dogs by 90% was 28 μg kg−1 both by i.v. and p.o. routes. Further, zacopride (1 mg kg−1 p.o.), administered after the onset of cisplatin-induced emesis, reduced the number of subsequent emetic episodes by 91%. Zacopride at 0·1, 1, or 3·16 mg kg−1 p.o. or i.v., reduced the number of emetic episodes due to dacarbazine, mechlorethamine, adriamycin, actinomycin D, or peptide YY by 100, 100, 86, 96 and 79%, respectively. However, zacopride was not effective in inhibiting emesis due to either apomorphine, copper sulphate, protoveratrine A, histamine, or pilocarpine. No adverse effects attributed to zacopride were observed. Zacopride is thus a unique and potent antiemetic agent as it selectively inhibits the emetic response to cancer chemotherapy agents and peptide YY.
Effects of 3,3′-di-O-methylquercetin on guinea-pig isolated smooth muscle
Authors: Abdalla Shtaywy , Zarga Musa Abu , Afifi Fatma , Al-Khalil Sulieman , Mahasneh Adel , Sabri Salim
Published: April 2011

The effects of the flavone 3,3′-di-O-methylquercetin (DOMQ) have been examined and compared with those of quercetin, on guinea-pig isolated ileum, trachea, and main pulmonary artery (MPA). Except for transient contractions induced by low concentrations (10−8-3 × 10−6 M), DOMQ and quercetin (up to 3 × 10−4M) caused reduction of the tone and the phasic contractions of the ileum. A23187 reversed the inhibitory effects of quercetin but not those of DOMQ. DOMQ and quercetin caused concentration-dependent relaxation of the trachea and the adrenaline-contracted MPA. DOMQ shifted to the right the concentration-effect curves induced by acetylcholine on the ileum and the trachea, and by adrenaline on MPA and those induced by CaCl2 on ileum, trachea and MPA. DOMQ also inhibited the contractions induced, in Ca2+-free EGTA-containing buffer, by histamine on ileum and by adrenaline on MPA. These observations suggest that DOMQ inhibits Ca2+ influx, Ca2+ release from intracellular stores and, more likely, Ca2+ binding to intracellular receptor proteins.
Pharmacokinetics of Quinacrine after Intrapleural Instillation in Rabbits and Man
Authors: Björkman Sven , Ove Elisson Lars , Gabrielsson Johan
Published: April 2011

Quinacrine was given by intrapleural instillation or intravenous infusion to 10 rabbits. The uptake of quinacrine from the pleural space was rapid and complete. The mean absorption half-life was approximately 7 min and the mean bioavailability was slightly in excess of 100%. Similar absorption characteristics generally applied in man, in a pilot study on four patients. In three of them, peak quinacrine plasma concentrations were reached that were far above the normal therapeutic range. Known systemic side-effects of quinacrine comprise CNS stimulation, toxic psychosis and convulsions. In view of the high bioavailability and the large doses used for pleural sclerosing (pleurodesis) in patients, neurological disease and psychiatric disturbances that predispose to CNS toxicity should be considered as contraindications to intrapleural quinacrine.
The influence of pH on the cardiac depressant action of tobramycin
Authors: Name C F , Vettore O , Antonio A
Published: April 2011

Tobramycin, like other aminoglycoside antibiotics, is a basic compound which causes a reduction of cardiac contractile force and inhibits the inotropic action of calcium. Its antagonistic action towards calcium had been analysed at different pH values of the solution bathing the rat left atrium. The isometric tension of the electrically driven atrium (4 Hz, 2 ms, supramaximal voltage) in response to cumulative increase in the bath calcium concentration (2·0 to 32·0 mM) was measured in the absence and in the presence of 20 × 10−5 M tobramycin. The increase in pH from 6·6 to 8·2, which decreased the ionization of tobramycin, reduced the cardiac depression. Similar experiments were carried with other cardiac depressants. Thus, the effect of methoxyverapamil (3·5 × 10−7 M), also a basic compound, was increased at higher values of pH; the acidic pentobarbitone (4 × 10−5 M) was less effective at more alkaline pH; the cardiac depression of the non-electrolyte ethanol (2 × 10−4 M) was practically the same over the pH range studied. The time for equilibrium of the antagonism was small for tobramycin, moreover, its antagonism could only be fully reversed by an increase in extracellular calcium. These results suggest a competitive type of antagonism, between the ionized fraction of tobramycin and calcium, for superficial sites of the sarcolemma. The effect of methoxyverapamil, pentobarbitone and ethanol seems to occur at a more internal site of the cardiac cell since the unionized form of the drug is the most active.
In-vitro evaluation of filaricidal activity of GABA and 1,3-dipalmitoyl-2-(4-aminobutyryl)glycerol HCl: a diglyceride prodrug
Authors: Deverre Jean R , Loiseau Philippe , Couvreur Patrick , Letourneux Yves , Gayral Philippe , Benoit Jean P
Published: April 2011

A diglyceride ester of γ-aminobutyric acid (GABA) has been synthesized and its filaricidal activity compared with GABA, and progabide in-vitro, on infective larvae and microfilariae of Molinema dessetae, a rodent filaria. GABA induced paralysis in infective larvae but was inactive on microfilariae. There were interactions between the culture medium and GABA. The ester drug at 0·1 mmol L−1 (1,3-dipalmitoyl-2-(4-aminobutyryl)glycerol HCl) was as active as progabide on infective larvae and hundredfold more potent than GABA. Its microfilaricidal activity at 1 mmol L−1 was lower than that progabide at 0·1 mmol L−1 but a delayed effect was observed. The data confirm filariae sensitivity to GABA derivatives.
Effect of lithium chloride on the neurotransmitter release from adrenergic nerve terminals of guinea-pig atria
Authors: Mantelli L , Ledda F
Published: April 2011

Lithium chloride at 1 and 10 mM produced a dose-dependent inhibition of the cardiac response to field stimulation of the adrenergic nerve terminals, without affecting myocardial contractility in electrically stimulated guinea-pig atria. This effect was calcium-independent and was also present in preparations super-fused with 10 mM myoinositol. Moreover, 10 mM lithium chloride reduced the positive inotropic effect of tyramine. These results indicate that lithium reduces the evoked release of noradrenaline from the adrenergic nerve endings, probably lowering the content of releasable neurotransmitter.
Rilmenidine Differs From Clonidine in that it Lacks Histamine-like Activity
Authors: Li C G , Rand M J
Published: April 2011

Studies were carried out to determine whether rilmenidine, a recently introduced antihypertensive agent with a similar mechanism of action of Clonidine, possesses histamine-like activity on tissues responding to histamine H2-receptor agonists. In guinea-pig isolated atria, both histamine and Clonidine caused concentration-dependent positive chronotropic effects which were blocked by the histamine H2-receptor antagonist Cimetidine (5 μM);.in contrast, rilmenidine produced a concentration-dependent negative chronotropic effect which was not altered by Cimetidine. In stilboestrol-treated rat isolated uterus contracted by KC1, histamine and Clonidine produces concentration-dependent relaxations which were blocked by Cimetidine (5 μM); rilmenidine also produced relaxation, but this was not affected by Cimetidine (5 μM). These findings suggest that rilmenidine, unlike Clonidine, does not activate histamine H2-receptors in either guinea-pig atria or rat uterus.
A new approach to prostate cancer
Authors: Ito Yoshikazu Z , Nakazato Yoichi , Petrow Vladimir
Published: April 2011

Growth of androgen-dependent human prostatic adenocarcinoma implanted in the nude mouse (Honda tumour), is inhibited by 6-methyleneprogesterone. This steroid is a potent inhibitor of both rat and human prostatic 5α-reductase in-vitro. In-vivo, at the studied dose level, it reduces metabolic conversion of testosterone to dihydrotestosterone with minimal effects upon circulating LH and testosterone. These data support the hypothesis that dihydrotestosterone and not testosterone is the main trophic androgen of the human prostatic neoplasm.
Effect of reserpine pretreatment on brown fat iodothyronine 5′-deiodinase of mouse
Authors: Muraki Takamura , Tsukahara Fujiko , Oike Nobuko , Nomoto Teruko
Published: April 2011

The effect of pretreatment with reserpine (1 mg kg−1 i.p. daily for 7 days) on the regulation of iodothyronine 5′-deiodinase (5′D) in mouse brown adipose tissue (BAT) has been examined. 5′D activity of BAT homogenate was assessed by the in-vitro formation of 3,5,3′-triiodothyronine from thyroxine and 3,3′-diiodothyronine from 3,3′,5′-triiodothyronine in the presence of 20 mM dithiothreitol. Reserpine treatment decreased the stimulation of BAT 5′D induced by acute cold exposure (4°C, 2h) without a significant decrease in the basal 5′D activity, whereas stimulation of BAT 5′D elicited by noradrenaline (0.4 and 0.8 mg kg−1 s.c. 2 h previously) was not augmented after reserpine treatment. Although both noradrenaline and acute cold exposure increase BAT 5′D through α1-adrenoceptors, our results show that chronic reserpine treatment prevents the effect of cold, but does not induce α1-adrenoceptor supersensitivity in BAT.
Calculation of Punch Displacement and Work of Powder Compaction on a Rotary Tablet Press
Authors: Oates R J , Mitchell A G
Published: April 2011

To calculate the work of compaction during tableting it is necessary to have accurate values of force and punch displacement. The direct measurement of punch displacement on a rotary press is both costly and complicated but calculated displacements will be in considerable error unless deflections in the press during compression are taken into account. By analysing the physical restraints imposed on the punches during tablet compression, an expression for punch displacement was derived. From preliminary measurements made on the tablet press of machine deflections and punch displacement under static conditions, the terms of this expression were evaluated for dynamic conditions. This analytic solution was then used to determine the true punch displacement and work of compaction from direct measurements of vertical force and turret position.
Influence of capsaicin-sensitive fibres on experimentally-induced colitis in rats
Authors: Evangelista Stefano , Meli Alberto
Published: April 2011

Systemic capsaicin pretreatment worsens trinitrobenzene sulphonic acid-induced colitis but has no effect on colitis induced by ethanol or acetic acid. The influence of capsaicin-sensitive fibres on experimentally-induced colitis seems to depend upon the type of ulcerogenic stimuli in relation to its chronic nature.
Postnatal effects of maternal nicotine exposure on the striatal dopaminergic system in rats
Authors: Fung Yiu K
Published: April 2011

The biochemical effects of continuous prenatal exposure to nicotine (1·5 mg kg−1 day−1) have been examined in 14 day old male and female rat pups. The ability of striatal tissue slices from the nicotine-exposed pups to synthesize [3H]dopamine from [3H]tyrosine was enhanced. However, the ability of (+)-amphetamine to stimulate formation and release of [3H]dopamine from [3H]tyrosine was not affected. Furthermore, prenatal exposure to nicotine increased the rate of striatal dopamine turnover in the male, but not the female nicotine-exposed pups.
Effect of Structural Variations of Non-ionic Surfactants on Micellar Properties and Solubilization: Surfactants with Semi-polar Hydrophobes
Authors: Attwood D , Elworthy P H , Lawrence M J
Published: April 2011

Novel non-ionic surfactants have been synthesized in which a polar group (either an ether or a keto group) has been introduced into the hydrocarbon chain of an octadecylpolyoxyethylene glycol monoether (C15En) with an oxyethylene chain length, n, of 17–18 units. Light scattering studies have indicated aggregation numbers for these semi-polar surfactants in aqueous solution of between 55–65% of that of an unsubstituted octadecylpolyoxyethylene glycol monoether, C18E22. The solubilizing capacities of the semi-polar surfactant micelles for test compounds which were mainly solubilized at the polyoxyethylene/core interface were lower than those of C18E22 whilst solubilizates which exhibited a reasonable degree of solubility in both the interface and the micellar core showed an increased solubilization.
Time Course of Verapamil Interaction with Morphine Effects on Physiological Parameters in Rats
Authors: Puppa Andrea Della , Ford-Rice Felicia , Snyder Frederick R , Cone Edward , London Edythe D
Published: April 2011

The effects of subcutaneous doses of morphine and verapamil on respiratory and cardiovascular parameters have been assessed in conscious rats. Verapamil (10 mg kg−1) was injected simultaneously with morphine (16 mg kg−1) or at 10, 30, or 60 min before morphine administration. Morphine induced respiratory depression, as indicated by marked hypercapnia, hypoxia and acidosis, and caused marked tachycardia. Although morphine produced only a minor and inconsistent (but statistically significant, P<0·01) reduction of mean arterial blood pressure, morphine potentiated verapamil-induced hypotension. Verapamil suppressed morphine-induced hypercapnia only when injected simultaneously with morphine. Verapamil alone did not affect arterial blood gases or pH, but decreased heart rate and mean arterial blood pressure. Verapamil attenuated and delayed the maximum positive chronotropic effects of morphine at all times tested. Antagonism by verapamil of respiratory depression and tachycardia produced by morphine was unrelated to morphine levels in plasma. Thus, the explanation of verapamil-morphine interactions on respiration and cardiovascular function is not pharmacokinetic.
Pharmacokinetics of Cyanamide in Dog and Rat
Authors: Obach R , Colom H , Arso J , Peraire C , Prun̂onosa J
Published: April 2011

A pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (E.C. 1.2.1.3) has been made in the beagle dog and Sprague-Dawley rat. Cyanamide plasma levels were determined by a sensitive high performance liquid chromatographic assay, specific for cyanamide. In the dog, i.v. administration of cyanamide at 1, 2 and 4 mg kg−1, produced a dose-dependent pharmacokinetic behaviour. Statistically significant changes were observed in plasma clearance values (12·6 to 19·7 mL kg−1 min−1), half life values (39 to 61 min) and mean residence times (50 to 79 min). Peak plasma concentrations, after oral administration of 4 mg kg−1 were achieved at 30 min and oral bioavailability was about 65%. In the rat after i.v. or oral administration, cyanamide (2 mg kg−1) had a half life of 30 min, a total plasma clearance of 117 mL kg−1 min−1 and a mean residence time of 26 min. Oral bioavailability was about 69%.
Ergometrine and 5-hydroxytryptamine binding sites in rat brain and myometrium
Authors: Hollingsworth M , Dascombe M J , Price D , Acton L
Published: April 2011

Functional studies suggest that ergometrine is a partial agonist involving 5-hydroxytryptamine (5-HT) receptors in rat uterus. Ergometrine displaced [3H]5-HT from specific binding sites in rat brain, but did not displace [3H]5-HT at functionally important concentrations in rat myometrium. These binding studies indicate that the agonist and antagonist actions of ergometrine in rat uterus arise from its initial interaction with binding sites other than those for 5-HT.
Age-dependence of the effects of pinacidil on rat aorta
Authors: Wanstall Janet C , O'Donnell Stella R , Zeng Xiang-Ping
Published: April 2011

The effect of the K+ channel opening drug, pinacidil, has been examined on aortic ring preparations from young (2 months) and aged (> 24 months) rats. The potency (neg log IC50) values for pinacidil in relaxing K+ (20 mM)-contracted preparations were in the range expected for its K+ channel opening (hyperpolarizing) effects but were not significantly different between young (6·34) and aged (6·31) rats. Thus, ageing does not affect the drug’s potency as a K+ channel opening drug. The more marked depression of the maximum response to noradrenaline by pinacidil (10 μM) in aged rats (85% reduction) compared with young rats (43% reduction), reflected a reduced α-adrenoceptor reserve for noradrenaline in preparations from aged rats. Pinacidil, in concentrations greater than 10 μM, was able to relax preparations contracted with 80 mM K+ suggesting that it may have a second mechanism which does not involve hyperpolarization. It was more potent in producing this effect on the preparations from aged rats.
β-Adrenoceptor antagonist activities and binding affinities of timolol enantiomers in rat atria
Authors: Karhuvaara Sakari , Kaila Timo , Huupponen Risto
Published: April 2011

S-Timolol is an effective anti-glaucoma drug, but has potentially hazardous side effects. Recently, R-timolol, also, has been reported to be effective in lowering elevated intraocular pressure. In the present study, the β-adrenoceptor antagonist activities and binding of RK- and S-enantiomers of timolol have been examined on rat atrial preparations. The β-antagonistic activities were investigated using spontaneously beating rat heart atria. Both timolol enantiomers inhibited (-)-isoprenaline-induced chronotropic action competitively. S-Timolol was about 54 times more potent than R-timolol. The apparent binding affinities of timolol enantiomers to β1 and β2-adrenoceptors were determined by a radioligand binding assay using (-)-[125I]iodocyanopindolol (ICYP) as a marker and CGP 20712 A as a β1- and ICI 118,551 as a β2-adrenoceptor antagonist. Both enantiomers of timolol inhibited ICYP binding in nanomolar concentrations with Hill coefficients near unity. Neither enantiomer showed selectivity between β1- and β2-adrenoceptors, but R-timolol was approximately 30 times less active than S-timolol. It is concluded that R-timolol is a relatively potent non-selective β-adrenoceptor blocking agent, but may possibly exert a more localized β-adrenoceptor action in the eye than S-timolol, thus improving the safety of ocular timolol therapy.
Disposition of alfentanil in patients receiving a renal transplant
Authors: Bower S , Sear J W
Published: April 2011

The disposition of alfentanil has been investigated in 10 anaesthetized patients with chronic renal failure undergoing kidney transplantation and compared with eight age matched anaesthetized patients with normal renal function. Plasma samples were collected to 660 min following intravenous administration of alfentanil 3–5 mg (50 μg kg−1). Drug concentrations were measured by RIA; and alfentanil binding to plasma proteins by equilibrium dialysis against 0·1 M phosphate buffer, pH 7·4. Alfentanil binding to plasma proteins was 87·6% (s.d. 2·0) in the patients with chronic renal failure, and 89·7% (1·2) in patients with normal renal function (P = 0·025). There was no correlation between alfentanil binding and plasma albumin, total plasma proteins, plasma urea or plasma creatinine concentrations. In both groups, the drug concentration-time profile decayed in a curvilinear manner; in the chronic renal failure patients, restoration of function did not influence the decay profile. Elimination half life, mean residence time and apparent volume of distribution at steady state were not different in the two groups of patients (mean values: 142·4 and 120·2 min; 128·5 and 136·0 min; and 40·5 and 27·6 L, respectively in chronic renal failure patients and patients with normal renal function). Total drug clearance and Vd area were significantly increased in the chronic renal failure patients: 341·9 vs 211·8 mL min−1; and 69·3 and 35·5 L. There were no differences in intrinsic clearance or apparent volume of distribution at steady state for unbound drug between the two patient groups.
In-vivo Radiolabelled Oxiracetam Binding to Rat Brain
Authors: Mennini Tiziana , Taddei Carlo , Cagnotto Alfredo , Ponzio Franca
Published: April 2011

The in-vivo binding of [3H]oxiracetam has been studied in brain areas of rats examined 30 min after i.c.v. injection. Soluble radioactivity accounted for more than 90% of total radioactivity in all the structures considered and was not affected by co-injection with a 1000-fold excess of unlabelled oxiracetam. Both total and bound radioactivity showed a marked regional distribution, with highest concentrations in the septum, followed by the hippocampus; the cerebral cortex, striatum and cerebellum had the lower concentrations of radioactivity. Computer-assisted quantitative autoradiography with [14C]oxiracetam confirms these findings. Analysis of [3H]oxiracetam bound to membranes indicated that, after co-injection with a 1000-fold excess of unlabelled oxiracetam, there was a significant reduction of binding only in the septum, hippocampus and cerebral cortex. These results suggest that in those cerebral structures oxiracetam binds to saturable sites.
Halothane, Isoflurane and Enflurane Potentiate the Effect of Noradrenaline on Ventricular Automaticity in the Rat Heart: Evidence of the Involvement of Both α- and β-Adrenoceptors
Authors: Cárceles M D , Laorden M L , Hernandez J , Miralles F S , Campos M
Published: April 2011

Direct evidence has been sought as to what extent the sensitization of heart to the arrhythmogenic action of sympathomimetic drugs in the presence of the inhalatory anaesthetics, halothane, isoflurane and enflurane, is mediated by either α- or β- adrenoceptors. For this purpose, the effects of isoprenaline, noradrenaline and phenylephrine on ventricular automaticity induced by local injury have been studied in the isolated right ventricle of the rat. Isoprenaline was more potent in increasing ventricular automaticity than either phenylephrine or noradrenaline. The anaesthetic potentiated the effects of noradrenaline, as well as that of higher concentrations of phenylephrine, but not those of isoprenaline. These results support the contention that increases in ventricular automaticity induced by sympathomimetic drugs are mainly mediated by adrenoceptors of the β-type. However, the simultaneous activation of both α- and β-adrenoceptors seems to be necessary for the effect of the anaesthetics in sensitizing the heart to sympathomimetic drugs.
The vascular relaxant effects of guanabenz are not mediated by α2-adrenoceptors in rat aortic rings
Authors: Soares-da-Silva P , Villanueva M M
Published: April 2011

The present experiments show that the α2-adrenoceptor agonist guanabenz produced a concentration-dependent relaxation in 5-hydroxytryptamine- and noradrenaline-preconstricted rat aortic rings, but not when tone was raised by high potassium in the medium. Similar findings were made for pinacidil. In 5-hydroxytryptamine-preconstricted preparations the relaxant effect of guanabenz was not affected by yohimbine, propranolol or by removal of the endothelium. In noradrenaline-preconstricted rings the relaxant effects of guanabenz and pinacidil were significantly antagonized by tetraethylammonium. The results suggest that guanabenz might act in the muscle tissue by opening potassium channels or antagonism of calcium mobilization from intracellular stores.
On the Use of Diazepam and Pro-diazepam (2-Benzoyl-4-chloro-N-methyl-N-lysylglycin anilide), as Adjunct Antidotes in the Treatment of Organophosphorus Intoxication in the Guinea-pig
Authors: Karlsson Britt , Lindgren Björn , Millquist Eric , Sandberg Maria , Sellström Åke
Published: April 2011

Diazepam and pro-diazepam (2-benzoyl-4-chloro-N-methyl-N-lysylglycin anilide) have been used as adjunct antidotes to pyridostigmine and atropine against the organophosphate, soman, in the guinea-pig. Both added significant protection to the pyridostigmine/atropine treatment. Animals pretreated with diazepam, 60 min before soman, were “better” protected than animals given an equimolar dose of pro-diazepam therapeutically 1 min after soman. A pretreatment with diazepam for three days further increased the protection. A therapeutic dose of pro-diazepam, 1 min after soman, gave no further protection, to the three day diazepam pretreatment. The serum concentrations of diazepam (given i.p.) and desmethyldiazepam (given i.m.) were determined by GLC after diazepam (i.p.) and pro-diazepam (i.m.) were given. The protection, relative to the control, provided by the diazepam pretreatment (60 min before and for three days before soman) correlated linearly, r = 0.9898, with the serum values of diazepam achieved at these times. Our data suggest that diazepam as adjunct to pyridostigmine and atropine administered as pretreatment gives a “safer” protection, than an equimolar dose of pro-diazepam given therapeutically.
Further Studies on the Metabolism of Methylamine by Semicarbazide-sensitive Amine Oxidase Activities in Human Plasma, Umbilical Artery and Rat Aorta
Authors: Lyles Geoffrey A , Holt Andrew , Marshall C M Susan
Published: April 2011

An ion exchange radiochemical assay has been developed to study the deamination of [l4C]methyIamine (MA) in homogenates of rat aorta and human umbilical artery, as well as in samples of human plasma. MA metabolism was found to be inhibited almost completely by 1 mM semicarbazide, but virtually unaffected by 0.1 mM clorgyline, suggesting that MA is a substrate for the semicarbazide-sensitive amine oxidase (SSAO) activities which also metabolize benzylamine (BZ) in these sources. Mean Km values for MA metabolism by aorta, umbilical artery and plasma were 182, 832 and 516 μM, respectively, with corresponding Vmax values in aorta and umbilical artery of 100 and 590 nmol (mg prot.)−1 h−1, and in plasma of 48 nmol (mL serum)−1 h−1. Kinetic constants determined for [14C]BZ metabolism in plasma (by an organic solvent extraction assay) and in umbilical artery (by the ion exchange assay) yielded mean Km values of 225 μM (plasma), 222 μM (umbilical artery), and Vmax values of 28 nmol (mL serum)−1 h−1 (plasma) and 377 nmol (mg prot.)−1 h−1 (umbilical artery). The deamination of [14C]MA was inhibited competitively by unlabelled BZ, with Ki values in umbilical artery and plasma of 220 and 172 μM, respectively. Also, metabolite formation from mixtures of [14C]BZ (200 μM) and [14C]MA (800 μM) was extremely close to that predicted for a single enzyme capable of metabolizing two alternative substrates in a competitive fashion. β-Aminopropionitrile was found to be a reversible, competitive inhibitor (Ki of 165 μM) of [14C]MA metabolism in umbilical artery, inhibitory properties characteristic of those found previously for the effects of β-aminopropionitrile upon BZ-metabolizing SSAO activities in other tissues. The possibility that vascular and plasma SSAO activities may be involved in the endogenous turnover of the biogenic amine MA is discussed.
Effect of Pinacidil on the Electrophysiological Properties in Guinea-pig Papillary Muscle and Rabbit Sino-atrial Node
Authors: Hirai Shozo , Kotake Hiroshi , Kurata Yasutaka , Hisatome Ichiro , Hasegawa Junichi , Mashiba Hiroto
Published: April 2011

The electrophysiological effect of the antihypertensive drug pinacidil has been examined in preparations of guinea-pig papillary muscle and rabbit sino-atrial node using a standard microelectrode method. In papillary muscle preparations, pinacidil (> 30 μM) shortened the action potential duration (APD), whereas it did not affect the maximum rate of rise (Vmax). Pinacidil (> 1 μM) also decreased APD of slow action potentials evoked by high K+ (27 mM) solution containing 0.2 mM Ba2+. At 30 μM, the drug reduced the Vmax of slow action potentials. In the spontaneously beating sino-atrial node, pinacidil (> 30 μM) shortened APD. At 100 μM, it also decreased the heart rate, Vmax, action potential amplitude and the rate of diastolic depolarization. It is concluded that pinacidil modifies the electrical activity of myocardial cells probably due to an increase in the potassium conductance although in high concentrations the compound might also reduce Ca2+ influx through the cell membrane, which would contribute to an obvious negative chronotropic action.
The effect of an antacid and food on the absorption of cimetidine and ranitidine
Authors: Desmond P V , Harman P J , Gannoulis N , Kamm M , Mashford M L
Published: April 2011

The effect of varying doses of a liquid antacid preparation containing magnesium hydroxide, aluminium hydroxide and simethicone on the absorption of the H2-receptor antagonists, cimetidine and ranitidine, was determined in 2 groups of 11 volunteers; one group fasted and one group fed a standardized breakfast. The antacid alone caused a significant decrease in the AUC of cimetidine (24%). Similarly, concomitant antacid caused a 59% decrease in the AUC of ranitidine. There were no effects on any of the other pharmacokinetic parameters examined. The absorption of both drugs was similar in fasted and fed volunteers, but in the fed volunteers the antacid did not produce the decrease in AUC seen in the fasted volunteers. These data suggest that H2-receptor antagonists should not be taken at the same time as antacids.
The selectivity of the opioid antagonist, naltrindole, for δ-opioid receptors
Authors: Rogers Helen , Hayes Ann G , Birch Philip J , Traynor John R , Lawrence Andrew J
Published: April 2011

In the mouse vas deferens, naltrindole gave pKB values of 9.7, 8.3, and 7.5 at the δ-, μ-, and K-sites and in binding assays, pIC50 values of 9.6, 7.8 and 7.2 at the same sites. The affinity of naltrindole for the δ binding site was increased in the presence of sodium ions and 5′-guanylylimidophosphate. Naltrindole is, thus, a potent opioid antagonist with marked selectivity for the δ-opioid receptor.
Suppression of ventricular arrhythmias resulting from acute coronary artery ligation in rat by imipramine
Authors: El-Mahdy Samiha A M , Alhaider A A , Mahgoub Afaf A , Bashandy Abdulwahab M
Published: April 2011

The potential antiarrhythmic activity of imipramine against ventricular arrhythmias induced by coronary artery ligation in rats has been investigated and compared with procainamide. Imipramide (1 and 5 mg kg−1) or procainamide (5 and 10 mg kg−1) or solvent were injected intravenously 30 min before ligation. Imipramine reduced the total number of ventricular ectopic beats as well as the incidence and duration of ventricular tachycardia and ventricular fibrillation. The drug did not significantly affect the blood pressure but reduced the heart rate. The antiarrhythmic activity of imipramine is postulated to be due to a quinidine-like effect and/or α-adrenergic blocking activity. The study confirms the potential utility of imipramine as an antiarrhythmic drug.
Some Differential Effects of 4-Diphenylacetoxy-N-(2-chloroethyl)-piperidine Hydrochloride on Guinea-pig Atria and Ileum
Authors: Barlow R B , Shepherd M K , Veale M A
Published: April 2011

4-Diphenylacetoxy-N-(2-chloroethyl)-piperidine hydrochloride (I) cyclizes at neutral pH to form an aziridinium salt. The formation and breakdown of the salt depend on the temperature (in the range 25 to 37°C). In solution at 30 C., peak levels, corresponding to 60–80% conversion, are reached after around 60 min and the half-life exceeds 100 min. In the presence of 0.9% NaCl conversion was reduced to 45–60%. I blocks muscarinic receptors in guinea-pig ileum and atria irreversibly and it is possible to produce dose-ratios on ileum with 10 nM I which are about 100 times those on atria. After about 30 min exposure to solutions of I (prepared 15–20 min previously so that formation of aziridinium ions is well-established) the graph of log (dose-ratio) against time is linear and similar plots were obtained with two different agonists, carbachol and ethoxyethyltrimethylammonium. With results for the ileum, extrapolation of the line suggests that it does not start from zero (dose-ratio = 1): this is because of an initial relatively rapid reversible block. This early phase is similar to that seen on ileum with 10 nM 4DAMP methobromide, which is a competitive antagonist, so is probably caused by competitive block by the aziridinium ion, which closely resembles 4DAMP metho-salts. The subsequent irreversible phase should be caused by alkylation of the receptors. I is easy to make and should be a valuable tool for the study of muscarinic receptors.
Effect of Nipradilol on Myocardial Energy Metabolism in the Dog Ischaemic Heart
Authors: Hayase Nobumasa , Chiba Kaoru , Ichihara Kazuo , Inagaki Shun-Ichi , Abiko Yasushi
Published: April 2011

The effect of nipradilol, a newly developed β-adrenoceptor blocking agent with a vasodilatory action, on myocardial energy metabolism has been examined in the dog ischaemic heart, and compared with that of propranolol. Ischaemia was induced by ligating the left anterior descending coronary artery. Either saline, nipradilol (0.3 mg kg1), or propranolol (1 mg kg−1) was injected intravenously 5 min before coronary ligation. After 3 or 30 min of coronary ligation, the ischaemic region of the myocardium was removed, and the endocardial portion used to determine the levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), creatine phosphate (CrP) and lactate. Ischaemia decreased the levels of ATP and CrP, and increased the levels of ADP, AMP and lactate. Immediately after the injection of nipradilol, rapid falls in blood pressure and heart rate were observed. Pretreatment with nipradilol lessened the decreases in the levels of ATP and CrP and the increases in the levels of AMP and lactate, caused by 3 min of ischaemia, to the same extent as propranolol. However, after 30 min of ishchaemia, nipradilol had no effect on myocardial metabolism unlike propranolol. These results indicate that nipradilol can reduce ischaemic influences on myocardial metabolism as well as propranolol, but only in the early stages of ischaemia.
The sorption of isosorbide-5-mononitrate to intravenous delivery systems
Authors: De Muynck C , Colardyn F , Remon J P
Published: April 2011

The sorption of isosorbide-5-mononitrate, diluted in 0.9% NaCl or 10% glucose solutions, to intravenous delivery systems was investigated. Infusion bags, burettes, a syringe, infusion tubings and end-line filters were tested in static and in dynamic experiments. No clinically significant sorption was detected during those experiments. The use of PVC tubings of different hardness did not influence the results.
Role of unstirred water layer in the exsorption of quinidine
Authors: Huang Jin-Ding
Published: April 2011

Intestinal exsorption of salicylic acid, thiopentone, theophylline, and quinidine was measured during perfusion of the intestinal lumen with Tyrode solution. The effect of pectin or bovine serum albumin added to the perfusate on intestinal clearance (CL,) was investigated. Increasing pectin concentration from 00 to 0.5, 1.0 and 1.5% gave CL, values for quinidine of 499 ± 18, 363 ± 35, 237 ± 56, and 300 ± 28 mL h−1 kg−1, respectively. One per cent of pectin in the perfusate also decreased the CL, of thiopentone, but had no effect on the CLi of salicylic acid or theophylline. Pectin may have increased the thickness of the unstirred water layer on the mucous membrane and the resistance of drug exsorption for some drugs. When bovine serum albumin was added, drug binding in the perfusate increased, and the CLi of salicylic acid, thiopentone, and theophylline increased; the CLi of quinidine was unaltered. Co-administration of theophylline with quinidine decreased the CLi of quinidine without affecting quinidine binding in serum or in the perfusate. The CLi theophylline was not affected by quinidine. These observations are consistent with the hypothesis that the exsorption of quinidine is rate-limited by diffusion through the unstirred water layer on the mucous membrane. The CLi of quinidine is affected by the microclimate-pH in the unstirred water layer. An alternative possibility is that quinidine exsorption is mediated by a carrier-transport pathway.
Survey Variation in the THC Content of Illicitly Imported Cannabis Products—1984–1989
Authors: Pitts J E , O'Neil P J , Leggo K P
Published: April 2011

The tetrahydrocannabinol (THC) content of more than 180 samples of fresh illicit Cannabis products, seized by H.M. Customs and Excise on entry into Great Britain and Northern Ireland over the period 1984–1989, has been determined by gas chromatography. The average THC content of herbal cannabis remained high due to good quality cannabis from Jamaica and the USA, but that of cannabis resin was slightly lower. Resin from Morocco has changed significantly in its physical appearance. There was no fresh seizure of cannabis oil in this period.
Nanoparticle Uptake by the Rat Gastrointestinal Mucosa: Quantitation and Particle Size Dependency
Authors: Jani Praful , Halbert Gavin W , Langridge John , Florence Alexander T
Published: April 2011

Polystyrene microspheres in the size range 50 nm to 3 μm were fed by gavage to female Sprague Dawley rats daily for 10 days at a dose of 1.25 mg kg−1. Previous histological evidence of the uptake of these particles and their absorption across the gastrointestinal tract and passage via the mesentery lymph supply and lymph nodes to the liver and spleen was confirmed by analysis of tissues for the presence of polystyrene by gel permeation chromatography. Measurement of radioactivity of tissues following administration of 100 nm and 1 μm I125-labelled polystyrene latex particles for 8 days was corroborative although less secure because of the potential lability of the labelled particles. The extent of absorption of 50 nm particles under the conditions of these experiments was 34% and of the 100 nm particles 26% (as measured by determination of polystyrene content), of which total, about 7% (50 nm) and 4% (100 nm), was in the liver, spleen, blood and bone marrow. Particles larger than 100 nm did not reach the bone marrow, and those larger than 300 nm were absent from blood. No particles were detected in heart or lung tissue.
The measurement of internal pressure of ampoules and its application to commercial products
Authors: Tatsuhara Tohru , Tabuchi Fumie , Imai Yoko
Published: April 2011

This paper reports a method for determining the internal pressures of ampoules, from the head space and the change in volume on opening, as measured by displacement of water. Using this method, internal pressures of commercial ampoules were shown to be lower than atmospheric pressure. For example, the ratio of internal pressure to atmospheric pressure in a commercial ampoule of 5 mL distilled water was 0.884 at room temperature (23°C).
Effect of myrcene on nociception in mice
Authors: Rao V S N , Menezes A M S , Viana G S B
Published: April 2011

Myrcene, a monoterpene isolated from lemon grass oil (Cymbopogon citratus) has been investigated for antinociception in mice by a low temperature (51.5 ± 0.5°C) hot plate method and by the acetic acid-induced writhing test. Significant inhibition of nociception was seen in the tests with myrcene at doses of 10 and 20 mg kg−1 (i.p.) or at 20 and 40 mg kg−1 (s.c), respectively. The antinociceptive effect was significantly antagonized by naloxone (1 mg kg−1) or yohimbine (2 mg kg−1). The results suggest that myrcene is capable of inducing antinociception in mice, probably mediated by α2-adrenoceptor stimulated release of endogenous opioids.
Oxidative deamination of aliphatic amines by rat aorta semicarbazide-sensitive amine oxidase
Authors: Yu Peter H
Published: April 2011

Rat aorta semicarbazide-sensitive amine oxidase (SSAO) exhibits very high affinity in the deamination of an homologous series of aliphatic amines of 1 to 18 straight chain carbon atoms. The Km value decreases substantially as the chain length of these amines increases. The Vmax values are higher for the short chain amines. Diamines are poor substrates for SSAO or are not acted upon by the enzyme. The substrate preference for SSAO differs from that for monoamine oxidase.
The (+)-enantiomer is responsible for the antiplatelet and anti-inflammatory activity of (±)-indobufen
Authors: Cerletti Chiara , Manarini Stefano , Colombo Monica , Tavani Alessandra
Published: April 2011

The racemic compound indobufen and its (+)-and (—)-enantiomers have been compared for their effects on blood platelet function and rat carrageenan pleurisy. The antiplatelet properties were studied in-vitro in human platelets by measuring the inhibition of platelet aggregation and generation of serum thromboxane (Tx) B2. In-vivo, the antiplatelet and anti-inflammatory properties were studied in rats by measuring the inhibition of serum TxB2, the amount of 6-keto-PGF1α in pleural exudate and pleural exudate volume. In all tests the (+)-enantiomer was slightly more potent than the racemate, while the (—)-enantiomer was far less potent. In the same rats, treatment with the lowest doses of the compounds giving 90% inhibition of serum thromboxane B2 generation was associated with occasional macroscopic lesions of the gastric mucosa.
Comparison of Sensitization to Ambulation-increasing Effects of Cocaine and Methamphetamine after Repeated Administration in Mice
Authors: Hirabayashi Makizo , Okada Shizuka , Tadokoro Sakutaro
Published: April 2011

The effects of repeated (5 times) subcutaneous administration of cocaine (10, 20 or 40 mg kg−1) and methamphetamine (1, 2 or 4 mg kg−1) at 3–4 day intervals have been compared in mice placed individually into tilting activity cages. A progressive enhancement of the ambulation-increasing effect was noted for 3–4 h after each administration, indicating that sensitization occurred. This occurrence and the existence of an optimal dose producing sensitization were similar for both drugs. However, enhancement of the effect after cocaine progressed rapidly and maximum sensitization was observed earlier than after methamphetamine administration. Moreover, the higher doses of cocaine (40 mg kg−1) caused stereotypies concurrent with preconvulsive signs of short duration that were enhanced by serial administration. In contrast, methamphetamine caused a more progressive enhancement, but stereotypies with no preconvulsive signs were produced by the higher dose (4 mg kg−1). The respective, effective doses for the development of enhancement suggested that cocaine was less potent than methamphetamine in producing sensitization. Cross-sensitization occurred between both drugs. Thus, sensitization to cocaine was distinct from that to methamphetamine due to differences in its rapidity, intensity, and the presence or absence of preconvulsive changes.