bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diazepam and desmethyldiazepam differ in their affinities and efficacies at ‘central’ and ‘peripheral’ benzodiazepine receptors
Authors: Gobbi M , Barone D , Mennini T , Garattini S 
Published: April 2011

Abstract
The in-vitro binding characteristics of three different ligands ([3H]Ro 15–1788, [3H]Ro 5–4864 and [3H]flunitrazepam) and the structural requirements for binding to ‘central’ and ‘peripheral’ benzodiazepine receptors have been evaluated in rat cerebral cortex, cerebellum and adrenal glands. [3H]Ro 15–1788 binding was detectable only in the brain. Clonazepam was the most potent inhibitor followed by diazepam and desmethyldiazepam, which showed the same affinity, and by premazepam; Ro 5–4864 did not show appreciable affinity. The same pattern was seen for [3H] flunitrazepam binding in brain areas while in adrenal gland the inhibition pattern was exactly superimposable on that with [3H]Ro 5–4864 in all the areas considered (Ro 5–4864 &gt; diazepam &gt; desmethyldiazepam &gt; clonazepam &gt; premazepam). These data confirm and extend previous reports. A methyl group in position 1 enhances the affinity for peripheral benzodiazepine binding sites which are labelled in the adrenal gland by [3H]Ro 5–4864 and [3H]flunitrazepam; in brain areas, [3H]flunitrazepam, like [3H]Ro 15–1788, selectively labels central binding sites. Methylation in position 1 did not change the affinity for these sites. Desmethyldiazepam is less active than diazepam as an anticonvulsant and in other tests. In-vivo experiments were therefore carried out to assess the ‘intrinsic activity’ of desmethyldiazepam: it appeared that this compound acts as a partial agonist at central benzodiazepine receptors.
Relationship between progesterone suppression and pregnancy in rats
Authors: Carnathan Gilbert W , Metcalf Linda E , Cochrane Robert L , Nutting E F , Black D L 
Published: April 2011

Abstract
Four luteolytic agents were administered to groups of pregnant rats to examine the quantitative relationship between serum progesterone levels and the maintenance of pregnancy. Each agent inhibited progesterone in a dose-dependent manner, however only three, azastene, thiosemicarbazone and dihydrotestosterone, adversely affected pregnancy. A statistical analysis of the data suggests that, regardless of the mechanism of action of a particular luteolytic agent, a treatment-induced depression of serum progesterone to concentrations less than 45% of that of the controls on day 11 of pregnancy is incompatible with pregnancy maintenance.
Ca2+ channel-blocking effect of the yohimbine derivatives, 14β-benzoyloxyyohimbine and 14β-p-nitrobenzoyloxyyohimbine
Authors: Watanabe K , Yano S , Horiuchi H , Yamanaka E , Aimi N , Sakai S 
Published: April 2011

Abstract
Yohimbine possesses a relatively selective α2-adrenoceptor antagonistic effect and a weak Ca2+ channel blocking activity, so two derivatives, 14β-benzoyloxyyohimbine and 14β-p-nitrobenzoyloxyyohimbine were compared with yohimbine using those parameters. The two derivatives blocked Ca2+-induced contraction of the rat perfused mesenteric vascular bed at 3 times 10−6 M, and developed dose-dependent shifts of the dose-response curve to the right in concentrations from 3 times 10−6 to 10−5M. Yohimbine showed a weak Ca2+ channel-blocking effect only at a concentration of 10−5M. On the other hand, both derivatives at 3 times 10−6 M did not affect the dose-response curve to noradrenaline-induced vasoconstriction. Furthermore, at 10−8 M they had no effect on the dose-response curve to clonidine-induced inhibition of the twitch response of the rat isolated vas deferens evoked by electric stimulation, whereas yohimbine significantly attenuated clonidine-induced inhibition. These results indicate that introduction of bulky substituents into the 14-position of yohimbine intensely potentiated the Ca2+ channel-blocking effects and reduced α-adrenoceptor antagonistic effects compared with those of yohimbine, and suggest that chemical modifications of yohimbine may lead to structurally new types of Ca2+ channel-blockers.
Common ion effect on solubility and dissolution rate of the sodium salt of an organic acid
Authors: Serajuddin Abu T M , Sheen Pai-Chang , Augustine Matthew A 
Published: April 2011

Abstract
The solubility and the dissolution rate of the sodium salt of an acidic drug (REV 3164; 7-chloro-5-propyl-1H,4H-[1,2,4]triazolo[4,3-a]quinoxaline-1,4-dione) decreased by the effect of common ion present in aqueous media. The solubility of the sodium salt of REV 3164 in a buffered medium was much lower than that in an unbuffered medium. Also, the presence of NaCl decreased its solubility in water. The apparent solubility product (K'sp ***of the salt, however, did not remain constant when the concentration of NaCl was changed. A decrease in K'sp value with the increase in NaCl concentration was observed; for example, the K'sp values at 0 and 1 M NaCl were 7&#x006d;̇84 times 10−4 and 3&#x006d;̇94 times 10−4 M2, respectively. Even when corrected for the effect of ionic strength, the solubility product decreased. This decrease in the solubility product in the presence of NaCl indicated a decrease in the degree of self-association (increase in activity coefficient) of the drug in aqueous media.
Cyclosporin: measurement of fraction unbound in plasma
Authors: Legg Brian , Rowland Malcolm 
Published: April 2011

Abstract
A reproducible ultracentrifugation method has been developed for the measurement of the fraction of cyclosporin (CyA) unbound in plasma. The sample is centrifuged to remove any particulate matter, ultracentrifuged in polyallomer tubes and then frozen in liquid nitrogen. Appropriate sections are then cut from the tube for determination of the concentration of radioactivity and calculation of fraction drug unbound. Using this method, the fraction unbound has been measured in plasma from renal transplant patients receiving CyA and found to range between 0&#x006d;̇04 to 0&#x006d;̇122. The binding is temperature-dependent and principally hydrophobic.
Effect of nadolol, a β-adrenoceptor blocking agent, on myocardial metabolism in the dog ischaemic heart
Authors: Ichihara K , ABIKO Y 
Published: April 2011

Abstract
The effect of nadolol at a dose of 1 mg kg−1, i.v. on the ischaemic myocardial metabolism has been examined in the dog. Ischaemia was induced by ligating the left anterior descending coronary artery for 3 min, and nadolol was injected 5 min before ligation. Ischaemia caused myocardial metabolic changes; it decreased energy charge potential and inhibited glycolytic flux through phosphofructokinase reaction. Pretreatment with nadolol lessened the decrease in energy charge potential and the inhibition of glycolytic flux being caused by ischaemia. Nadolol may have a beneficial effect on the ischaemic myocardium.
Effects of diclofenac sodium and disodium ethylenediaminetetraacetate on electrical parameters of the mucosal membrane and their relation to the permeability enhancing effects in the rat jejunum
Authors: Yamashita Shinji , Saitoh Hidetaka , Nakanishi Kunio , Masada Mikio , Nadai Tanekazu , Kimura Toshikiro 
Published: April 2011

Abstract
The effects of diclofenac sodium and disodium ethylenediaminetetraacetate (EDTA) on electrical parameters of rat jejunal membrane were investigated, together with measurement of the mucosal-to-serosal flux of sulphanilic acid or L-phenylalanine. Both adjuvants increased the flux rate of sulphanilic acid to a similar extent when added to the mucosal solution at 10 mM, but there were apparent differences in their effects on the electrical parameters. The addition of EDTA induced the gradual reduction in the membrane resistance (Rm) by 6–8 ohm cm−2, while the effect of diclofenac on Rm was complicated and concentration-dependent. The short circuit current (Isc) was reduced rapidly to the level of 30–40 μA cm−2 by the addition of diclofenac, but was less affected by EDTA. The flux rate of L-phenylalanine was decreased extensively by diclofenac or the 10 mM concentration of EDTA, suggesting an inhibition of carrier-mediated transport systems in the membrane. Together with our preceding communication (Yamashita et al 1985, J. Pharm. Pharmacol. 37: 512–513), it became obvious that the sites of action of diclofenac and EDTA were different, the former directly interacting with the epithelial cell to alter the permeability and functions of the cell membane, while the primary effect of EDTA could be at the intercellular junctions.
L-Dopa esters as potential prodrugs: behavioural activity in experimental models of Parkinson's disease
Authors: Cooper D R , Marrel C , Van De Waterbeemd H , Testa B , Jenner P , Marsden C D 
Published: April 2011

Abstract
Intraperitoneal administration of the 2-tetrahydropyranylmethyl, phenoxyethyl, ethyl, 2-hydroxypropyl and methyl ester prodrugs of L-dopa produced locomotor activity in reserpine-pretreated mice with equal intensity and duration to that observed following administration of L-dopa itself. Administration of the 2-(1-methoxy)propyl ester produced a more prolonged effect while the p-methoxyphenylethyl, n-propyl, phenylethyl, m-trifluoromethylbenzyl, cyclohexyl, p-chlorophenylethyl and benzyl ester prodrugs were less active than L-dopa itself. On oral administration, the ethyl and methyl ester prodrugs were more effective than L-dopa in reversing reserpine-induced akinesia in mice. The 2-tetrahydropyranylmethyl, 2-(1-methoxy)propyl, 2-hydroxypropyl, n-propyl, benzyl and phenoxyethyl ester prodrugs produced effects comparable with those of L-dopa. In contrast, the cyclohexyl, m-trifluoromethylbenzyl, phenylethyl, p-chlorophenylethyl and p-methoxyphenylethyl ester prodrugs were less effective than L-dopa on oral administration. Intraperitoneal administration of L-dopa and the ester prodrugs of L-dopa to rats with a prior 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB) produced contraversive circling responses. Rotation observed following administration of the n-propyl, 2-tetrahydropyranylmethyl, methyl and ethyl ester prodrugs was more intense than that observed following administration of L-dopa itself. Rotation produced by the administration of L-dopa and the cyclohexyl, 2-(1-methoxy)propyl, phenylethyl, p-chlorophenylethyl, p-methoxyphenylethyl, benzyl, 2-hydroxypropyl, phenoxyethyl and m-trifluoromethylbenzyl ester prodrugs was identical. Ester prodrugs of L-dopa may be as effective as L-dopa itself in producing motor activity but overall none of the compounds tested was markedly more potent or of longer duration than L-dopa itself.
The cardiovascular actions of dopexamine hydrochloride, an agonist at dopamine receptors and β2-adrenoceptors in the dog
Authors: Smith George W , Hall Janet C , Farmer John B , Simpson Wilfrid T 
Published: April 2011

Abstract
The receptor pharmacology of the cardiovascular effects of dopexamine hydrochloride in the anaesthetized dog (given by i.v. infusion of 3 times 10−9-10−7 mol kg−1 min−1) has been analysed by the use of selective receptor antagonists and of ganglionic blockade. The increases in cardiac output, contractility, and rate were antagonized by the β2-adrenoceptor antagonist, ICI 118551. Renal blood flow rose secondary to reduction in renal vascular resistance and this was antagonized by SCH 23390, a highly selective DA1-receptor antagonist. Peripheral vasodilation and reduction of blood pressure were mediated by a combination of DA1 and DA2-receptor and β2-adrenoceptor stimulation. In a separate group of dogs, the cardiac stimulant effects of dopexamine HCl were partially reflex and were reduced by ganglion block, revealing responses due to stimulation of cardiac β2-adrenoceptors. Thus the β2-adrenoceptor agonist action of dopexamine HCl is not only partly responsible for afterload reduction but also leads to direct cardiac stimulation. From its cardiovascular profile, dopexamine HCl is likely to be of use in acute treatment of heart failure.
Determination of the apparent failure viscosity of tablets
Authors: Patel C I , Staniforth J N 
Published: April 2011

Abstract
Quantitative differences in the plasticity of several direct compression excipients were found to be distinguishable using normalized work of failure determinations. New parameters were developed to characterize the importance of changes in strain rate application during a diametral crushing test. Failure viscosity was found to have a similar sensitivity to normalized work of failure measurements and was also able to distinguish small changes in plastic behaviour. In cases where it is not possible to measure tablet deformation during tablet crushing, failure viscosity determinations could provide an alternative method for characterizing differences in deformation behaviour.
Unloaded polyisobutylcyanoacrylate nanoparticles: efficiency against bloodstream trypanosomes
Authors: Lherm C , Couvreur P , Loiseau P , Bories C , Gayral P 
Published: April 2011

Abstract
The potential use of polyisobutylcyanoacrylate nanoparticles in antiparasitic chemotherapy is described. The nanoparticles on their own proved to have trypanocidal activity against Trypanosoma brucei brucei in-vitro but not against Trichomonas vaginalis or Entamoeba histolytica. The trypanocidal activity was partly confirmed in-vivo with T. brucei-infected mice.
Non-specific prolongation of the effects of general depressants by pyrazole and 4-methylpyrazole
Authors: Taberner P V , Unwin J W 
Published: April 2011

Abstract
The liver alcohol dehydrogenase inhibitors, pyrazole and 4-methylpyrazole, have been tested for their ability to prolong drug-induced sleep times in mice. Both drugs (at 1 mmol kg−1 i.p.) prolonged the duration of loss of righting reflex following chloral hydrate, pentobarbitone, barbitone, temazepam and halothane, but not diethyl ether. This suggests that the effects of these pyrazoles are not specific to the inhibition of liver alcohol dehydrogenase.
Inhibitory role of D-1 dopamine receptors for the jerks induced by B-HT 920 in rats
Authors: Grabowska-Andén M , Andén N-E 
Published: April 2011

Abstract
Jerks of the head and upper trunk produced by the dopamine agonist B-HT 920 in reserpine-treated rats were abolished by the D-1 dopamine receptor agonist SKF 38393. The combined treatment with SKF 38393 and B-HT 920 instead resulted in stereotypies and locomotion. B-HT 920 also caused jerks when given after the D-1 receptor antagonist SCH 23390 to rats not pretreated with reserpine. The results indicate that B-HT 920 induces jerks by stimulation of postsynaptic D-2-like dopamine receptors provided that the D-1 receptors are not activated.
Persistent depletion of striatal dopamine and its metabolites in mice by TMMP, an analogue of MPTP
Authors: Fuller Ray W , Hemrick-Luecke Susan K 
Published: April 2011

Abstract
TMMP (1-methyl-4-[methylpyrrol-2-yl]-1,2,3,6-tetrahydropyridine) mimicked MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in causing persistent depletion of striatal dopamine and its metabolites one week after the last of four daily subcutaneous injections in mice. MMPP (1-methyl-4-[1-methylpyrrol-2-yl]-4-piperidinol) produced no depletion of dopamine or its metabolites under these conditions. None of the three compounds affected dopamine or its metabolites when administered orally. TMMP was even more rapidly oxidized by type B monoamine oxidase in-vitro than was MPTP, but MMPP was a very poor substrate for the enzyme. The lack of neurotoxicity of MMPP toward nigrostriatal dopamine neurons when it was given orally or subcutaneously to mice contrasts with previously reported results in monkeys, in which case MMPP was reported to be neurotoxic.
Some factors affecting the release of imipramine from gel-precipitated aluminium hydroxide spheres
Authors: Ramsey M P , Newton J M , Shaw G G , Sammon D C , Lane E S 
Published: April 2011

Abstract
Changing the pH of the dissolution medium has been found to affect the release of imipramine from gel-precipitated aluminium hydroxide spheres. Release from unwashed, unheated spheres into solutions of pH 1·2 was controlled by dissolution of the gel matrix, whereas that into solutions of pH 3 and pH 5 appeared to be under diffusion control. The liberation of drug from unwashed, heated spheres into the media of higher pH exhibited more complex kinetics. Washed spheres failed to release significant amounts of imipramine into the solutions of pH 3 and 5. Changing the ionic strength of the media had little effect on drug release. These phenomena have been explained with reference to model theories of the precipitation and ageing of aluminum hydroxide gels and their pH-solubility profiles.
A highly sensitive HPLC method for the assay of propantheline used to measure its uptake by rat intestinal brush border membrane vesicles
Authors: Saitoh Hiroshi , Kobayashi Yukari , Miyazaki Katsumi , Arita Takaichi 
Published: April 2011

Abstract
A simple, sensitive, high-performance liquid chromatographic method for propantheline has been developed. Propantheline was quantitatively hydrolysed into xanthene-9-carboxylic acid in neutral or alkaline medium and the hydrolysate assayed by reversed phase high-performance liquid chromatography. This method measured to 2 pmol per injection and was used to investigate the uptake of the drug by rat intestinal brush border membrane vesicles. Propantheline was highly bound to the membrane and this binding was inhibited to varying extents by several quaternary ammonium compounds. Mepenzolate and methylbenactyzium inhibited it significantly, and neostigmine, butylscopolamine and N-methylnicotinamide inhibited it moderately. Choline, acetylcholine and thiamine had no effect.
In-vivo studies of amphotericin B liposomes derived from proliposomes: effect of formulation on toxicity and tissue disposition of the drug in mice
Authors: Payne Nicholas I , Cosgrove Raymond F , Green A Peter , Liu Lin 
Published: April 2011

Abstract
The repeat dose toxicity of various liposomal formulations containing amphotericin B has been determined in mice. In general, small liposomes (e.g. 100–150 nm) were found to be more toxic than their larger counterparts (e.g. about 2000 nm). However, the repeat dose toxicity of small liposomes could be diminished substantially by the inclusion of sterol (i.e. ergosterol) into the liposomal membranes. Tissue accumulation studies of amphotericin B after repeat dosing may be a useful adjunct to formulation development.
The antagonistic effect of morphine on rhein-stimulated fluid, electrolyte and glucose movements in guinea-pig perfused colon
Authors: Verhaeren E H C , Geeraerts V C J , Lemli J 
Published: April 2011

Abstract
Rhein (1,8-dihydroxy-3-carboxyanthraquinone), in a concentration of 6 × 10−4 M, inhibits water absorption from the colon and causes a net transfer of fluid and electrolyte into the intestinal lumen. Morphine (4 × 10−4 M) counteracted the water and electrolyte secretion. Prior perfusion with morphine protected the large intestine from the laxative effect of a rhein perfusion. Differences in absorption rate of 99mTc-EDTA, a poorly absorbable marker, were found, as morphine caused nearly all radioactive compound to be retained in the colon, while rhein significantly facilitated the transfer of marker from colon through mucosal barrier to blood. The route followed by the 99mTc-EDTA complex was not the same as that followed by water, suggesting that 99mTc-EDTA travels by a paracellular route. Morphine counteracted the inhibition of Na+ absorption caused by rhein and antagonized the massive loss of K+ incurred by the presence of rhein in the colon. Cl− absorption is reversed to secretion in the presence of rhein while normal values were restored by morphine. Neither the HCO−3 content nor the pH were affected by either drug. Active absorption of glucose was completely blocked in the presence of rhein; the block could be antagonized by morphine.
Locomotor activity and contracture of isolated ileum precipitated by naloxone following treatment of guinea-pigs with a single dose of morphine
Authors: Chahl Loris A , Thornton Cynthia A 
Published: April 2011

Abstract
Guinea-pigs treated with a single dose of morphine, 15 mg kg−1 s.c., exhibited an increase in locomotor activity 2 h later on injection of naloxone, 4 mg kg−1 i.p. At the same time, contracture of ileal preparations isolated from morphine-treated guinea-pigs occurred on addition of naloxone 1 μM. Contracture of the ileum was inhibited by the tachykinin antagonist, spantide, and was therefore presumably mediated by a substance P-like agent. This study has established a useful model for the parallel investigation of central and enteric nervous system mechanisms of opiate dependence.
The topical anti-inflammatory effects of a topical preparation of meclofenamic acid on carrageenan-induced footpad swelling in mice
Authors: Schrier Denis J , Moniot Susan , Gluckman Melvyn I , Gilbertsen Richard B 
Published: April 2011

Abstract
A topical preparation of meclofenamic acid (Meclomen) was tested for anti-inflammatory activity in a murine model of carrageenan footpad oedema. The preparation significantly inhibited swelling when applied to the carrageenan-injected paw. Maximum inhibition was observed 4–5 h after carrageenan injection. The topical effects could not be attributed to systemic absorption because the preparation was more inhibitory when applied topically to the carrageenan-injected paw than to a distant site or orally.
Effects of microiontophoretic pentobarbitone on conditioned inhibitions mediated by GABA-A receptors in the cuneate nucleus of the rat in-vivo
Authors: Andres-Trelles F , Orviz P 
Published: April 2011

Abstract
We have studied the effects of microiontophoretic sodium pentobarbitone on the conditioned inhibition of the negative potential (N-wave) evoked in the cuneate nucleus of the rat by electrical stimulation (5 V, 0.2 ms, 0.5 Hz) of the ipsilateral forepaw. Five- or seven-barelled micropipettes were used, the tip being placed at a depth of 600–900 μm below the dorsal surface of the medulla oblongata. The conditioned inhibition was elicited by a previous identical stimulus. When the interval between the stimuli is shorter than about 40 ms (short duration) the inhibition is thought to be mediated by γ-aminobutyric acid (GABA), acting on GABA-A receptors. When it is longer (long duration conditioned inhibition) GABA-A receptors are not thought to be involved. Microiontophoretic sodium pentobarbitone potentiated both short (15 ms) and long (45 ms) duration conditioned inhibitions. The effect was current-dependent and appeared whether or not the first N-wave was depressed. Microiontophoretic application of (-)- bicuculline methiodide (a GABA-A antagonist) reduced the potentiation by pentobarbitone up to the basal inhibition when the interval between the stimuli was 45 ms or longer and to a greater extent when it was 30 ms or shorter. It seems likely that pentobarbitone prolongs the GABA-ergic mechanism which produces the short duration inhibiton, making it visible with long stimulus intervals, superimposed upon the normal long duration conditioned inhibition which is not potentiated by local pentobarbitone.
Evidence for spare α1-adrenoceptors for the accumulation of inositol phosphates in smooth muscle
Authors: Fox Anthony W , Friedman Paul A 
Published: April 2011

Abstract
The accumulation of inositol phosphates (IP) in smooth muscle from rat vas deferens and caudal artery was maximally increased 3- to 4-fold in response to exposure of the tissues to 100 μM noradrenaline. Clonidine (up to 3 mM) was a partial agonist. Pretreatment of the tissues with the irreversible α-adrenoceptor antagonist phenoxybenzamine (0.3–10 μM) shifted the noradrenaline concentration-response curve to the right before depressing the maximum. The maximum of the clonidine concentration-response curve was depressed without significant change in the EC50 by the same treatment. These data, which are most easily interpreted as demonstrating the presence of a receptor reserve for IP accumulation, are discussed.