bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of ethanol dependence on drug responsiveness of mouse isolated vas deferens
Authors: de Moraes Sergio , Capaz Francisco Ruy
Published: April 2011

The effects of ethanol dependence on the responsiveness of the mouse vas deferens to noradrenaline (NA), carbachol, barium and calcium were studied. Ethanol dependence increases the maximum responses to NA and carbachol whereas responsiveness to barium remains unaltered. The concentration-effect curve to calcium was shifted to the left (3·0-fold at the EC50 level). It is concluded that in vas deferens isolated from ethanol-dependent mice the increased responsiveness to NA, carbachol and calcium is a consequence of an enhanced calcium entry through voltage-independent calcium channels, as it has been reported for brain tissue.
Forensic aspects of the metabolism and excretion of cannabinoids following oral ingestion of cannabis resin
Authors: Law B , Mason P A , Moffat A C , Gleadle R I , King L J
Published: April 2011

Following oral ingestion of cannabis resin, δ9-THC−11−oic acid and its O-ester glucuronide were detected using RIA and combined hplc/RIA and shown to be major plasma metabolites of δ9-THC. δ9-THC−11−oic acid was not excreted in the urine in significant concentrations, the glucuronide conjugate being the major urinary metabolite detected. δ9-THC metabolites were detected in blood for up to 5 days and in urine for up to 12 days following a single oral dose of δ9-THC (20 mg). Estimates for the half life of δ9-THC−11−oic acid and its glucuronide in plasma, and total metabolites in urine have been obtained. Interpretation of blood or urine total cannabinoid levels is most difficult, however, drug/metabolite ratios and metabolite/metabolite ratios may have potential for indicating recent cannabis use.
The metabolism of dopamine, NN-dialkylated dopamines and derivatives of the dopamine agonist 2−amino-dihydroxy−1,2,3,4−tetrahydronaphthalene (ADTN) by catechol-O-methyltransferase
Authors: Youde Ian R , Raxworthy Michael J , Gulliver Peter A , Dijkstra Durk , Horn Alan S
Published: April 2011

A variety of dopamine derivatives and analogues were investigated to assess their potential to act as catechol-O-methyltransferase (COMT) substrates using purified, homogeneous pig liver enzyme. This enabled accurate kinetic constants to be determined as opposed to previous in-vivo studies (Rollema et al 1980; Horn et al 1981; Costall et al 1982; Feenstra et al 1983). 2−Amino−6,7−dihydroxy−1,2,3,4−tetrahydronaphthalene (A−6,7−DTN) proved to be a far better substrate (Km = 0·082 mm; Vmax = 300 mu mg−1 protein) than its 5,6−dihydroxy isomer (Km = 2·60 mm; Vmax = 113·9 mu mg−1 protein). This result supports evidence suggesting that differences in brain concentration of these isomers are due to their differential susceptibility to O-methylation by COMT (Rollema et al 1980). A similar result was obtained with a series of NN-di-n-alkyl substituted ADTN derivatives: the same pattern of preferential O-methylation of A−6,7−DTN derivatives over the corresponding A−5,6−DTN isomers was observed. However, increasing the length of the alkyl chain increased the susceptibility of both isomers to metabolism by COMT as shown by a decline in Km. An homologous series of NN-di-n-alkylated dopamines showed a similar trend implying that more hydrophobic compounds are better COMT substrates.
BRL 20459, a novel topically active non-steroidal anti-inflammatory drug
Authors: Green A P , Mangan F R , Thomson M J , Randall K E , Boyle E A
Published: April 2011

BRL 20459 is a novel compound which displays anti-inflammatory activity when applied topically in the croton oil and cantharadin rat ear inflammation models. The compound does not inhibit uv-induced erythema in the guinea-pig or granuloma formation in the cotton pellet test in the rat. BRL 20459 does not inhibit prostaglandin synthesis nor does it interact with corticosteroid receptors in the thymus. In contrast to hydrocortisone, BRL 20459 did not cause thymus involution or reduce body weight gain in rats. BRL 20459 would seem to have a different mechanism of action to hydrocortisone, but this mechanism is as yet unknown.
Cooling-induced contraction in ileal longitudinal smooth muscle of guinea-pig
Authors: Nasu T , Sakai N , Washibe T , Ishida Y
Published: April 2011

The ileal longitudinal smooth muscle developed a transient contraction on cooling from 37 °C to 1 °C in normal Ca2+ (2.5 mm) medium. The transient contraction was not inhibited by pretreatment with the Ca2+ antagonist, D−600 (1 times 10−6 m). The contractions were sustained by cooling to 1 °C in the presence of added Ca2+ greater than 10 mm. After the pretreatment with D−600, when the muscle incubated in normal medium with added 20 mm Ca2+ had been cooled to 1 °C, a phasic response was only seen. However, D−600 did not inhibit the sustained contraction at 1 °C after incubation in the presence of added 20 mm Ca2+. It is suggested that the transient and sustained contraction at 1 °C is maintained by Ca2+ release from a cellular site, probably the cell membrane and it requires more calcium for the sustained tension.
The use of liposomes in the topical application of steroids
Authors: Vermorken A J M , Hukkelhoven M W A C , Vermeesch-Markslag A M G , Goos C M A A , Wirtz P , Ziegenmeyer J
Published: April 2011

The effect of topical application of the androgen 5α-dihydrotestosterone (DHT), both encapsulated in liposomes and solved in acetone, has been evaluated using the female hamster flank organ as a model system. Systemic absorption of DHT was significant from the acetone solution, but negligible from the liposome system. The topical biological effect is, however, proportionally diminished when the liposome system is used. Under the experimental conditions used, the liposome system had no advantages over application in acetone in this model.
Effect of l-dopa on glutamate decarboxylase activity in the hypothalamic and amygdaloid nuclei
Authors: Itoh Masatoshi , Nohtomi Akito , Yufu Nobuo , Uchimua Hideyuki
Published: April 2011

Repeated administration of l-dopa methylester produced a significant increase in glutamate decarboxylase (GAD) activity without pyridoxal-5′-phosphate in the lateral hypothalamic area and medial amygdaloid nucleus. The effect of l-dopa on GAD activity was opposite to that of haloperidol in the lateral hypothalamic area.
Competitive antagonism of α1-adrenoceptor mediated pressor responses in the rat mesenteric artery
Authors: McPherson G A , Coupar I M , Taylor D A
Published: April 2011

(-)-Noradrenaline-mediated pressor responses in the rat mesenteric artery preparation are blocked by α1-adrenoceptor antagonists, BE2254 and prazosin with pA2 values of 8·59 and 8·52 respectively. The α2-adrenoceptor selective antagonist rauwolscine, does not influence responses to (-)-noradrenaline in concentrations up to 10 μm. This rank order is consistent with an α1-adrenoceptor mediated effect. Shifts in the (-)-noradrenaline dose-response curve produced by BE2254 and prazosin were parallel and there was no significant effect on the observed maximal response. Slope values from Schild plots were not significantly different from unity indicating that these antagonists were behaving as classical competitive antagonists.
Comparison between in-vivo and in-vitro tissue-to-plasma unbound concentration ratios (Kp,f) of quinidine in rats
Authors: Harashima Hideyoshi , Sugiyama Yuichi , Sawada Yasufumi , Iga Tatsuji , Hanano Manabu
Published: April 2011

The comparison between in-vivo and in-vitro tissue-to-plasma concentration ratio of drug unbound (Kp,f) has been made using quinidine as a model for weak basic drugs. In-vitro Kp,f-values were calculated from the binding data to tissue homogenates determined by equilibrium dialysis. In-vivo Kp,f-values were calculated from the tissue distribution data after intravenous administration of quinidine, by considering the difference in the unbound concentration between plasma and the tissues produced by the pH difference across the cell membrane. It was concluded that the extensive tissue distribution of quinidine observed in-vivo may be explained by tissue binding and the pH-difference across the cell membrane in most tissues.
Elevation of serum corticosterone in rats by bremazocine, a κ-opioid agonist
Authors: Fuller Ray W , Leander J David
Published: April 2011

Bremazocine at doses of 0·01 mg kg−1 s.c., and higher, increased serum corticosterone concentration several-fold in rats. The increase occurred within 20 min, was maximum at 40–60 min and subsided after 120 min. Pretreatment with naloxone (1–10 mg kg−1 s.c.) antagonized the corticosterone increase. These data support the view that κ-opioid agonist activity of bremazocine mediated the corticosterone increase.
PK 10139 and quinidine: interactions with digoxin concentrations in rats and dogs
Authors: Rougeot C , Jozefczak C , Mestre M , Fur G Le , Uzan A
Published: April 2011

Quinidine induced an increase in digoxin plasma concentrations in rats and dogs. PK 10139, an antiarrhythmic agent 10 times more potent than quinidine, did not change digoxin plasma concentrations in these species. The results indicate that PK 10139 could be associated with digoxin without risk of side-effects.
An in-vitro investigation of drug availability from lipophilic solutions
Authors: Armstrong N A , James K C , Pugh W K L
Published: April 2011

An in-vitro model, previously described, has been modified and used to investigate the effects of volume and concentration on the release of 4-hydroxybenzoic acid from 1-octanol and isopropyl myristate. Solutions encapsulated in soft gelatin shells have also been examined. The quantity of solute released can be increased by reducing the volume of solvent used to prepare the solution, or by increasing the concentration of the solution. The release profile from an encapsulated solution is different from that obtained with the same, unencapsulated solution. The difference is attributed to absorption of the solute by the capsule shell.
Binding of amiodarone by serum proteins and the effects of drugs, hormones and other interacting ligands
Authors: Lalloz M R A , Byfield P G H , Greenwood R M , Himsworth R L
Published: April 2011

Amiodarone is chiefly bound to albumin (62·1%) and much of the remainder (33·5%) is carried on a high molecular weight protein, probably β-lipoprotein. Analysis of data for amiodarone binding to albumin revealed a high affinity primary binding site (Ka 5·6 times 106 litre mol−1) with about four secondary sites (average Ka 1·9 times 105 litre mol−1). Studies of the binding of amiodarone in serum revealed one type of binding site only with an affinity constant (Ka 4·2 times 106 litre mol−1) similar to that of the primary site on albumin. The secondary albumin binding sites do not seem therefore to be utilized in whole serum and the affinity of the lipoprotein must be similar to that of the primary amiodarone binding site on albumin. The effects of a wide range of compounds on albumin binding of amiodarone were examined by equilibrium dialysis. Quinidine, amitriptyline, cephazolin and palmitate decreased albumin-bound [125I]amiodarone. Neither warfarin nor digoxin affected the binding of amiodarone by albumin, thus of the three drugs known to be potentiated by concomitant amiodarone administration, only potentiation of quinidine could be explained by displacement from serum albumin. Rifampicin, frusemide, phenytoin, (-)-adrenaline, bromocresol green, (-)-noradrenaline and bromocresol purple were found to increase binding of [125I]amiodarone by albumin. Amiodarone had no influence on the distribution of iodothyronines amongst their binding proteins nor were the concentration or binding properties of these proteins altered after prolonged treatment with the drug. Thus altered iodothyronine concentrations in amiodarone-treated patients cannot be attributed even in part to effects at the serum binding protein level.
Investigation on central dopaminergic receptors (D-2) using the antagonistic properties of new benzamides
Authors: Rumigny Jean-Francois , Benedetti Margherita Strolin , Dostert Philippe
Published: April 2011

The topography of the central dopaminergic receptor (D−2) has been studied using some analogues of tropapride, a new benzamide derivative, and sulpiride and clebopride as reference drugs. The compounds were compared by testing their ability to compete with [3H]spiperone in an in-vitro binding test and by measuring their potency as antagonists of apomorphine-induced climbing in mice. Tropapride was the most active compound, both in-vitro and in-vivo. With the amide group substituted in the 2−position of the tropane ring, the antidopaminergic activity of the compounds was much less than that of the 3−substituted derivatives. The interaction of the tropane derivatives with the D−2 receptor site is stereoselective as the equatorial stereoisomer was much more active than the axial isomer. The ethylene bridge present in the tropane derivatives but not in the corresponding piperidinyl analogues increases the affinity of the tropane derivatives for the D−2 receptor. Interaction with the D−2 receptor was confirmed as being Na+-dependent. The presence of a benzyl substituent on the basic nitrogen atom seems to be essential in the tropane series emphasizing the important role played in this series by the lipophilic auxiliary binding site postulated in Olson. In conclusion, the tropane skeleton may be considered a useful pharmacophoric group in the design of new dopaminergic drugs.
Histamine responses mediated via H1 and H2−receptors in the isolated portal vein of the dog
Authors: Toshimitsu Yoshinobu , Uchida Kohsuke , Kojima Shu-ichi , Shimo Yasuo
Published: April 2011

The effects of histamine were studied on the isolated circular muscle strip and longitudinal muscle strip of the dog portal vein. Histamine-induced contractions of the circular muscle were inhibited by H1-receptor antagonist pyrilamine but increased by H2-receptor antagonist ranitidine. When the tissues were contracted with PGF2α in the presence of pyrilamine, histamine produced the relaxation of the circular muscle but not longitudinal muscle. The relaxation of the circular muscle was inhibited by ranitidine in a concentration dependent manner, the pA2 value for ranitidine being 6·97 (6·55–7·39). It is concluded that the response of the circular muscle to histamine is the sum of two components, H1-receptor mediated contraction and H2-receptor mediated relaxation.
Pretreatment with aspirin does not influence the pressor response to α2-adrenoceptor agonists in conscious rabbits
Authors: Hannah J A M , Hamilton C A , Reid J L
Published: April 2011

It has proved relatively easy to demonstrate pressor responses mediated via α2-adrenoceptors in-vivo and in whole blood perfused vascular beds, but not in in-vitro work. The possibility that platelet α2-adrenoceptor activation, with subsequent release of vasoactive prostanoids, contributes to the pressor response to α2-adrenoceptor agonists was investigated. The pressor response to the α2-adrenoceptor agonist BHT 920 (Alefexole) was compared in rabbits pretreated with distilled water or aspirin (3 times 200 mg kg−1 by gavage). Aspirin pretreatment had no significant effect on responses to BHT 920; thus, prostanoid formation does not appear to be an important mechanism contributing to postsynaptic α2-adrenoceptor activation.
Haloperidol treatment increases the biosynthesis and release of endorphins in guinea-pig ileum
Authors: MilanéS M V , Vargas M L , Puig M M
Published: April 2011

Guinea-pigs treated acutely (5 mg kg−1 i.p.) and chronically (2 or 5 mg kg−1 day−1 for 4 days) with haloperidol, show an increase of the inhibitory response produced by electrical stimulation at 10 Hz of the ileum myenteric plexus-longitudinal muscle (MPLM) preparation. The response can be reversed by the specific narcotic antagonist naloxone (5 times 10−7 m), which suggests that the increase in the response produced by haloperidol is mediated by release of endorphins. When haloperidol-treated guinea-pigs received cycloheximide (24 and 12 h before death), there was a substantial decrease in the response indicating that the biosynthesis and release of endorphins are increased by haloperidol.
Potentiation by sulphydryl agents of the responses of guinea-pig isolated ileum to various agonists
Authors: Fontaine Jeanine , Famaey Jean-Pierre , Reuse Jean
Published: April 2011

Sulphydryl agents (dithiothreitol, mercaptoethanol, monothioglycerol, cysteine, glutathione) increase non-specifically the potency of various agonists (acetylcholine, 5-hydroxytryptamine, nicotine, bradykinin, prostaglandin E2) on the guinea-pig ileum. These effects are of non-cholinergic origin and are not related to prostaglandin synthesis. Sulphydryl agents act directly on the smooth muscle cells of the guinea-pig ileum most probably by reducing disulphide bonds located on the membrane surface and by this mechanism modulate the muscular contractile activity.
Effect of dopamine on dog distal colon in-vitro
Authors: Grivegnée A R , Fontaine J , Reuse J
Published: April 2011

The effects of dopamine, isoprenaline, adrenaline and noradrenaline in dog isolated colon strips were studied. All these drugs produced in the preparation relaxations which were inhibited by propranolol and sotalol or, in the case of noradrenaline, by a mixture of propranolol and phentolamine. A selective β1-adrenergic antagonist, practolol, had the same inhibitory effects on the relaxations induced by all the agonists, suggesting the existence of β1- and β2-adrenoceptor subtypes in the dog distal colon. There is no evidence for the presence of specific dopaminergic receptors in this preparation.
Rifampicin curing of plasmids in Escherichia coli K12−rifampicin resistant host
Authors: Obaseiki-Ebor E E
Published: April 2011

The in-vitro rifampicin curing of R-plasmids JR225, BN102, BN106 and F’-plasmid F’lac+/R386 in Escherichia coli K12 rifampicin-resistant host J62–2 is described. The minimum rifampicin curing concentration and the frequency of curing of plasmids from the rifampicin-resistant host cell J62–2 and the isogenic rifampicin-sensitive J62–1 host cell were similar. However, rifampicin did not cure some test R-plasmids such as R222 and RP4 from rifampicin-resistant and rifampicin-sensitive host cells, indicating that it is the R-plasmid itself and not the host strain that determines rifampicin curing.
Antipropulsive effects of central and peripheral morphine in the rat gastrointestinal tract
Authors: Stewart John J , Curd Cheryl D
Published: April 2011

The antipropulsive effects of centrally or peripherally administered morphine have been examined at three levels of the rat gastrointestinal tract. Adult male rats were anaesthetized with pentobarbitone (50 mg kg−1 i.p.) and were implanted with an intraluminal catheter in either the proximal duodenum or mid-jejunum. Other animals were also implanted with a cannula in the right lateral cerebral ventricle. Gastric emptying and transit were determined selectively by measuring the progression of a radioactive chromium (CR-51) solution, given intragastrically for tests of gastric emptying or instilled into the proximal or distal intestinal catheter for determination of intestinal transit, 30 min after administration of morphine or saline given either subcutaneously (s.c.) or intracerebroventricularly (i.c.v.). Morphine given either s.c. (5 mg kg−1) or i.c.v. (30 μg, total dose) significantly inhibited gastric emptying and transit through bulk portions of the small intestine indicating that by either route it inhibits propulsion at all three levels of the gastrointestinal tract.
The pinna reflex and its inhibition by clonidine: Relationship to sedation and quantitation of central α2-antagonist potency
Authors: Handley Sheila L
Published: April 2011

The relationship between sedation and pinna reflex inhibition has been measured for a range of centrally acting drugs. Ability to abolish the pinna reflex was not related to sedative activity as assessed by a behavioural method. Thus, at equisedative doses, diazepam, haloperidol, mianserin, prazosin and indoramin failed to abolish the pinna reflex while phenobarbitone and chlorpromazine caused partial- and clonidine complete-inhibition. At the ED50 for pinna reflex inhibition, guanabenz and guanfacine were significantly less sedative than clonidine. Mepyramine, yohimbine, RS−21361, idazoxan and phenylephrine produced little or no sedation and did not inhibit the reflex. When these agents (except for guanabenz and guanfacine) were tested for their ability to prevent clonidine-induced pinna reflex inhibition, all except the drugs with α2-adrenoceptor antagonist activity were inactive. The potency order of the active agents was idazoxan > yohimbine > RS−21361 = mianserin. Antagonism of clonidine-induced pinna reflex inhibition may therefore prove to be a useful quantitative model for assessing the central potency of α2-adrenoceptor antagonists.
Central pressor activity of cimetidine in spontaneously hypertensive rats
Authors: Dadkar N K , Aroskar V A , Gupte R D , Dohadwalla A N
Published: April 2011

The systemic blood pressure effect of cimetidine given intracerebroventricularly (i.c.v.) in anaesthetized spontaneously hypertensive (SH) rats has been investigated. Cimetidine (250 μg i.c.v.) caused a gradual long lasting rise in mean in mean arterial blood pressure with maximum of 31·6 ± 4·5 mm Hg. Chemical degeneration of catecholaminergic neurons with 6−OHDA treatment, central administration of phentolamine and prazosin, and the bilaterial adrenalectomy significantly inhibited the pressor response of cimetidine, while propranolol (i.c.v.) had no effect. From these results it appears that the hypertensive response of cimetidine is mediated by central catecholaminergic pathways and is due to an increase in efferent sympathetic outflow and release of catecholamine from the adrenal medulla.
Theoretical estimation of punch velocities and displacements of single-punch and rotary tablet machines
Authors: Charlton B , Newton J M
Published: April 2011

The speed of travel of punches during compaction by a Manesty F3 single punch and D3B Rotary punch tablet machine has been derived from machine dimensions, normal operating speeds and by consideration of the consolidation of a theoretical compact. The analysis may also be used for machines with other dimensions, operating at different speeds with other materials, but would require modification if the punch head design on the rotary machine differed significantly. Punch speeds at the beginning of the compression cycle were similar for the two types of machines, namely 10·36 and 10·24 cm s−1 for the single and rotary machines. The time to reach maximum compression and the total time of contact between punches and powder for the single punch machine was 0·1 s for a compaction force of approximately 40 KN. For the rotary machine operating at approximately the same force, these two parameters were found to be 0·052 and 0·083 s respectively. The additional contact time is associated with a period during which there is no vertical movement of the punch, providing a ‘dwell’ time of 0·0314 s when the powder is held at a constant volume.
Plasma protein binding of frusemide in renal failure rabbits: investigation of endogenous protein binding inhibitors
Authors: Ikeda Katsumi , Yoshitomi Hironori , Nakayama Taiji , Goto Shigeru , Kimura Toshikiro
Published: April 2011

The reduction mechanism of frusemide-protein binding in the plasma of renal failure was investigated. The drug-albumin binding was inhibited by the low molecular-weight fraction obtained from acute renal failure rabbits, suggesting the presence of the inhibitors in the plasma. Further, this fraction was divided into six subfractions by Bio-Gel P-2. Fractions II and V2 showed significant inhibition of the protein binding of frusemide. Among uraemic toxins, four indole derivatives markedly inhibited the protein binding. Analysis by hplc confirmed that the concentration of indican was markedly increased in acute renal failure rabbit plasma. It is suggested that this compound could be one of the major inducers of the protein binding defect.
The effects of chronic inhalation of salbutamol on the acute airway responsiveness to salbutamol and ipratropium bromide in the conscious and the anaesthetized guinea-pig
Authors: Woodsford P V , Tomlinson D R , Ward M J , Palmer Julie P , Poole T R
Published: April 2011

The effects of chronic exposure to a nebulized mist of salbutamol on the capacity of systemic salbutamol to prolong the time taken for inhaled histamine to produce bronchospasm in guinea-pigs have been examined. Initially a reproducible cough time to inhalation of histamine acid phosphate (0·5 ml ml−1) in 100% O2 was established. Antagonism of this response by intraperitoneal salbutamol or ipratropium Br was assessed to establish submaximal responses to these drugs. A fresh group of animals was then exposed to a persistent mist of nebulized water for 16 days, before and during which each animal was tested by exposure to histamine mist either alone or shortly after salbutamol (10 μg kg−1 i.p.) or ipratropium Br (5 μg kg−1 i.p.). The nebulized water had no effect on the response to the drugs. The same animals were rested for 7 days and then exposed to nebulized salbutamol solution (5 mg ml−1) for 15 days, during which time tachyphylaxis developed to salbutamol (i.p.) but not to ipratropium Br. At the end of the 15 days the animals were anaesthetized and total lung resistance (RL) measured. At this time, the protective effect of intravenous salbutamol was also diminished by comparison with untreated guinea-pigs while the response to ipratropium Br was unaffected. A separate group exposed to 1 mg ml−1 of nebulized salbutamol for 20 days developed selective tachyphylaxis to intraperitoneal salbutamol. The animals were then allowed to breathe room air and the reponse to intraperitoneal salbutamol after 13 days returned to normal as did the effects of intravenous salbutamol on the RL response to histamine.
The role of opioid receptor sub-types in tifluadom-induced feeding
Authors: Jackson H C , Sewell R D E
Published: April 2011

There is now considerable evidence that opioid agonists and benzodiazepines increase food and water intake in a variety of animal species. The appetitive effects of the novel opioid-benzodiazepine tifluadom have been investigated. (±)-Tifluadom significantly increased food intake in freely-feeding rats. This stimulation of appetite was attributable principally to the activity of the (+)-isomer. Furthermore tifluadom-induced feeding was blocked by the opioid antagonists naloxone, naltrexone, Mr 1452 and Mr 2266 but not by the δ-opioid receptor antagonist ICI 154, 129, or by the benzodiazepine antagonist Ro 15–1788. These results suggest that tifluadom exerts its effect on food intake by interaction with opioid as opposed to benzodiazepine receptors and that this activity is mediated by κ and/or μ- rather than δ-opioid receptor sub-types.
Warfarin—sulfinpyrazone interaction on binding to human serum albumin
Authors: Larsen F G , Larsen C G , Brodersen R
Published: April 2011

Sulfinpyrazone displacement of warfarin from human serum albumin was studied in-vitro. At low sulfinpyrazone concentrations one molecule of warfarin is displaced on binding by one molecule of sulfinpyrazone. Clinical plasma concentrations of sulfinpyrazone are, however, too low to cause significant displacement.
o- and m-Iodohippurate binding to plasma proteins as a model drug transport mechanism
Authors: Lázníček M , Květina J
Published: April 2011

The pharmacokinetics of two isomers, o- and m-iodohippurate, were determined in rabbits and rats and the effect of protein binding on their elimination is demonstrated. Both isomers are rapidly eliminated by transport systems in the kidney and their clearance by the kidney approaches the renal plasma flow regardless of protein binding, m-Iodohippurate is more highly bound to plasma proteins than o-iodohippurate and its rate of elimination is enhanced in comparison with o-iodohippurate. In the case of these two isomers, the binding to plasma proteins should be considered as a transport mechanism and not as a storage depot.
The effects of phenylpropanolamine and other sympathomimetics on food consumption and motor activity in mice
Authors: Cairns M J , Foldys Janet E , Rees J M H
Published: April 2011

The effects of phenylpropanolamine on motor activity and on food intake were compared with those of S-amphetamine, ephedrine, 2-aminoindane and fenfluramine in groups of mice. Motor activity was additionally measured in mice pretreated with levodopa and benserazide, and food intake in mice pretreated with α-methyl-p-tyrosine. Amphetamine (2·5 mg kg−1) increased motor activity, phenylpropanolamine (10–40 mg kg−1) and 2-aminoindane (2·5–10 mg kg−1) decreased activity whilst ephedrine (2·5–40 mg kg−1) had a biphasic effect. Fenfluramine (10–40 mg kg−1) had negligible effect on activity. In mice pretreated with levodopa and benserazide both phenylpropanolamine and 2-aminoindane caused a massive increase in motor activity whilst fenfluramine’s action was not affected in the same way. Whilst the anorectic action of fenfluramine was considerably potentiated in mice pretreated with α-methyl-p-tyrosine, that of amphetamine, ephedrine, 2-aminoindane and phenylpropanolamine was either unaffected or initially antagonized. It is concluded that the mechanisms of motor and anorectic actions of phenylpropanolamine are similar to those of amphetamine.
Tensile strengths of paracetamol and Avicel powders and their mixtures
Authors: Bangudu A B , Pilpel N
Published: April 2011

Measurements were made of the tensile strengths of paracetamol and Avicel powders and of their mixtures. Two quantities were derived from the results; m, a universal constant whose value was 1·00 + 0·23 and α, a constant of the material. The value of α for paracetamol was much larger than that for Avicel and increased slightly with increase in particle size. Adding 25% w/w of Avicel to paracetamol produced a significant decrease in α and this fact may account for its use as an excipient in the tableting of paracetamol.
Development of an intravenous formulation for the unstable investigational cytotoxic nucleosides 5-azacytosine arabinoside (NSC 281272) and 5-azacytidine (NSC 102816)
Authors: Mojaverian P , Repta A J
Published: April 2011

In aqueous solutions 5-azacytosine arabinoside (aza-A) (NSC 281272) exhibits complex and rapid degradation of a type analogous to 5-azacytidine (aza-C) (NSC 102816). Consequently, it is not amenable for use as slow i.v. infusions. This study has determined that both compounds are relatively stable in dry dimethylsulfoxide (DMSO) or dimethylacetamide (DMA). In mixed aqueous-organic solvents, as the water content is reduced the rate of degradation is descreased. Based on these findings, aza-A may be dissolved in DMSO at 100 mg ml−1, sterile filtered, and sealed in ampoules. The contents appear to be adequately stable at 4 °C, and may at the time of use be diluted with water to yield a 70% DMSO solution which retains >90% potency for 24 h at 25 °C and is compatible with commercially available i.v. infusion tubing. The diluted solution may be added in-line to a flowing i.v. vehicle, resulting in a physiologically acceptable solution in which the drug is unstable (t90 2 h). Its short residence time before reaching the bloodstream precludes any significant loss.
Renal aminopyrine demethylation in several species determined by a sensitive radiometric method
Authors: Ohno Yasuo , Kawanishi Toru , Takahashi Atsushi , Takanaka Akira , Kasuya Yutaka , Omori Yoshihito
Published: April 2011

Renal microsomal aminopyrine demethylation activities of several species were measured by a sensitive radiometric method using [dimethylamino-14C-]aminopyrine as a substrate and 2,4-dinitrophenylhydrazine as a trapping agent for the formaldehyde formed. The activity was highest in hamsters (0·75 nmol min−1 mg−1 protein) and that in rabbits, rats, mice, and guinea-pigs was 19·7, 7·0, 4·5 and 3·7%, respectively, of the hamster values. These species differences did not correlate with species differences in cytochrome P-450 content or in NADPH cytochrome c reductase activity. Aminopyrine demethylation activities in sliced renal tissues of several species were also compared. This activity was also found highest in hamsters (0·54 nmol min−1 g−1 wet tissue) and the activities in rabbits, rats, and guinea-pigs were 9·2, 1·8 and 2·5%, respectively, of the hamster values.
B-HT 958 stimulates dopamine autoreceptors but blocks noradrenaline autoreceptors in the brain
Authors: Grabowska-Andén Maria , Andén Nils-Erik
Published: April 2011

B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo 5,4-d azepine) blocked the γ-butyrolactone-induced increase in the synthesis of dopamine and slowed down the α-methyltyrosine-induced disappearance of dopamine in the mouse brain by haloperidol-sensitive mechanisms. In reserpine-treated mice, B-HT 958 produced at most a weak locomotion and no change in the apomorphine-induced increase in motor activity. The motor activity of normal mice was reduced by B-HT 958. At high doses, B-HT 958 accelerated the α-methyltyrosine-induced disappearance of noradrenaline and it inhibited the effects of clonidine on the turnover and on the synthesis of noradrenaline in the mouse brain. The findings indicate that the dopamine autoreceptors can be selectively stimulated by B-HT 958 but that the α2-adrenoceptors can be blocked following high doses.
Presynaptic agonist effect of phentolamine in the rabbit vas deferens and rat cerebral cortex
Authors: Ennis C , Lattimer N
Published: April 2011

Clonidine inhibited the electrically-induced twitch response of the rabbit and rat isolated vas deferens preparations and also the K+-evoked release of [3H]noradrenaline from rat cortical slices. This effect of clonidine was antagonized competitively by yohimbine. Phentolamine inhibited the electrically-induced twitch response of the rabbit, but not the rat, vas deferens and in low concentrations (<·1 μm) also inhibited the K+-evoked release of [3H]NA from rat cortical slices. These inhibitory effects of phentolamine were antagonized by yohimbine in a competitive manner but were not antagonized by indoramin, an α1-adrenoceptor antagonist. In the rabbit vas deferens, the effects of phentolamine were shown not to be due to the stimulation of β-, H1-, H2-, 5-HT- or muscarinic receptors. These results are consistent with the view that phentolamine can act as an agonist at presynaptic α2-adrenoceptors in the rabbit vas deferens and rat cortex but not in the rat vas deferens.
Nmr study of theophylline-ethylenediamine interaction in aqueous solution
Authors: Tashma Zeev
Published: April 2011

The behaviour of the H(8) nmr signal of theophylline in D2O solutions containing various amounts of ethylenediamine, indicates that in no case is the latter doubly charged, and so at an ethylenediamine to theophylline molar ratio of 0·5 (corresponding to that found in aminophylline) about half of the theophylline is present in a non-ionic form. At higher ratios an increase in its degree of ionization occurs, as evident from the continued upfield shift of the H(8) signal. The behaviour of the N-methyl signals differed from that of H(8). As the proportion of ethylenediamine increased from zero to 1·2 times that of theophylline, these signals first shifted upfield, but then moved back to approximately their initial positions. It is suggested that at low ratios, including that in aminophylline, the solution is composed of monocations of ethylenediamine paired to negatively charged aggregates of theophylline, in which both neutral molecules and ions co-exist. The ions thus act as solubilizing agents for the neutral, and usually slightly soluble, form of theophylline. At high ethylenediamine to theophylline ratios, the latter is fully ionized and the aggregates disintegrate.
Effect of egg yolk phospholipids plasma elimination and tissue distribution of coenzyme Q10 administered in an emulsion to rats
Authors: Yamaguchi Hiroyuki , Watanabe Keiichi , Hayashi Masahiro , Awazu Shoji
Published: April 2011

When coenzyme Q10 (CoQ10) in fat emulsion emulsified with egg yolk phospholipids (PL) was administered intravenously to rats, CoQ10 was eliminated more rapidly than when it was solubilized with a polyoxyethylene derivative of hydrogenated castor oil. Although CoQ10 in emulsion form is distributed mainly to liver, increase of PL concentration in the emulsion increased the distribution of CoQ10 to heart which is a target organ for CoQ10.
Invariable susceptibility to blockade by nifedipine of vasoconstriction to various α2-adrenoceptor agonists in pithed rats
Authors: Timmermans Pieter B M W M , Mathy Marie-Jeanne , Thoolen Martin J M C , De Jonge Adriaan , Wilffert Bob , Zwieten Pieter A van
Published: April 2011

The sensitivity of the increase in diastolic pressure brought about by the selective agonists of α2-adrenoceptors, B-HT 920, B-HT 933, xylazine, UK-14,304, M-7, TL-99 and DP-6, 7-ADTN in pithed normotensive rats to blockade by the calcium entry inhibitor nifedipine has been investigated. To exclude any participation of vascular α1- and β2-adrenoceptors, as well as cardiac β1-adrenoceptors, in the pressor responses, the study was made after treatment of the pithed rats with prazosin (0·1 mg kg−1) and (-)-propranol (1 mg kg−1). Without exception, the preferential agonists of α2-adrenoceptors elicited vasoconstrictor responses which were susceptible to inhibition by nifedipine (0·03–1 mg kg−1) in a dose-dependent manner regardless of the differences in intrinsic activity of the compounds. The pressor activity was almost completely abolished after 1 mg kg−1 of nifedipine. The results show that vasoconstriction induced in pithed rats by various selective stimulating agents of postjunctional vascular α2-adrenoceptors is invariably and equally sensitive to attenuation by nifedipine. This susceptibility of α2-adrenoceptor-mediated vasoconstriction to impairment by blockade of calcium entry is not dependent on the nature, the potency or the efficacy of the agonist.
Physicochemical properties of endotoxins in large volume parenterals
Authors: Baggerman C , Pathmamanoharan C , Spies F , Joosten J G H , Junginger H E
Published: April 2011

Endotoxins of Escherichia coli, Salmonella abortus equi and Serratia marcescens were examined using freeze-etch electronmicroscopy and light scattering techniques, with emphasis on their aggregation state. These endotoxins show distinct features of particle size and mass and they may be affected by the presence or absence of Ca2+ ions. No important differences were observed in the particle characteristics of the respective endotoxins in various infusion fluids.
Effects of saikosaponin-d on enhanced CCl4-hepatotoxicity by phenobarbitone
Authors: Abe Hiroko , Orita Machiko , Konishi Hiroyoshi , Arichi Shigeru , Odashima Shizuo
Published: April 2011

The effects of saikosaponin-d extracted from the roots of Bupleurum falcatum L. on increased toxicity of CCl4 and increased activities of microsomal enzymes induced by phenobarbitone have been examined. Saikosaponin-d showed protection against the CCl4-hepatotoxicity enhanced by phenobarbitone. It also inhibited increases in the content of cytochrome P450 and NADPH-cytochrome c reductase activity, which are induced by the phenobarbitone treatment, but the spectral characteristics of P450 were not altered. The rate of microsomal lipid peroxidation by NADPH and CCl4 was significantly lowered in-vitro in rats pretreated with phenobarbitone and saikosaponin-d compared with those pretreated with phenobarbitone alone.
The effect of temperature on the conductivity of gels and emulsions prepared from cetrimide and cetostearyl alcohol
Authors: Rowe R C , Patel H K
Published: April 2011

The conductivity of gels and emulsions containing cetrimide, cetostearyl alcohol, liquid paraffin and water has been studied over the temperature range +35 to −10°C. All samples froze at temperatures below −5°C and exhibited hysteresis on rewarming to room temperature with an initial increase in conductivity up to 15°C followed by a decrease to 25°C. The amount of hysteresis was dependent on the cetostearyl alcohol content and appeared to be related to changes in the microstructure of the liquid crystalline network.
A comparative study of the bioavailability of five different phenytoin preparations
Authors: Hirji M R , Measuria H , Kuhn S , Mucklow J C
Published: April 2011

The concentration of phenytoin in saliva has been measured in 8 healthy volunteers at intervals after an intravenous dose and after single oral doses of five formulations commercially available in the United Kingdom. The six doses (all 300 mg) were given in random order and at least one week apart. There were no significant differences in the mean values of the peak saliva concentration, the time-to-peak and the area under the saliva concentration-time curve between the five oral formulations. The absolute bioavailability of phenytoin varied between 68 and 74%.
Ring-substituted β-methoxyphenethylamines: a new class of psychotomimetic agents active in man
Authors: Lemaire D , Jacob P , Shulgin A T
Published: April 2011

Four members of a new class of psychotomimetic agents have been synthesized and evaluated in man. These compounds, which incorporate a β-methoxy group onto a β-phenethylamine sidechain, are the first reported psychotomimetics which are structural analogues of the neurotransmitter noradrenaline. These substances are more potent than the corresponding phenethylamines (lacking a β-methoxy group) but less potent than the correspondingly substituted amphetamine derivatives.
Location of the mechanism of the clonidine withdrawal tachycardia in rats
Authors: Jonkman F A M , Man P W , Thoolen M J M C , van Zwieten P A
Published: April 2011

Withdrawal of chronic infusion of clonidine elicits severe tachycardia and short-lasting blood pressure elevations (upswings). Withdrawal of clonidine in low dosage (30 μg kg−1 day−1 i.c.v., 7 days) elicited a maximum of 10.9 ± 0.5 upswings h−1. Cessation of s.c. infusion of clonidine (30 μg kg−1 day−1 7 days) evoked a maximum of 1.9 ± 0.5 upswings h−1. After cessation of the two clonidine infusions no overshoot of heart rate occurred. Withdrawal of a higher dose of clonidine (300 μg kg−1 day−1 s.c., 7 days), however, induced tachycardia (from 302 ± 8 to 433 ± 8 beats min−1) and 7.6 ± 1.4 upswings h−1. The administration of the α2-adrenoceptor antagonist yohimbine precipitated withdrawal tachycardia in animals treated with oxymetazoline, a hydrophilic α-adrenoceptor agonist. Yohimbine (3 mg kg−1 i.p.) precipitated a severe rise in heart rate from 285 ± 14 to 520 ± 5 beats min−1 in oxymetazoline (300 μg kg−1 day−1s.c., 7 days) treated rats and from 320 ± 13 to 420 ± 11 beats min−1 in saline-treated animals. Upswings were not induced by yohimbine treatment. It is concluded, that the blood pressure upswings after clonidine withdrawal are due to a central mechanism, whereas the mechanism of the overshoot of heart rate is located peripherally, probably at the cardiac presynaptic level.
Contraction induced by (-)-tartaric acid on rat isolated gastric fundus and its inhibition with indomethacin
Authors: Tug̀rul Levent , Özer Asli
Published: April 2011

Tartaric acid-evoked contractions of the rat isolated fundus could not be antagonized by atropine sulphate or methysergide hydrogen maleate, but were partially reduced by mepyramine hydrochloride. The contractions were prevented by indomethacin (25 μ ml−1) although the tissue remained sensitive to PGE2.
Effects of isoxicam and other non-steroidal anti-inflammatory drugs on arachidonic acid metabolism by rat peritoneal leucocytes
Authors: Tavares I A , Capasso F , Vine N D , Bennett A
Published: April 2011

Inhibition of prostaglandin formation from [14C]arachidonic acid by rat peritoneal leucocytes occurred with nonsteroidal anti-inflammatory drugs, their order of potency being indomethacin > piroxicam > naproxen > ibuprofen > isoxicam. At the lowest concentration tested (1 μg ml−1), indomethacin markedly increased the accumulation of lipoxygenase products in the cell incubates. Naproxen, ibuprofen or piroxicam 1 or 10 μg ml−1 resulted in smaller increases of lipoxygenase products, and there was only a small rise with these concentrations of isoxicam.
Pyridoxamine as inhibitor of the blood plasma benzylamine oxidase and other copper-containing amine oxidases
Authors: Buffoni F , Banchelli G , Dolara P , Ignesti G , Pirisino R , Raimondi L , Ziche M
Published: April 2011

Pyridoxamine inhibits rabbit and pig plasma benzylamine oxidase (BAO), the diamine oxidase of pig kidney and the lysyloxidase of pig aorta in-vitro. In-vivo in the rabbit, the inhibitory activity of pyridoxamine on plasma BAO is antagonized by an increase in the level of this enzyme that is dependent on an increase in rate of synthesis, there being no variation in the degradation rate constant.
Relationship between particle packing and the physical stability of powder mixes
Authors: Staniforth John N
Published: April 2011

The segregation tendency of powder mixes containing sugar-based direct compression tableting excipients with comparable particle size distributions and flow properties was studied under different vibration conditions. It was found that Tabfine and fine-particle pyridoxine hydrochloride mixes were virtually segregation-free, whereas segregation occurred in each of the other powder mixes containing Fast-flo, Dipac and Nu-tab. The segregation tendency of a specific powder mix following vibration was considered to be influenced by the packing of excipient particles in the powder bed. In general, the more densely packed the particles under given vibration conditions, the lower the segregation tendency. This was considered to be due to the tightly packed powder bed restricting individual particle movement and thereby reducing particle or ordered unit rearrangement.
Gastrointestinal transit of pellet systems in ileostomy subjects and the effect of density
Authors: Bechgaard Helle , Christensen F N , Davis S S , Hardy J G , Taylor M J , Whalley D R , Wilson C G
Published: April 2011

The transit of pellets of different densities (0.94 and l.96g cm-3) through the gastrointestinal tract of ileostomy subjects has been followed using the technique of gamma scintigraphy. In contrast with earlier reported results, the transit of the pellets was not affected by particle density.
The effect of iontophoresis and vehicle pH on the in-vitro permeation of lignocaine through human stratum corneum
Authors: Siddiqui Ovais , Roberts Michael S , Polack Alan E
Published: April 2011

The effect of iontophoresis and the pH of aqueous vehicles on the rate and extent of permeation of lignocaine through excised human stratum corneum was investigated. In the absence of iontophoresis, the rate of penetration was greatest at the higher pH values where lignocaine exists mainly in the unionized form; iontophoresis was most effective at the lower pH values where lignocaine is mainly ionized. At pH 3.4 and 5.2, the flux increased during iontophoresis, by approximately 8.5 and 4 times, respectively, relative to that occurring without iontophoresis. The present results suggest that some weak electrolytes which show poor percutaneous penetration may be administered topically using iontophoresis provided the drug is kept in a highly ionized form.
Cytoprotective action of carbenoxolone sodium on ethanol-induced gastric lesions in rats and its inhibition by indomethacin
Authors: Wan B Y C , Gottfried The Late S
Published: April 2011

Carbenoxolone produced a marked and dose-related inhibition of ethanol-induced gastric lesions in rats. This cytoprotective action was inhibited progressively and significantly by increasing doses of indomethacin. The evidence presented confirms previous suggestions that prostaglandin(s) are involved in the cytoprotective action of carbenoxolone.