bluuebunny/crossref_metadata_2025 huggingface dataset:
3-Amino-1-hydroxypropylidene-1,1-diphosphonate (APD): a novel enhancer of rectal cefoxitin absorption in rats
Authors: van Hoogdalem E J , Wackwitz A T E , de Boer A G , Breimer D D
Published: April 2011

The promoting action of the calcium chelating compound EDTA on intestinal drug absorption is supposed to be based on Ca2+ depletion, inducing widening of tight junctions. The aim of the present study was to evaluate the effects of the calcium-binding agent 3-amino-1-hydroxypropylidene-1,1-diphosphonate disodium salt (APD) on rectal cefoxitin absorption in rats. The extent of rectal cefoxitin absorption was enhanced by 0·5 to 6% w/v of APD, on rectal infusion as well as on bolus delivery, the latter regimen tending to result in lower bioavailabilities. A maximal cefoxitin bioavailability of 85 ± 10% was achieved by infusion with 4% w/v of APD, compared with 14 ± 12% without APD.
L-Ascorbic acid produces hypoglycaemia and hyperinsulinaemia in anaesthetized rats
Authors: Cheng J T , Hsieh-Chen S C , Tsai C L
Published: April 2011

L-Ascorbic acid (Vitamin C) produced a marked reduction in the blood glucose concentration following intravenous injection (20–100 mg kg−1) to anaesthetized rats. This hypoglycaemic effect was accompanied by an increase in plasma insulin concentration. D-ascorbic acid produced a similar hypoglycaemic effect.
Serum glucose and insulin levels in normotensive (WKY) and spontaneously hypertensive (SH) rats during and after the cessation of continuous (10 day) Clonidine infusion
Authors: Lewis S J , Dunlop M , Jarrott B
Published: April 2011

The concentrations of glucose were elevated whereas those of insulin were decreased in the sera of normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats on day 10 of a continuous subcutaneous infusion of Clonidine (10 μg kg−1 h−1 for 10 days). Fifteen to 18 h after cessation of infusion, the glucose levels of both strains had fallen to below those of the respective controls whereas the insulin levels remained suppressed. As such the hypoglycaemia may be related to the general increase in metabolic requirements associated with the post-infusion ‘withdrawal syndrome’.
Preparation of Drug-Diluent Hybrid Powders by Dry Processing
Authors: Ishizaka Takafumi , Honda Hirotaka , Kikuchi Yuji , Ono Kenji , Katano Toshio , Koishi Masumi
Published: April 2011

New hybrid powders have been produced by the dry processing of six drugs (oxyphenbutazone, prednisolone, theophylline, indomethacin, phenacetin and aspirin), with potato starch used as a core material, by means of an electric mortar and a powder suface reforming system designed to produce hybrid powders. The hybrid powders obtained immediately after production differed in their structure from interactive mixtures. With the hybrid powders the drug was spread on the surface of the core particle by friction and collision that occurred in the dry process, but with interactive mixtures the drug simply adhered as intact particles to the surface of diluent particles. Scanning electron microscopy and powder X-ray diffractometry indicated that the mechanochemical phenomenon was essential for the production of the hybrid powders. With time, a shape change in the adhering drug was observed as a relaxation process took place, with recrystallization resulting from the release of accumulated energy. The change with time might depend upon the method of producing powders and the physical properties of the drug used, e.g. the smooth layer of indomethacin produced by the powder surface reforming system reverted to fine particles tightly adhering to the starch surface, though no change was observed with prednisolone.
Dissolution of Theophylline from Film-coated Slow Release Mini-tablets in Various Dissolution Media
Authors: Fassihi A R , Munday D L
Published: April 2011

The dissolution of an experimental formulation of film-coated slow release theophylline mini-tablets has been investigated using the USP paddle apparatus in test media at pH 1·2 (hydrochloric acid), pH 5·4 and 7·4 (phosphate buffers) at 37°C. Monitoring of in-vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1·2 is substantially greater (95% of total drug content released in < 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5·4 and 7·4, respectively. However, in-vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in-vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasize the usefulness of an animal model for assessment of in-vivo drug release and subsequent absorption, during the development of modified release dosage forms.
In-vitro Bioassays for Cholecystokinin
Authors: Sjödin Lars , Nederman Thore , Olsson Per Anders , Viitanen Eila
Published: April 2011

Two in-vitro methods for the bioassay of cholecystokinin (CCK) are described. They should be useful for determinations of potencies of pharmaceutical formulations of CCK. Both are based on the hormone’s ability to stimulate exocrine pancreas. The stimulatory effect on 45Ca efflux from preloaded suspended acinar cells or on release of amylase from pancreatic acini from the guinea-pig has been recorded. The assay based on stimulation of 45Ca outflux is more specific and precise than the method using measurements of amylase secretion. Therefore, the calcium assay was further validated against the conventional guinea-pig gall-bladder contraction assay. Both methods gave similar potency readings but the results from the in-vitro assay were more precise.
Human liver and plasma aspirin esterase
Authors: Williams Faith M , Mutch E M , Nicholson E , Wynne H , Wright P , Lambert D , Rawlins M D
Published: April 2011

The plasma, in addition to the liver, is a major site of hydrolysis of aspirin. Human plasma and liver aspirin esterase activities in samples from a group of patients varied over a two fold range and there was a significant correlation between individual plasma and liver activities. Human liver aspirin esterase was present in the cytosolic and microsomal fractions. Cytosolic and microsomal enzymes had different activities and apparent affinities for aspirin.
Alphaxalone reveals GABAA receptor-mediated inhibition in guinea-pig ileum
Authors: Healing Claire , Hilton Trudi , Simmonds Michael
Published: April 2011

Contractions of the transmurally stimulated guinea-pig ileum were not affected by 10 μM bicuculline, a competitive GABAA receptor antagonist. The GABAA potentiator alphaxalone depressed the responses to 2 and 20 Hz stimulation by 20% and 40%, respectively, but had no effect on 0·2 Hz responses. The depressions were prevented by 10 μM bicuculline. This suggests that endogenous activation of GABAA receptors during transmural stimulation was normally subthreshold but, when pharmacologically potentiated, inhibitory effects were seen.
The effect of Ca deprivation and of Ca-blocking drugs on oxytocin-induced contractions of the male mouse anococcygeus
Authors: Gibson A , Shaw C R
Published: April 2011

Oxytocin (4 nM)-induced contractions of the male mouse anococcygeus were rapidly and completely lost in EGTA (2 mM)-containing, Ca-free Krebs solution. Contractions were also lost, although more slowly, in Ca-free Krebs solution without EGTA; under such conditions, readdition of Ca did not by itself cause contraction, but readdition of Ca (0·1–2·5 mm) in the presence of 4 nM oxytocin resulted in a rapid contractile response. These Ca-induced responses, in the presence of oxytocin, and those to oxytocin in normal Ca-containing Krebs solution, were unaffected by nitrendipine (0·01–1 μM). Contractions to oxytocin were completely blocked by the calmodulin antagonists trifluoperazine (50 μM) and W-7 (75 μM). It is concluded that oxytocin-induced contraction of the mouse anococcygeus does not require opening of nitrendipine-sensitive Ca channels, and there is no Ca-independent component of the contractile response; the cellular mechanisms linked to the oxytocin receptor in the anococcygeus are therefore different from those in the uterus.
Deamination of hordenine by monoamine oxidase and its action on vasa deferentia of the rat
Authors: Barwell C J , Basma A N , Lafi M A K , Leake L D
Published: April 2011

The selectivity of the naturally occurring mine, N,N-dimethyltyramine (hordenine) for monoamine oxidase (MAO) and its action upon isolated vasa deferentia of the rat was investigated. Hordenine was deaminated by rat liver MAO with a Michaelis constant of 479 μM and maximum velocity of 128 nmol (mg protein)−1 h−1 compared with 144 μM and 482 nmol (mg protein)−1 h−1 for tyramine. Studies, with selective irreversible inhibitors of MAO, showed that hordenine was a highly selective substrate for MAO-B of liver and that it was not deaminated by the MAO-A of intestinal epithelium. In contrast to tyramine, hordenine did not produce contractions of isolated vasa deferentia. However, 25 μM hordenine potentiated contractile responses of vasa, from control animals, to submaximal doses of noradrenaline and inhibited responses to tyramine. It did not alter responses, to noradrenaline, of vasa denervated by chronic pretreatment of rats with guanethidine. Therefore, it appears that hordenine acted as an inhibitor of noradrenaline uptake, in isolated vasa deferentia. These results indicate that dietary-hordenine is unlikely to be deaminated by intestinal MAO as this is predominantly MAO-A. Consequently, it is likely to be absorbed and could affect the sympathetic nervous system, by virtue of its action as an inhibitor of noradrenaline uptake.
The Effect of Captopril on the Membrane Properties of Central Neurons In-vitro
Authors: Robinson E L , Greenfield S A
Published: April 2011

Captopril, a potent antihypertensive that acts via inhibition of angiotensin converting enzyme also has apparent central actions. Its effects on membrane properties on particular central neurons in-vitro has therefore been investigated. In the substantia nigra, where there is a high concentration of angiotensin converting enzyme, captopril caused a dose-dependent depolarization without any apparent change in conductance, but possibly requiring the integrity of the dendritic arbour. A similar effect occurred when captopril was applied to neurons in either the thalamus or hippocampus, where levels of angiotensin converting enzyme are relatively low. Further studies with homologues of captopril revealed that the — SH group on the molecule was a prerequisite of the effect observed. It is concluded that the — SH group on the captopril molecule has an electrogenic effect on diverse central neurons, independent of inhibition of angiotensin converting enzyme, but preferentially manifest at the level of the dendrite.
The Effects of Enprostil and RS-86505-007 on In-vitro Intestinal Permeability of Rabbit and Monkey
Authors: Grass George M , Sweetana Stephanie A , Bozarth Carol A
Published: April 2011

Enprostil is a prostaglandin E2 analogue characterized as a racemic mixture of four stereoisomers. Enprostil and a single isomer, RS-86505-007, were evaluated for their effects on the permeability of actively and passively transported compounds in segments of small intestine from rabbits and monkeys. Consistent with human in-vivo studies, which have demonstrated decreases in absorption of D-xylose, both compounds inhibited D-glucose transport. The passively transported compounds mannitol and progesterone were also less permeable in this model in the presence of enprostil or RS-86505-007. In contrast to the concentration-dependent inhibition displayed by ouabain, RS-86505-007 had no effect on purifed Na+K+-ATPase. It is suggested that an effect of a general nature, possibly an increase in the barrier properties at the intestinal surface, may explain the transport inhibition. Of two other enprostil isomers, RS-86812-007 inhibited D-glucose transport in rabbit small intestine, while RS-86505-008 had no effect. The prostaglandin E1 analogue misoprostol was ineffective in monkey and poorly effective in rabbit. This suggests that the inhibition of D-glucose transport by enprostil and its active stereoisomers is mediated through some structurally specific receptor interaction.
Induction of hepatic microsomal drug metabolizing enzyme system by levamisole in male mice
Authors: Dalvi R R , Terse P S
Published: April 2011

To examine the effect of levamisole on the hepatic drug metabolizing enzyme system of mice, levamisole at a dose of 20 mg kg−1 day−1 was administered i.p. for 5 days. Compared with the control values, the levamisole treatment significantly increased the amount of cytochrome P450 and cytochrome b5 and the in-vitro activities of aminopyrine N-demethylase, benzphetamine N-demethylase and aniline hydroxylase. In contrast, there was no change in microsomal NADPH-cytochrome c reductase activity in-vitro or in the relative liver weight and microsomal protein content compared with the corresponding values for control mice. Furthermore, in-vivo induction of drug metabolism was demonstrated by decreased pentobarbitone sleeping times after levamisole pretreatment. These results indicate that certain hepatic microsomal mixed function oxidases of mice are induced by levamisole, the drug that is frequently used as an anthelmintic in veterinary medicine and as an immunostimulant drug in human medicine.
The preferential effects of chloroquine on the IgM and IgG subclass responses to TI and TD antigens in BALB/cAn mice
Authors: Lewis G M , Slack J H
Published: April 2011

This study has determined the effects of chloroquine on the IgM and the IgG subclass responses of BALB/cAn mice to both thymus-independent (TI) and thymus-dependent (TD) antigens, and has found that in antigen-unprimed BALB/cAn mice chloroquine adversely affects antibody responses to both TI and TD antigens. However, in antigen-primed mice the immune responses to TD antigens were unaffected by chloroquine. The IgG1 subclass response, but not necessarily other IgG subclass or IgM responses to TI and TD antigens, was adversely affected by chloroquine in unprimed mice only. Thus, in unprimed, but not in antigen-primed, BALB/cAn mice, chloroquine preferentially decreased the IgG1 subclass responses to both TI and TD antigens.
Differential effects of ketoprofen on the pharmacokinetics of sulphadimethoxine in fast and slow acetylator rabbits
Authors: Imamura Yorishige , Mori Hiroyuki , Otagiri Masaki
Published: April 2011

Intravenously co-administered ketoprofen decreased the plasma concentration of sulpha-dimethoxine (SDM) after intravenous bolus administration to fast acetylator rabbits, and significantly increased the total body clearance (CLtot) and steady-state volume of distribution (Vdss) of SDM. On the other hand, ketoprofen had little effect on the plasma concentration of SDM in slow acetylator rabbits. When SDM was intravenously administered in combination with ketoprofen, an increase in the plasma concentration of N4-acetylsulphadimethoxine, a major metabolite of SDM that strongly displaces SDM from its binding sites, was observed in all rabbits, but the increase was much larger in fast acetylators. We conclude that the acetylation capacity for SDM is a factor determining the pharmacokinetic interaction between SDM and ketoprofen in rabbits.
Inhibition of noradrenaline release from cerebrocortical synaptosomes and stimulation of synaptosomal Na+, K+-ATPase activity by morphine in rats
Authors: Nishikawa Takashige , Shimizu Shin-Ichiro
Published: April 2011

The effects of morphine on noradrenaline (NA) release from rat cerebrocortical synaptosomes and on the synaptosomal Na+, K+-ATPase activity were determined. Morphine (10−3-10−5 M) caused a dose-related inhibition of enhanced prelabelled [3H]NA release evoked by a high concentration of K+ from synaptosomes and this inhibitory action of morphine was antagonized by the specific antagonist naloxone (10−4, 10−5 M). Morphine dose-dependently stimulated the synaptosomal Na+, K+-ATPase activity but not Ca2+-ATPase activity in the incubation medium containing 2.2 × 10−6 4.7 × 10−7 M free Ca2+, and this stimulatory effect was antagonized by naloxone. These results suggest that morphine may have some role in the suppression of membrane depolarization and/or the release of NA through its stimulatory action on the Na+, K+-ATPase activity in rat cerebral cortex.
Model Systems for the Evaluation of Mucolytic Drugs: Acetylcysteine and S-Carboxymethylcysteine
Authors: Livingstone Carina R , Andrews Mary A , Jenkins Susan M , Marriott Christopher
Published: April 2011

The therapeutic place of mucolytic drugs remains uncertain; clinical studies have seldom demonstrated significant benefit and the activity of such agents is poorly understood. In this study the effects of the mucolytic agents acetylcysteine (AC) and S-carboxymethylcysteine (SCMC) have been assessed in-vitro, using purified mucus gels and tracheal explant systems and in-vivo, in the mini-pig tracheal pouch model, in order to elucidate their mechanisms of action. A reduction in the elastic modulus (up to 70% over the frequency range 0.2-20Hz) was apparent after treatment of mucus gels in-vitro with AC (p < 0.05), but not with SCMC. Gel chromatography indicated that AC reduced the mucus glycoprotein to smaller subunits and a breakdown of gel structure was apparent when visualized using a cryofracture technique. SCMC treated gels were comparable with control samples. Mucus production was assessed in isolated rat trachea by monitoring the uptake and release of [3H] glucosamine. AC (5–15 mM) did not affect secretion whereas SCMC (5 and 10 mM) reduced the production of radiolabelled material (24 and 37%, respectively) over 24 h (P < 0.05). Single oral doses of SCMC and AC (20 mg kg−1) were administered to mini-pigs and mucus collected from tracheal pouches; no significant changes in the rheological or biochemical properties of the secretion could be determined. The in-vitro mucolytic activity of AC depends upon a direct action on the secretion, SCMC appears able to reduce production of the mucus glycoprotein. Wide inter-and intra-individual variation in the properties of the secretion would suggest that such effects are not readily demonstrated in-vivo.
In-vitro Effect of Pirenzepine on Motility of Canine Gall-bladder
Authors: Pozo M J , Salido M D , Madrid J A , Salido G M
Published: April 2011

The action of pirenzepine as an antimuscarinic drug has been investigated on motor responses of muscle strips in the canine gall-bladder. Pirenzepine was further used to examine whether gall-bladder motor responses to synthetic sulphated cholecystokinin octapeptide (CCK-8) are sensitive to pirenzepine. Pirenzepine (10−9-10−5 M) antagonized muscle contractions in response to acetylcholine (10−9-10−2 M) and CCK-8 (10−11-10−6 M) in a significant manner. These findings indicate that pirenzepine is a potent antagonist of two substances that are the principal contractile mediators of gall-bladder contraction and suggest that long-term administration of pirenzepine could contribute to stasis of the gall-bladder.
The Actions of Fenfluramine and Interaction with 5-HT3 Receptor-Antagonists to Inhibit Emesis in the Ferret
Authors: Costall Brenda , Naylor Robert J , Tattersall F David
Published: April 2011

The racemate and (+)- and (-)-isomers of fenfluramine (5 mg kg−1 i.p., 1 h pretreatment) antagonized cisplatin-induced retching and vomiting in the ferret. The intravenous injection of (±)-fenfluramine administered on an established cisplatin-induced emesis antagonized the response within minutes of injection. The administration of a lower dose of (±)-fenfluramine (10 mg kg−1 i.p., 1 h pretreatment) failed to antagonize cisplatin-induced emesis when administered alone but enhanced the antiemetic effects of metoclopramide and ICS 205–930. This pretreatment with (±)-fenfluramine failed to enhance the antiemetic effects of zacopride. It is considered that an action of the racemate on presynaptic 5-HT/catecholaminergic systems to reduce neurotransmitter release may enhance the action of certain 5-HT3 receptor antagonists in controlling emesis induced by cisplatin.
Effects of Cularine and Other Isoquinoline Alkaloids on Guinea-pig Trachea and Human Bronchus
Authors: Candenas M L , Naline E , D'Ocón M P , Cortes D , Advenier C
Published: April 2011

The relaxant effects of the isoquinoline alkaloids, cularine, antioquine, obaberine and 6, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, with structures related to that of papaverine, have been studied on the guinea-pig isolated trachea and human bronchus against contractions induced by acetylcholine (ACh), histamine, neurokinin A (NKA) and KCl. These effects were compared with those of papaverine and theophylline. Among the alkaloids tested, the most potent was cularine, the relaxant activity of which, in terms of pD2, was between those of papaverine and theophylline. The results showed that for the guinea- pig isolated trachea and the human bronchus, the cularine concentrations required to inhibit K+-induced contractions were close to those necessary to counteract ACh-, histamine- and NKA-induced contractions. The relaxant activity of cularine was not modified when it was tested on tracheal preparations under resting tone or after epithelium removal. In addition, cularine was able to inhibit Ca2+-induced contractions in a Ca2+-free, K+-enriched solution at the same concentrations as those which inhibited the action of the different contractile agents in normal K rebs solution. All these data show that cularine displays non-specific antispasmogenic activity on guinea-pig and human airways. The lower relaxant activity (pD2) of cularine compared with papaverine suggests the importance of free rotation of the isoquinoline-benzyl ring linkage as well as of the degree of hydrogenation of the heterocyclic ring in the spasmolytic effects of isoquinoline compounds.
Cephalosporin C acylase in the autolysis of filamentous fungi
Authors: Reyes F , Martinez M J , Alfonso C , Copa-Patiño J L , Soliveri J
Published: April 2011

Cephalosporin C acylase activity was studied using fluorescamine determination of free — NH2 groups produced in the deacylation of cephalosporin C by the enzyme. Fourteen fungi from different genera were studied and low extracellular cephalosporin C acylase activity was found in the genera Aspergillus, Fusarium and Penicillium. Forty one fungi of these genera were checked but not all presented acylase activity. The enzyme was generally found to be an extracellular enzyme and during the process of autolysis its activity increased with incubation time and with increasing pH of the medium. In no case was β-lactamase activity detected. Penicillium rugulosum and Penicillium griseofulvum were identified as good cephalosporin C acylase producers. Deacetyl esterase activity was also detected in these fungi.
Inhibitory effects of catecholamines on cholinergically and non-cholinergically mediated contractions of guinea-pig isolated bronchial muscle
Authors: Kamikawa Yuichiro , Shimo Yasuo
Published: April 2011

The actions of catecholamines on the responses evoked by electrical field stimulation or by acetylcholine and substance P in guinea-pig bronchial strip chain have been examined. Electrical field stimulation evoked a biphasic contraction, consisting of a cholinergically-mediated fast contraction followed by a non-cholinergically-mediated slow contraction. All catecholamines tested caused a concentration-dependent reduction in the height of the biphasic contraction, where non-cholinergic contractions were more potently inhibited. The inhibitory effect of isoprenaline was largely prevented by propranolol (2 μM) alone, whereas those of noradrenaline and adrenaline were prevented by treatment with both propranolol (2 μM) and yohimbine (2 μM). The inhibitory effect of dopamine was unaffected either by propranolol (2 μM), yohimbine (2 μM) or haloperidol (10 μM). Submaximal contractions of bronchial muscle evoked by exogenous acetylcholine (2 μM) or substance P (0.2 μM) were also inhibited by catecholamines, except dopamine, but the effects were antagonized by propranolol (2 μM) alone. The results suggest that in guinea-pig isolated bronchial muscle, catecholamines can inhibit both cholinergic and non-cholinergic excitatory neurotransmissions not only by postjunctional β-adrenoceptors but also by prejunctional α2-adrenoceptors.
Effect of nicardipine on the relationship of renal blood flow and of renal vascular resistance to perfusion pressure in dog kidney
Authors: Ogawa Nobuyuki
Published: April 2011

The effect of nicardipine, a Ca channel blocker, on autoregulation of renal blood flow and perfusion pressure-vascular resistance relationship has been investigated in perfused kidneys of anaesthetized dogs. In control animals excellent autoregulation of renal blood flow and pressure-dependent elevation of vascular resistance were observed above 100 mmHg of perfusion pressure. However, intra-arterial infusion of nicardipine at doses of 3 and 10 μg min−1 showed dose-dependent impairment of the autoregulatory response and of elevation of vascular resistance. Infusion of nicardipine (2.5 μg min−1) into the renal artery also inhibited renal vasoconstriction induced by YC-170, a Ca channel activator. These results suggest that the inhibitory effect of nicardipine upon renal autoregulation may be due to its Ca2+ channel blocking action.
Kinetics of the Intestinal Uptake of Zinc Acexamate in Normal and Zinc-depleted Rats
Authors: Torres-Molina F , Martínez-Coscollá A , Gisbert S , Quintana E , Sendrós S , Peris-Ribera J E , Plá-Delfina J M
Published: April 2011

The uptake of zinc as acexamic acid salt in the small intestine of the anaesthetized rat was shown to be a two-phase process in normal animals. The first phase is rapid mucosal binding which satisfies the Freundlich isotherm equation and which involves about 30 per cent of the initially perfused zinc. The second phase was characterized as an apparent absorption step which obeys Michaelis-Menten and first-order combined kinetics, with the following parameters: Vm = 6.51 mg h−1; Km = 2.96 mg; ka = 0.306 h−1. In largely non-saturated conditions, an apparent global rate constant of about 2.50 h−1 was calculated. No significant interference due to endogenous zinc excretion into the small intestine was observed during the absorption period. In zinc-deficient animals, the two phases were not so well characterized. Binding was non-linear and apparent absorption efficiency was much greater at high zinc concentrations, so no evidence of saturable kinetics was found, thus confirming the hypothesis of a homeostatic zinc regulation mechanism.
Differential Influence of Laboratory Anaesthetic Regimens upon Renal and Hepatosplanchnic Haemodynamics in the Rat
Authors: Gumbleton Mark , Nicholls Paul J , Taylor Glyn
Published: April 2011

Renal blood flow in rats anaesthetized with the combination alphaxolone/alphadolone (3.90 mL min−1 (g tissue)−1) was significantly (P < 005) greater than in rats anaesthetized with ketamine/midazolam (3.24 mL min−1 (g tissue)−1), pentobarbitone (3.19 mL min−1 (g tissue)−1), fentanyl/fluanisone/midazolam (2.84 mL min−1 (g tissue)−1) or urethane (1.99 mL min−1 (g tissue)−1). Renal blood flow in the urethane anaesthetized rats was significantly (P < 0.05) lower than in animals anaesthetized with the other anaesthetic regimens, and is consistent with literature reports of a depressive effect of urethane anaesthesia upon xenobiotic renal clearance in the rat. Hepatosplanchnic blood flow was highest in the alphaxolone/alphadolone anaesthetized animals (71.7 mL min−1 kg−1), with the urethane anaesthetized animals demonstrating a significantly (P < 0.05) lower (33.4 mL min−1 kg−1) blood flow. The fentanyl/fluanisone/midazolam (65.4 mL min−1 kg−1), pentobarbitone (61.1 mL min−1 kg−1), and ketamine/midazolam (51.4 mL min−1 kg−1) regimens resulted in hepatosplanchnic blood flows of intermediate magnitude. The observed marked differential effects of the anaesthetic regimens upon renal and hepatosplanchnic blood flows may dramatically influence drug disposition in the experimental animal, and be of significance to laboratory pharmacokinetic studies in which anaesthesia is used.
Gonadal Influence on the Metabolism and Haematological Toxicity of Dapsone in the Rat
Authors: Coleman M D , Tingle M D , Winn M J , Park B K
Published: April 2011

Administration of dapsone (33 mg kg−1) to intact rats resulted in a marked elevation of methaemoglobin levels in male (435.0 ± 105.2% met Hb h) compared with female rats (59.0 ± 17.2% met Hb h). However, the clearance of dapsone was significantly faster in males compared with females. Female rats showed very low levels of methaemoglobin which were accompanied by significantly higher blood concentrations of parent drug. Clearance of dapsone in castrated animals was less than one-third of that of the intact sham-operated males (252.2 ± 67.2 vs 81.4 ± 33.0 mL h−1). Likewise, clearance of dapsone in ovarectomized rats was approximately half that of intact females. There were no significant differences in the disposition of dapsone between the ovarectomized (AUC, 431.0 ± 31.7 μg h mL−1; t 1/2, 15.62 ± 1.8 h) and castrated (AUC, 450.6 ± 150.9 μg h mL−1; t 1/2, 17.6 ± 7.9 h) animals. However, methaemoglobin levels in castrated males, although less than a third of those of intact males, significantly exceeded those of ovarectomized animals. There was no significant difference between the four groups of animals with respect to red cell sensitivity to the methaemoglobin-forming capacity of the toxic metabolite of dapsone, the hydroxylamine. Metabolic conversion of dapsone to the hydroxylamine in the presence of NADPH was 7.6 ± 1.5% for liver microsomes from intact males and was significantly greater (P < 0.05) than the corresponding values for liver microsomes from castrated rats (5.3 ± 0.59%). Conversion of dapsone to dapsone-NOH by liver microsomes from intact females and ovarectomized animals was below 1 % in both cases. This study illustrates the androgenic control of N-hydroxylation in the rat.
A Possible Reduction in the Renal Clearance of Ciprofloxacin by Fenbufen in Rats
Authors: Naora Kohji , Katagiri Yoshihiro , Ichikawa Nobuhiro , Hayashibara Masakazu , Iwamoto Kikuo
Published: April 2011

The change in plasma concentration-time profile, serum protein binding and renal and biliary clearances of ciprofloxacin caused by coadministration of fenbufen has been studied in rats administered an intravenous dose of ciprofloxacin (5 mg kg−1) alone or with fenbufen (10 mg kg−1). Coadministered fenbufen significantly prolonged the plasma elimination half-life of ciprofloxacin from 40.5 to 57.6 min and tended to reduce the total body clearance of this quinolone by about 20%. The extent of ciprofloxacin binding to rat serum protein was not affected by fenbufen, nor did it affect the biliary clearance of the quinolone. However, fenbufen tended to reduce renal clearance and significantly decreased the cumulative renal excretion of the quinolone during at least the first 3 h after drug administration. These results suggest a possible reduction of ciprofloxacin clearance owing to inhibition of renal excretion by fenbufen.
Pharmacokinetics of GM1 Ganglioside Following Parenteral Administration
Authors: Cornelli Umberto , Panucci Aldo , Zingali Gaetano , Kirschner Günter , Baggio Carlo , Cogo Roberto
Published: April 2011

The pharmacokinetic parameters of monosialotetrahexosylganglioside (GM1) have been determined in healthy volunteers at 3 dose levels: 100, 200, 300 mg. Each dose was administered to separate groups of 12 volunteers. GM1 levels were determined in plasma, urine, and faeces by a method based on the property of the cholera toxin β subunit to react specifically with GM1 ganglioside. A non-compartmental model was applied to determine standard pharmacokinetic parameters. The average AUC increased with dose (1002 ± 121.2, 1306 ± 146.1, 3155 ±121.6 μg mL−1 h after 100, 200, 300 mg, respectively). Plasma clearance was less than 3 mL min−1 and the distribution volume was close to the plasma volume (on average between 4.3 and 7.2 L). Mean residence time was about 43 h for all doses. GM1 was not detected in urine, while in faeces the amount of GM1 determined was similar to the baseline values obtained before dosing.
Renal Responses to Magnesium Lithospermate B
Authors: Yokozawa Takako , Lee Tae Woong , Chung Hae Young , Oura Hikokichi , Nonaka Gen-Ichiro , Nishioka Itsuo
Published: April 2011

Renal responses to magnesium lithospermate B isolated from Salviae miltiorrhizae radix were examined in normal rats. Urinary sodium, potassium, prostaglandin E2 and kallikrein excretion was significantly increased after magnesium lithospermate B administration, whereas excretion of urinary 6-keto-prostaglandin F1α and thromboxane B2 was unchanged. Rats administered with the drug also revealed a slight elevation of plasma renin activity and the levels of angiotensins I and II. Plasma aldosterone was decreased slightly. No significant changes were observed in angiotensin-converting enzyme or blood pressure.
Potentiating Effect of Daunorubicin on Vasocontractile Responses to KCl and BAY K 8644 in Rat Aorta
Authors: Wakabayashi Ichiro , Sakamoto Kunihiro , Kakishita Eizo
Published: April 2011

The effects of daunorubicin on vasocontraction by several agonists have been investigated on isolated aortic strips from rats. Pretreatment of the strips with daunorubicin (17.7 μM) potentiated the contractile response to low concentrations of KCl or to BAY K 8644 but not to phenylephrine or clonidine. The maximal contractile response to KCl was not affected by the pretreatment while that to BAY K 8644 was increased. The potentiated response to KCl could be eliminated by addition of nifedipine (1 μM) or use of a calcium-free solution. The maximal contractile response to BAY K 8644 was greatly increased by partial depolarization with KCl (10 mM, final concn) in the control solution but only slightly increased by the partial depolarization in the solution with daunorubicin. These results suggest that daunorubicin facilitates activation of the voltage-dependent calcium channel and increases the contractile responses to KCl and BAY K 8644 in rat aorta.
Distribution of griseofulvin in the rat: comparison of the oral and topical route of administration
Authors: Nimni Marcel E , Ertl Delia , Oakes Roger A
Published: April 2011

Effective penetration of griseofulvin across the dermal barrier has been achieved using an anhydrous solvent system of benzyl alcohol (10%), acetone (40%), and isopropanol (50%). There were quantitative differences in the relative accumulation of griseofulvin in skin compared with internal organs, when the topical and oral routes of administration were compared. The topical route enhanced localized concentrations of griseofulvin at the site of application, and these persisted for several days. After daily topical application a steady state was reached at day 3, when the diffusion across the skin barrier and epidermal loss seemed to equal the total amount applied to the skin surface. The application of griseofulvin topically, required a much smaller amount of drug to achieve similar integumentary levels compared with the amount required orally.
The excitatory effect of dopamine on isolated canine tracheal smooth muscle
Authors: Shue Chung-Hung , Chen Ching-Ju
Published: April 2011

The effect of exogenous dopamine on canine tracheal smooth muscle has been studied in-vitro. Dopamine at concentrations over 10−5 M induced contractions of tracheal muscle strips and repeated exposures resulted in desensitization (tachyphylaxis) of the muscle. The sensitivity of the response varied dramatically among muscle strips. At lower concentrations, dopamine caused neither muscle relaxation nor inhibition of contractions evoked by 10−6 M acetylcholine. Both a dopaminergic antagonist, haloperidol (10−5 and 10−4 M), and an α-adrenoceptor antagonist, phentolamine (10−7 to 10−5 M), attenuated the contraction to 10−3 M dopamine. The β-adrenoceptor antagonist, propranolol (10−8 to 10−6 M), enhanced the contraction. However, the contraction could only be abolished by phentolamine at 10−4 M. Thus, in canine tracheal smooth muscle, the contractile response to dopamine is predominantly through the activity of α-adrenoceptors and the role of dopaminergic receptors is vague. It is suggested that the weakness of the dopamine-induced contraction results from an antagonism between α- and β-adrenoceptor effects and the dopamine tachyphylaxis may reflect a gradually decreased activation of the α-adrenoceptor mechanism in comparison with the β-adrenoceptor mechanism.
Cytotoxic drugs and the aquatic environment: estimation of bleomycin in river and water samples
Authors: Aherne G Wynne , Hardcastle Anthea , Nield Alan H
Published: April 2011

A radioimmunoassay has been used to determine levels of the anticancer drug bleomycin in sewage treatment works effluent, river and potable water samples. Samples were concentrated 100-fold by lyophilisation and a final limit of detection of 5 ng L−1 was achieved. Concentrations of immunoreactive bleomycin of between 11 and 19 ng L−1 were found in the effluents but a lower concentration range < 5–17 ng L−1 was found in river and potable water samples. The risk to human health of ingesting water (in SE England) with such low levels of this cytotoxic drug appears to be minimal in relation to the normal chemotherapeutic doses administered (20–30 mg m−2).
Evaluation of In-vitro Percutaneous Absorption across Human Skin and in Animal Models
Authors: Přborský Jan , Mühlbachová Elfa
Published: April 2011

The in-vitro permeability characteristics of human skin have been examined and compared with results in laboratory animals using various types of penetration enhancers. The study was focused on evaluation of predictable validity of the data obtained in animals mostly used in permeation studies. The results in man using the same penetration enhancers were about 30% of the value in the rat. The least potent enhancer was dimethylsulphoxide and the maximum efficacy was observed with sodium laurylsulphate in the rat experiments while in man the results were approximately equal when using any of the studied enhancers. Comparison of the results of experiments performed with N-methyl-2-pyrrolidone in several laboratory animals and man showed that the skin permeability in man is approximately 4 times lower than with the rat. Man and guinea-pig were not significantly different in these experiments. There were no significant differences in laurocapram penetration enhancing effect in the concentration range 0.1 to 0.5%, but there was an optimum concentration of laurocapram of 1%. The results showed quantitative differences in percutaneous absorption in various animal species in comparison with man. These differences should be considered in selecting a suitable model for preclinical drug evaluation. The guinea-pig skin penetration seems to be most similar to that in man.
Erythrocytes as Carriers for L-Asparaginase. Methodological and Mouse In-vivo Studies
Authors: Kravtzoff R , Ropars C , Laguerre M , Muh J P , Chassaigne M
Published: April 2011

L-Asparaginase has been encapsulated in Swiss mouse or human erythrocytes by hypotonic haemolysis followed by isotonic resealing and reannealing. The details of incorporation and properties of carrier erythrocytes are presented. When L-asparaginase loaded into 51Cr-labelled erythrocytes, was infused intravenously, the same half-life was found for asparaginase and 51Cr. In addition, L-asparaginase loaded into erythrocytes was much more effective in eliminating plasma asparagine compared with the same dose of free L-asparaginase injected in solution, during a sustained period (14 days).
Influence of the Endothelium on Vascular Responses of Aortae from Endotoxic Rats
Authors: Wakabayashi Ichiro , Hatake Katsuhiko , Kakishita Eizo , Hishida Shigeru
Published: April 2011

Intraperitoneal injection of endotoxin diminished the in-vitro contractile response of rat aorta to phenylephrine or clonidine, whether the intimal layer was disrupted or not. The relaxing responses to acetylcholine and sodium nitroprusside in aorta precontracted with 10−6 M phenylephrine were similar between control and endotoxic groups. However, when the precontractile force following phenylephrine was adjusted to an equivalent level, the relaxing responses to acetylcholine and sodium nitroprusside were diminished in the endotoxic aorta compared with the controls. There was no significant difference between the two groups in the increase in cyclic GMP levels induced by acetylcholine or by sodium nitroprusside. These results suggest that aortae from endotoxic rats show decreased responsiveness to α-adrenoceptor stimulation not because of enhancement of the endothelium-derived relaxing factor but because of abnormality in the vascular smooth muscle which is not specific for subtypes of the α-adrenoceptor.
Role of Presynaptic Purinoceptors and Cyclic AMP on the Noradrenaline Release in Cat Cerebral Arteries
Authors: Rivilla Fernando , Güemes Magdalena , Sanchez-Ferrer Carlos F , Ibañez Carmen , Salaices Mercedes , Marin Jesus
Published: April 2011

Field electrical stimulation (ES), K+ (50 mM) or ionophore X-537A (0.01 mM) induced tritium release from cat cerebral arteries preincubated with [3H]noradrenaline (NA). Adenosine and AMP (0.5 mM) did not modify tritium release caused by ionophore X-537A, but these agents and ATP (0.5 mM) significantly reduced that elicited by ES and K+; this reduction was antagonized by 1-methyl-3-isobutylxanthine (MIX; 0.05 mM). Inosine (0.5 mM) and the agonist of purinergic A2-receptors, 5′ N-ethylcarboxamide adenosine (NECA; 0.5 mM) had no effect, but the agonist of purinergic A1-receptors L-N6-phenylisopropyl adenosine (L-PIA; 0.1 mM) diminished tritium efflux caused by ES and K+. The adenosine inhibition of ES-induced radioactivity release was not affected by indomethacin (0.05 mM). MIX (0.05 mM) increased tritum release evoked by ES and K+. Agents that increase intracellular cyclic (c)AMP levels, such as dibutyryl cAMP (0.5 mM), the phosphodiesterase inhibitor Ro 20–1724 (01 mM), and the activators of adenylate cyclase, forskolin (0.005 mM) and NaF (2 mM) reduced tritium secretion elicited by ES and K+. However, the intracellular increase of cyclic GMP (cGMP) caused by 8-Br-cGMP did not affect this secretion. Dipyridamole (0.05 mM) and the adenosine deaminase inhibitor erythro-9-2-hydroxy-3 nonyl adenosine (EHNA; 0.1 mM) also produced inhibition of tritium secretion elicited by ES and K4. Dipyridamole reduced both the uptake of [3H]NA and [3H]adenosine. These results indicate that in these vessels: (1) presynaptic inhibition of exocytotic NA release induced by adenosine, ATP, and AMP is mainly mediated by purinoceptors of the A1-subtype, without participation of prostaglandins; (2) the nonexocytotic release is not presynaptically modulated; (3) intracellular increases of cAMP, but not of cGMP, reduced NA release; and (4) the effects of dipyridamole and EHNA appear to be mediated by augmentation of intracellular levels of adenosine by preventing its neuronal uptake and its adenosine deaminase inactivation, respectively.
The Pharmacokinetics and Pharmacodynamics of a New Thromboxane Synthetase Inhibitor, 6-(1-Imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (DP-1904) in Man after Repeated Oral Doses
Authors: Tanaka Makoto , Ono Kenji , Hakusui Hideo , Takegoshi Toshio , Shiozawa Tomoo , Suzuki Tomoyoshi , Nii Shigenori , Shibata Hisao
Published: April 2011

The pharmacokinetics of DP-1904, a new potent and selective thromboxane synthetase inhibitor, and its effects on ex-vivo prostanoid formation have been studied in groups of Japanese normal male volunteers, who received repeated oral doses of 200 mg every 12 h for 4 doses, or 400 mg every 24 h for 2 doses, or 200 mg every 12 h for 14 doses. The drug was well tolerated by all subjects without evidence of adverse reactions. Repeated administration showed no significant changes in half-lives, tmax values, cmax values and AUC values. DP-1904 did not exhibit time-dependent kinetics. Its plasma levels were lower than the quantifiable level (50 ng mL−1) at 12 h after each dose. These data suggest no significant accumulation of DP-1904 in normal volunteers. DP-1904 reduced the serum thromboxane B2 by about 80% during the medication, the serum concentrations returning to about 44, 75 and 20% of the predrug control values at 36 h after the last 200 mg doses and 48 h after the last 400 mg dose.
Interspecies Pharmacokinetic Scaling of Some Iodinated Organic Acids
Authors: Lázníček Milan , Lázníčková Alice , Štětovská Marie , Květina Jaroslav
Published: April 2011

We have investigated the possibility of interspecies scaling of relationships between the structure and total plasma clearance in a group of nine organic acids (iododerivatives of benzoic, phenylacetic and hippuric acids) in rabbits, rats and mice. The intercompound comparison established the dependence of total plasma clearance predominantly on the molecular structure in all the animals under study, but the dependence on drug lipophilicity was also meaningful. For interspecies scaling of total plasma clearance, the use of a biological clock with an effective renal plasma flow as the unit seemed most suitable and is probably connected with the principal role of the kidney in the elimination of the compounds under study.
Paracetamol potentiates stress-induced gastric ulceration in rats
Authors: Cho C H , Ogle C W
Published: April 2011

The effect of paracetamol on gastric ulcers produced by restraint at 4°C for 2 h (stress) was studied in rats. Paracetamol treatment s.c or p.o., with a dose as high as 250 mg kg−1, did not produce any haemorrhagic lesions in the glandular mucosa. Oral administration with 250 mg kg−1, however, significantly reduced the mast cell count in the gastric glandular mucosa and potentiated haemorrhagic ulceration but not mast cell degranulation caused by stress. The potentiating action was maximum when paracetamol was given between 15 and 30 min before stress. Ranitidine, astemizole, dimethylsulphoxide, sucralfate and verapamil did not protect against the adverse action of paracetamol on stress-evoked lesions. This study suggests that paracetamol worsens stress-induced stomach ulceration by an action which appears not to be due to histamine release, free radical production or intracellular calcium disturbance in the gastric mucosa.
Effect of phospholipid emulsifiers on physicochemical properties of intravenous fat emulsions and/or drug carrier emulsions
Authors: Ishii Fumiyoshi , Sasaki Ichiro , Ogata Hiroyasu
Published: April 2011

The physicochemical properties of soybean oil emulsions stabilized with purified egg lecithins (phosphatides) of various concentrations have been examined. The zeta potential of the emulsion droplets and the mean particle size of oil droplets in 10% (w/w) o/w-type emulsion decreased with increasing emulsifier concentration and then levelled off at more than 1.2% (w/w). In rheological measurements, at the initial stage, the viscosity of 10% (w/w) o/w-type emulsion gradually increased with increasing purified egg lecithin concentration, at the next stage, a plateau was reached at about 1.0–1.4% (w/w), and at the final stage, the viscosity curve showed a dramatic increase. These results indicate that emulsions stabilized by purified egg lecithin at more than 1.2% (w/w) are likely to be sufficiently stable.