bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of reserpine and stress on feeding behaviour in the light and dark phases of the diurnal cycle in rats
Authors: Gorka Z , Adamik P
Published: April 2011

The effect of reserpine (2·5 mg kg−1 subcutaneously) and stress (3 h restraint) on food and water consumption and body weight change in the light and dark phases of the diurnal cycle in rats was investigated. Reserpine increased water intake and body weight loss in the light phase (250 and 180% of the control, respectively). In the dark phase the reserpinized rats consumed less food and water (20 and 30% of the control, respectively) and body weight gain was reversed (–250% of the control). After stress, rats consumed more food and water (200 and 500% of the control, respectively) and their body weight loss was diminished (60% of the control) in the light phase. In the dark phase the consumption of food and water in the stressed rats was diminished (80 and 85% of the control, respectively) without any change in body weight gain. The dark/light phase ratio for food consumption, water intake and body weight change (gain/loss) was highly statistically significant in the stressed and reserpine-treated rats. The results indicate that evaluation of behaviour in animal models should be carried out during both phases of the diurnal cycle.
Dependency of salivary excretion of mexiletine on the plasma concentration in rats
Authors: Nagasako Sadao , Iwamoto Kikuo , Hayashibara Masakazu , Katagiri Yoshihiro
Published: April 2011

The effect of steady-state plasma concentrations on the salivary excretion of mexiletine was investigated following simultaneous bolus intravenous injection of the loading dose (2·7 or 16·1 mg kg−1) and constant-rate intravenous infusion of the maintenance dose (15 or 102 μg min−1 kg−1) in male Wistar rats. Parotid and mandibular saliva was collected separately by stimulating salivation with a constant-rate infusion of pilocarpine (50 μg kg−1 min−1) in each rat. The low and high steady-state levels of mexiletine in blood plasma were attained at 0·259 + 0·123 and 1·616 ± 0·475 μg mL−1, respectively, within the first 1–2 h after drug administration. Similarly, the two different steady-states in both parotid and mandibular saliva were attained. Although the mexiletine levels in both types of saliva were lower than that in plasma, the drug level in parotid saliva was always higher than that in mandibular saliva at any steady-state (P < 0·001 or 0·01). In parotid saliva, the high steady-state produced greater saliva to plasma drug concentration ratios (S/P ratio, 0·475 + 0·160) than that (0·386±0·131) at the low steady-state (P < 0·05). The S/P ratio for mandibular saliva at the high (0·204 ± 0·060) steady-state was also greater than that at the low (0·158 ± 0·050) steady-state (P < 0·01). These changes in the S/P ratio could not be explained by the pH for either parotid or mandibular saliva, but partially by the change in the unbound fraction of the drug which tended to be consistent with that in the ratio for both salivary glands. These findings suggest that the salivary excretion of mexiletine may be dependent on the plasma unbound concentration in rats.
Long-term Effects of the Anticholinesterases Sarin and Soman on Latencies of Muscle Action Potentials in Mouse Diaphragm Muscle
Authors: Smith A P
Published: April 2011

In-vivo administration of the irreversible anticholinesterases sarin and soman has been shown to produce long-term effects on latency and variability of latency of muscle action potentials in in-vitro mouse diaphragm muscle preparations. The maximum observed effects occurred three days post-soman administration and seven days post-sarin administration, and were no longer detectable 28 days later. With both anticholinesterases the increase in latency, and variability of latency, was reduced by pyridostigmine pretreatment. Therapeutic administration of pralidoxime mesylate effectively prevented the sarin-induced effects when given after a delay of 24 h. In contrast, the effectiveness of pralidoxime mesylate declined rapidly when its administration was delayed following soman. These findings are consistent with this action of soman and sarin being a product of acetylcholinesterase inhibition. The results obtained with sarin suggest that a period of acetylcholinesterase inhibition in excess of 24 h is required to trigger the events leading to the production of this long-term effect.
Uptake of Concentrated Perfluorocarbon Emulsions into Rat Lymphoid Tissues
Authors: Bentley P K , Johnson O L , Washington C , Lowe K C
Published: April 2011

The effects of injecting (10–30 mL kg−1) either perfluorodecalin (FDC) emulsions of increasing phase fraction (20–60% w/v) or the commercial formulation, Fluosol, on lymphoid tissues have been studied for up to 7 days in male rats. Tissue weights increased by up to 123% (P < 0·05) in proportion with quantity of perfluorochemical (PFC) injected, with spleen responses consistently greater than those of the liver. PFC droplets recovered from these tissues at 72 h after injection of 30% (w/v) FDC emulsion (10 mL kg−1) had mean diameters in the 1–10 μm range, with those from the spleen being larger than those from the liver. Recovered droplet diameters were considerably greater than freshly-prepared emulsion mean particle sizes (0·21–0·25 μm). These results suggest that coalescence of emulsion droplets following accumulation in lymphoid tissues is a pre-requisite for the eventual excretion of PFC vapour through the lungs.
1,3-Diacylaminopropan-2-ols and Corresponding 2-Acyl Derivatives as Drug Carriers: Unexpected Pharmacological Properties
Authors: Lambert D M , Neuvens L , Mergen F , Gallez B , Poupaert J H , Ghysel-Burton J , Maloteaux J-M , Dumont P
Published: April 2011

The design of lipid vectors (pseudotriglycerides, PTGs), achieved by the amide isosteric substitution of the ester moieties of 1,3-diacylglycerols, is based on the structural similarity with natural triglycerides facilitating the passage of pharmacological agents across biological membranes. 2-S-Acetylthiorphan (hemiacetorphan) pseudotriglycerides, Z-glycine pseudotriglycerides and 1,3-diacylaminopropan-2-ols vector molecules differing by the nature of the acid side-chain are examined in acute toxicity, radioligand binding and guinea-pig ileum experiments. These evaluations have led us to distinguish two types of compounds. Linear derivatives, palmitoyl and decanoyl, are devoid of toxicity and intrinsic activity. Cyclic derivatives, which contain in the acyl chain a phenyl, cyclohexyl, cyclopentyl or adamantoyl ring, present additional properties. Cyclic derivatives of hemiacetorphan are lethal after intravenous administration. The mortality is governed by the 2-hemiacetorphan moiety in the cyclic vector molecules. Hemiacetorphan alone is also lethal. Cyclic vector molecules and related compounds inhibit the contractile response of the guinea-pig ileum induced by electrical stimulation, histamine or acetylcholine (noncompetitive antagonism) whereas linear entities and parent compounds are not active. In particular, the 2-hemiacetorphan 1,3-diadamantoylamide PTG presents pD'2 values 7·87 ± 0·29 (vs histamine) and 7·97 ± 0·12 (vs acetylcholine).
Immune Response to Nasal Delivery of Antigenically Intact Tetanus Toxoid Associated with Poly(l-lactic acid) Microspheres in Rats, Rabbits and Guinea-pigs
Authors: Almeida A J , Alpar H O , Brown M R W
Published: April 2011

Tetanus toxoid was adsorbed onto poly(l-lactic acid) microspheres. Analyses by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and Western blotting suggest that the formulation procedure does not affect the stability or the antigenic properties of the protein. After nasal administration to guinea-pigs, the resulting preparation enhanced the immune response to the tetanus toxoid when compared with the free antigen. The increase in systemic immunoglobulin G titre was almost immediate in the group treated with the adsorbed tetanus toxoid (time zero, 140; week 2, 1550; week 4, 2760), reaching 36000 two weeks after the booster (week 7), whereas the free antigen produced an immune response similar to that found in non-treated animals. In a parallel experiment, latex particles of a similar size to poly(l-lactic acid) microspheres, administered to both rats and rabbits, were detected in the blood stream. These findings with tetanus toxoid demonstrate the use of microsphere delivery systems for nasal application of antigens. These had a profound effect on the immune response, and indicate possibilities for overcoming some of the barriers to drug absorption in general.
Local and Systemic Actions of Loperamide on Fluid Transport and Transmural Potential Difference Across Rat Small Intestine
Authors: Goldhill J , Hardcastle J , Hardcastle P T
Published: April 2011

The ability of loperamide to influence intestinal fluid transport was assessed using a dual loop preparation. Loperamide was applied to the lumen of the oral, but not the aboral loop, yet basal and prostaglandin-stimulated fluid transport was affected in both, indicating that the drug can act systemically in addition to any local actions. Loperamide had both pro-absorptive and anti-absorptive effects, the latter only occurring when basal fluid absorption was high. The effects of loperamide were greater in the aboral loop to which it was available only via the systemic route. This difference may reflect the absence of counteracting local influences in the aboral loop or a variation in the sensitivity of different regions of the gut to loperamide.
Stimulation of brain dopamine autoreceptors by remoxipride administration in reserpine-treated male rats
Authors: Ahlenius Sven , Ericson Evalena , Wijkström Agneta
Published: April 2011

Male Sprague-Dawley rats were treated subcutaneously with reserpine (5 mg kg−1, — 18 h) and with the aromatic amino acid decarboxylase inhibitor, NSD-1015 (3-hydroxybenzylhydrazine) (100 mg kg−1 -30 min). Remoxipride 0 -8, 3 -2 or 12 -8 mg kg−1 was administered subcutaneously at -50 min. Immediately following decapitation (0 h), the ventral striatum and the anterior neocortex were dissected. Dopa and 5-hydroxytryptophan accumulation in these brain areas were analysed by HPLC with electrochemical detection. Reserpine produced a marked increase in striatal and neocortical dopa accumulation, in comparison with glucose vehicle + NSD-1015-treated controls, and this increase was dose-dependently antagonized by remoxipride treatment. Thus, together with demonstrated dopamine receptor antagonist actions in intact animals, remoxipride behaves as a mixed dopamine receptor agonist-antagonist. Such properties could contribute to the favourable endocrine and extrapyramidal side effect profile of remoxipride as an antipsychotic agent.
Inhibitory effect of CP-96,345, a non-peptide neurokinin-1-receptor antagonist, on neurogenic responses of guinea-pig isolated airway smooth muscle
Authors: Kamikawa Yuichiro , Shimo Yasuo
Published: April 2011

The actions of CP-96,345, a non-peptide neurokinin-1 receptor antagonist, on the responses evoked by electrical-field stimulation or by acetylcholine and substance P in guinea-pig tracheal and bronchial muscle strips were examined. Electrical-field stimulation evoked a biphasic response, consisting of a cholinergically-mediated fast contraction followed by non-adrenergically-mediated relaxation in tracheal muscle and by a non-cholinergically-mediated slow contraction in bronchial muscle. CP-96,345 (1–10 μM) caused a concentration-dependent and non-selective inhibition in the amplitude of these neurogenic responses, where non-cholinergic contractions were more profoundly inhibited. Submaximal contractions of tracheal and bronchial muscles evoked by exogenous substance P (01–3 μm) were partly inhibited by CP-96,345 (1–10 μm), but acetylcholine-induced contractions were hardly inhibited. The results indicate that in guinea-pig isolated airway smooth muscle, CP-96,345 can non-selectively inhibit neurogenic responses probably via neurokinin-1 receptor-dependent and independent mechanisms.
Histamine H3 agonist decreases arterial blood pressure in the guinea-pig
Authors: Kim L Ea , Javellaud J , Oudart N
Published: April 2011

Intravenous injection of an H3-agonist, (R)-α-methylhistamine, dose-dependently caused a transient fall in mean arterial pressure of guinea-pigs. This pressor response was not reduced by combined mepyramine/cimetidine (up to 1 mg kg−1), atropine or propranolol, but was attenuated by either a selective H3-antagonist, thioperamide, or a competitive inhibitor of nitric oxide synthesis, NG-monomethyl l-arginine. The reduction by the inhibitor of nitric oxide synthesis was reversed by l- but not d-arginine. Histamine activated the H3-sites since its depressor response (obtained with mepyramine and cimetidine) was similar to that of (R)-α-methylhistamine. Our data indicate that H3-sites could exist in the cardiovascular system of guinea-pigs and that their stimulation might be mediated through the l-arginine/nitric oxide pathway.
Design and In-vitro Evaluation of a Modified-release Oral Dosage Form of Nifedipine by Hybridization of Hydroxypropyl-β-cyclodextrin and Hydroxypropylcellulose
Authors: Wang Zheng , Horikawa Takashi , Hirayama Fumitoshi , Uekama Kaneto
Published: April 2011

To modify the release rate of nifedipine, a potent calcium channel antagonist, a double-layer tablet was designed, anticipating a more balanced oral bioavailability and a prolonged efficacy than the simple plain tablet. Amorphous nifedipine powders prepared by spray-drying with 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) and nonionic surfactant HCO-60 were employed as a fast-release portion to attain an initial rapid dissolution of nifedipine. Hydroxypropylcelluloses (HPCs) with different viscosity grades (type L, M, and H) were used for a slow-release portion to provide an appropriate sustained-release. Taking into account the physiological conditions of the gastrointestinal tract (pH and motility), an optimal formulation of the double-layer tablet was obtained by changing the mixing ratios of each component. For example, the tablet consisting of HP-β-CyD with 3% HCO-60/(HPC-L:HPC-M) in the weight ratio 1/2(1:1) provided a sufficient slow release of the drug over a wide pH region following an initial rapid dissolution. The release of nifedipine from the double-layer tablets was little affected by pH of the medium and rotation speed of paddle after accelerated storage conditions (60°C, 75% r.h.). The present results suggest that a combination of HP-β-CyD, HCO-60 and HPCs can serve as a modified-release carrier for poorly water-soluble nifedipine.
Use of Enzymatic Activity for Design of Orally Administered Enteric Dosing Forms
Authors: Nishihata Toshiaki , Yamamoto Ken , Ishizaka Mayumi
Published: April 2011

Liquid and semi-solid enteric dosage forms were prepared by entrapping drug with an appropriate partition coefficient in a lipid base vehicle which would then be released by the action of intestinal enzymes. Lipid ester derivatives such as glyceryl monocaprylate and polysorbate 80 were used as vehicles. These vehicles readily dissolved the poorly water-soluble compounds used in the study, itazigrel, indomethacin and the dye, sudan II, and were digested by lipase and esterase, releasing the test drugs with time profiles similar to those observed in dissolution studies. The vehicles released little or only a small amount of the drugs into aqueous medium in the absence of an appropriate enzyme. The enzyme-sensitive enteric vehicles when containing sudan II did not release the dye in the stomach of rats after oral administration, but released significant amounts of the dye in the small intestine.
KCl Contractions in the Rat Isolated Seminal Vesicle
Authors: Sharif Suleiman I
Published: April 2011

Potassium chloride (K+) produced dose-dependent contractions of the rat isolated seminal vesicle with no sign of tachyphylaxis. The contractile response was biphasic in nature and composed of an early rapid phasic contraction and a slowly developing, but more sustained, tonic response separated by a transient relaxation. Neither cocaine nor depletion of tissue catecholamines by reserpine influenced responses to K+. Moreover, guanethidine, phentolamine, phenoxybenzamine, atropine and physostigmine all failed to modify responses of the tissue to K+. Thus, the possibility of K+ acting via release of endogenous noradrenaline or acetylcholine is excluded. Calcium-free conditions with or without EGTA reduced both the components of K+-induced contraction. The rate of reduction of both responses was faster in the presence of EGTA with part of the tonic response being resistant even to calcium deprivation in the presence of EGTA. On the other hand, verapamil reduced both responses in a similar manner, whereas nifedipine produced dose-dependent rightward shifts of the concentration-response curves of both the phasic and tonic responses to K+. However, in the presence of nifedipine, the maximum response of only the phasic contraction was significantly lowered. It is concluded that both phases of KCl contraction in the rat seminal vesicle use extracellular Ca2+, of which some is tightly bound with high affinity, probably to plasma membranes. In addition, two subtypes of voltage-sensitive Ca2+ channels may exist, one of which is preferentially sensitive to nifedipine and both are sensitive to verapamil.
Effect of the Selective A1 Adenosine Antagonist 8-Cyclopentyl-1,3-dipropylxanthine on Acute Renal Dysfunction Induced by Escherichia coli Endotoxin in Rats
Authors: Knight R J , Bowmer C J , Yates M S
Published: April 2011

The effect of the selective A1 adenosine antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX), on Escherichia coli endotoxin-induced acute renal dysfunction was determined in anaesthetized rats. Bolus administration of endotoxin at doses of either 1 or 20 mg kg−1 evoked decreases in inulin clearance, renal blood flow, urine flow and excretion of sodium, potassium and chloride. The changes in renal function produced by 20 mg kg−1 endotoxin were more severe than those noted with 1 mg kg−1 toxin and, by contrast to this lower dose, renal function showed no signs of recovery. Intravenous administration of CPX (0·1 mg kg−1) elicited a statistically significant, although modest, attenuation of the decline in inulin clearance, renal blood flow, urine output and electrolyte excretion induced by 20 mg kg−1 endotoxin. By contrast, treatment with 0·1 mg kg−1 CPX resulted in statistically significant protection against the falls in excretory function evoked by 1 mg kg−1 endotoxin but not against the reductions in renal blood flow and inulin clearance produced by the lower dose of toxin. These results suggest that adenosine may play a role, albeit not a major one, in the pathophysiology of endotoxaemic acute renal failure.
A factorial design study on the physical stability of 3-in-1 admixtures
Authors: Li L C , Sampogna T P
Published: April 2011

The effects of dextrose concentration, the compounding method, and storage conditions, on the physical stability of 3-in-1 admixtures were investigated using a 2n factorial design. The main effect of these three variables on the weight percent of oil globules larger than 5 μm (by HIAC) was found to be statistically significant. However, the effects of interaction amongst these variables, except the two-way interaction between dextrose concentration and storage conditions, were found to be statistically insignificant. A higher dextrose concentration was shown to enhance the physical stability of the admixtures, while low-temperature storage (three days at 5 C) was more favourable for maintaining the physical stability of the admixtures with a low dextrose concentration. Although sequential pumping produced admixtures with a slightly lower final weight percentage of larger oil globules (> 5 μm), the method of compounding has the least impact on the physical stability of the admixtures in comparison with the other two variables evaluated in this study. The storage of the admixtures at room temperature for one day was shown to have a greater adverse effect on admixtures with a low dextrose concentration.
Differences in the mode of cough augmentation by four angiotensin-converting enzyme inhibitors in guinea-pigs
Authors: Takahama K , Fuchikami J , Suzuki A , Tabata T , Kai H , Miyata T
Published: April 2011

The effects of four angiotensin-converting enzyme (ACE) inhibitors, captopril, enalapril, quinapril and alacepril, on the cough responses caused by citric acid and capsaicin inhalation were studied in normal and bronchitic guinea-pigs. After an oral dose of 10 mg kg−1, none of the ACE inhibitors had an effect on the citric acid-induced coughing response in normal guinea-pigs. Enalapril 10 mg kg−1 significantly increased the number of coughs caused by capsaicin inhalation. In bronchitic guinea-pigs, 10 mg kg−1 captopril and enalapril significantly increased the number of capsaicin-induced coughs. When administered daily for 8 days, captopril was the only ACE inhibitor which significantly increased the number of coughs due to citric acid inhalation. The present results indicate that the ACE inhibitors had different modes of cough augmentation.
Influence of heparin on the chemotactic activity of human thrombin
Authors: Morin A , Arvier M Marchand , Humbert J C , Doutremepuich F , Vigneron C
Published: April 2011

Chemoattractant properties of human thrombin have been studied, by polymorphonuclear leucocyte migration under agarose gel, in the presence of various sulphated macromolecules such as standard heparins, low molecular weight heparins, CY216, K2165, PK10169 and pentosane polysulphate. These compounds did not attract polymorphonuclear leucocytes within the range of concentrations used, whilst thrombin alone is a cytotaxin for these cells. Addition of heparins to thrombin led to an increase in the chemoattractant activity of this enzyme for at least one of the doses studied. Augmentation of the chemoattractant activity of thrombin by heparins was shown at concentrations equivalent to those found in-vivo after administration of therapeutic doses of heparin. Pentosane polysulphate, at the studied concentrations, did not lead to a significant rise in the chemoattractant activity of thrombin.
A new antimicrobial quinolone (AM-1155) analysed in hair as an index of drug exposure and as a time-marker
Authors: Uematsu T , Kusajima H , Umemura K , Ishida R , Ohkubo H , Nakashima M
Published: April 2011

Scalp hair samples were obtained at one-month intervals for up to four months after the administration from each of twelve healthy male volunteers participating in a phase I study of a new antimicrobial quinolone, AM-1155, (±)-1-cyclopropyl-6-fluoro-1, 4-dihydro-8-methoxy-7-(cis-3,5-dimethyl-1-piperazinyl)-4-oxo-3-quinoline carboxylic acid. After hair was sectioned into 1 cm lengths from the scalp end, corresponding portions from five pieces of hair were dissolved in 1 m NaOH and assessed for AM-1155 by HPLC. In all subjects who had taken a single dose (600 mg, n = 6) or repeated doses (300 mg twice daily for 6·5 days, n = 6), the drug was detected in hair. The hair portions containing the drug were shown in most subjects to move outwards month by month at the rate of about 1 cm month−1. A single hair, which was obtained from each subject of the repeated-dose study 3 months after the completion of administration, was cut into 2·5-mm lengths from the scalp side and analysed for AM-1155. The drug was shown to be contained in 4 to 6 consecutive 2·5-mm lengths, showing that there was no large axial diffusion of the drug along the hair shaft even after 3 months. These findings indicate the utility of measuring this quinolone derivative in hair as an index of drug exposure and, furthermore, as a time marker for analysing other drugs in hair.
A Chloroform Extract of the Herb Feverfew Blocks Voltage-dependent Potassium Currents Recorded from Single Smooth Muscle Cells
Authors: Barsby R W J , Knight D W , McFadzean I
Published: April 2011

We have studied the effects of a chloroform extract of fresh leaves from the herb feverfew (Tanacetum parthenium) on potassium currents in smooth muscle. The currents were recorded from single cells dissociated from the rat anococcygeus and the rabbit ear artery using the whole-cell patch-clamp technique. When applied to cells isolated from the rat anococcygeus, the extract reduced the inactivating voltage-dependent potassium current in a concentration-related manner, with an IC50 value (the concentration that reduced the current by 50%) of 56 μg mL−1. Complete block of the current occurred at 1 mg mL−1. In addition to reducing the peak current, feverfew decreased the time to peak of the current and increased the rate of decay of the current. These effects can be explained by the feverfew extract blocking open potassium channels. In single cells isolated from rabbit ear artery the feverfew extract again reduced the voltage-dependent potassium current, whilst at the same time having no effect on the spontaneous transient outward currents which arise as a consequence of activation of calcium-dependent potassium channels. These results suggest that chloroform extracts of feverfew leaf contain an as yet unidentified substance capable of producing a selective, open-channel block of voltage-dependent potassium channels.
Flumazenil and lignocaine-induced toxicity: is the inverse agonist type activity circadian-time dependent?
Authors: Bruguerolle Bernard , Emperaire Nicolle
Published: April 2011

We have investigated the possible influence of time of day on the activity of flumazenil on lignocaine-induced toxicity in mice. The circadian pattern of the period of latency for convulsions and the induced mortality for lignocaine alone and for lignocaine plus flumazenil was not statistically significant (cosinor or analysis of variance) but the influence of flumazenil on lignocaine-induced toxicity was circadian-time dependent (F = 27·8, P = 00001).
Pharmacokinetics and Absolute Bioavailability of Cyclosporin Following Intravenous and Abomasal Administration to Sheep
Authors: Charles Bruce G , Filippich Lucio J , Pass Michael A
Published: April 2011

Cyclosporin A pharmacokinetics were studied following intravenous and abomasal dosing in an open, crossover study in healthy, merino ewes. Five different doses of cyclosporin A were dispersed in milk and administered into the abomasum through a surgically inserted fistula which simulates oral administration. Cyclosporin A was well tolerated. Whole blood concentrations of cyclosporin A were measured by HPLC and mean clearance (0·45 ± 0·05 L h−1 kg−1), distribution volume (4·4 ± 2·0 L kg−1), mean residence time (9·6 ± 4·1 h) and half-life (12·1 ± 3·1 h) were calculated. Negligible cyclosporin A was excreted in urine or bile. Area under the curve increased proportionally with doses up to 26·3 mg kg−1, but was curvilinear above this dose. Abomasal bioavailability at 6·4 mg kg−1 was 0·26 ± 0·09, and mean absorption time was 4·7 ± 11·1 h. Considerable pharmacokinetic variability was observed, particularly after abomasal administration. Cyclosporin A pharmacokinetics in sheep lie within the values reported in man after renal, bone marrow and cardiac transplantation.
Impact of free magnolol excretions in asthmatic patients who responded well to Saiboku-To, a Chinese herbal medicine
Authors: Homma Masato , Oka Kitaro , Kobayashi Hitoshi , Niitsuma Tomoyuki , Yamamoto Shinobu , Itoh Hisao , Takahashi Noriyuki
Published: April 2011

Saiboku-To, a mixture of ten different herbal extracts, has been used in Japan and Czechoslovakia for corticosteroid-dependent severe asthma to reduce the maintenance doses of corticosteroid. Magnolol has been considered to be an active component of Saiboku-To as an inhibitor of 11β-hydroxysteroid dehydrogenase and T-lymphocyte proliferation resulting in corticosteroid-sparing. To investigate the relationship between magnolol and the clinical effects of Saiboku-To, urinary magnolol excretion was compared in responders and non-responders under long-term Saiboku-To treatment. The clinical outcome of the Saiboku-To treatment was evaluated in nine asthmatic patients at 52 weeks after the onset of the treatment, using individual fluctuation of asthmatic points obtained from the patients' diary cards. Three patients whose clinical conditions were improved by the treatment were termed responders and six others were termed non-responders. The difference in the amounts of the total magnolol excreted were not significant; however, free (or non-conjugated) amounts of magnolol excreted in the responders were 7 times those in the non-responders (P < 0·05). These results suggest that the magnolol might be responsible for the therapeutic effect of Saiboku-To, indicating practical bioavailability in the responders.
Effects of Different Agents on the Contractile Response Elicited by Extracellular Calcium after Depletion of Internal Calcium Stores in Rat Isolated Aorta
Authors: Noguera M Antonia , D’Ocon M Pilar
Published: April 2011

Noradrenaline, 1 μm, induced a sustained contractile response in rat isolated aorta in the presence and in the absence of extracellular Ca2+. After depleting the noradrenaline-sensitive intracellular Ca2+ stores, an increase in the basal tone of the aorta was observed during the incubation period in the presence of Ca2+ and in the absence of the agonist. We have tested the possible pathways through which Ca2+ enters the cell to refill the previously depleted Ca2+ pools, a process that is accompanied by an increase in tension. The magnitude of this increase does not depend on the presence of Mg2+ in the extracellular medium nor on the temperature, suggesting that it is mediated by an event that does not depend on intracellular energy or Ca2+, Mg2+-ATPase. It is inhibited in a concentration-dependent manner by an unspecific relaxing compound, caffeine, and an organic Ca2+ entry blocker, verapamil, but not by an inorganic Ca2+ entry blocker, lanthanum. Caffeine (10 Mm) and verapamil (10−5 m) completely inhibited the increase in the resting tone, but only verapamil abolished the refilling of the noradrenaline-sensitive Ca2+ pools, indicating that the extracellular Ca2+ enters the cell through voltage-operated Ca2+ channels. Caffeine inhibited the increase in the resting tone without blocking the refilling process of the stores at 37°C, but at 25°C a partial inhibition of the repletion of internal Ca2+ pools was observed. These results confirm previous work that showed a temperature-dependent activity of caffeine.
Ca2+-Channel Blockade in Rat Thoracic Aorta by Crychine Isolated from Cryptocarya chinensis Hemsl
Authors: Ko Feng-Nien , Wu Yang-Chang , Lu Sheng-Teh , Teng Che-Ming
Published: April 2011

The pharmacological effects of crychine, isolated from Cryptocarya chinensis Hemsl, on rat thoracic aorta were examined. In the high-K+ medium (60 Mm), Ca2+ (0·03–3 Mm)-induced vasoconstriction was inhibited by crychine in a concentration-dependent manner (10–100 μg mL−1). Increasing the incubation time from 5 to 30 min did not cause more pronounced inhibitory effect on KCl-induced contraction. The tonic contractions elicited by KCl (60 Mm) and Bay K 8644 (0·1 μm) were also relaxed by the addition of crychine and were more marked in the 1·9 Mm than in the 5 Mm Ca2+ medium. The noradrenaline concentration-response curves were antagonized non-competitively by crychine (10–100 μg mL−1). At the plateau of noradrenaline-induced tonic contraction, the addition of crychine also caused relaxation. This relaxing effect of crychine was not antagonized by indomethacin (20 μm) or methylene blue (50 μm), and was still present in denuded aorta or in the presence of nifedipine (2 μm). Caffeine (10 Mm)-induced contraction and cAMP or cGMP levels were not affected by crychine. It is concluded that crychine relaxes the rat thoracic aorta mainly by suppressing the Ca2+ influx through both voltage- and receptor-operated calcium channels.
Dual Inhibition of Platelet-activating Factor and Arachidonic Acid Metabolism by Ajmaline and Effect on Carrageenan-induced Rat Paw Oedema
Authors: Saeed Sheikh Arshad , Simjee Rukhsana Usman , Mahmood Farah , Rahman Nurun Nahar
Published: April 2011

The effects of ajmaline on human platelet aggregation, arachidonate metabolism and platelet activating factor (PAF)-induced lethality in rabbits were examined. Platelet aggregation induced by several stimuli (ADP, collagen, and PAF) was inhibited by increasing concentrations of ajmaline. The potency of ajmaline was higher when PAF was employed as stimulating agent in comparison with other agonists (IC50 70, 270 and 380 μm for PAF, ADP and collagen, respectively) whereas ajmaline had no effect against arachidonic acid-induced aggregation. In contrast however, ajmaline inhibited arachidonate metabolism by platelet homogenates. The formation of both thromboxane A2 and 12-hydroxy-eicosatetraenoic acid was inhibited by ajmaline with comparable potencies. Pretreatment of rabbits with ajmaline (50 mg kg−1) completely abolished the lethal effects of PAF (11 μg kg−1) given intravenously (P < 0·001). In addition, ajmaline at doses ranging from 50 to 100 mg kg−1 inhibited carrageenan-induced rat paw oedema (P < 0·001). In this test ajmaline was three times more potent than aspirin. In the light of these results we conclude that ajmaline, a known anti-arrhythmic agent is a PAF antagonist and a dual inhibitor of platelet cyclo-oxygenase and lipoxygenase enzymes with anti-inflammatory properties.
Chronic Administration Does Not Alter the Pharmacokinetic Profile of L-Dopa in the Rat
Authors: Rose S , Jenner P , Marsden C D
Published: April 2011

Chronic administration of L-dopa (200 mg kg−1 day−1 for 12 months) plus carbidopa (25 mg kg−1 day−1) or carbidopa (25 mg kg−1 day−1) alone did not alter the t½, AUC0–∞ k10, k12, k21, CLp or Vdss of L-dopa following intra-aortic (i.a.) administration (50 mg kg−1) alone or after carbidopa (25 mg kg−1, i.p.) pretreatment, or the t½, AUC0–∞, tmax or the bioavailability (F) of L-dopa (50 mg kg−1) administered orally, alone or after acute pretreatment with carbidopa (25 mg kg−1 i.p.). The peripheral metabolism of l-dopa was unaltered by chronic administration of L-dopa plus carbidopa or carbidopa alone as measured by unaltered AUC0·360 min for 3-O-methyldopa, dopamine, DOPAC or homovanillic acid in the plasma of rats following acute administration of L-dopa (50 mg kg−1, p.o. or i.a.) alone or following pretreatment with carbidopa, and unaltered hepatic dopa decarboxylase activity.
The Effect of Fluorine Substitution on the Physicochemical Properties and the Analgesic Activity of Paracetamol
Authors: Barnard Sallyann , Storr R C , O’Neill P M , Park B K
Published: April 2011

The physicochemical properties and analgesic action of six fluorinated analogues of 4-hydroxyacetanilide (paracetamol) have been investigated. Fluorine substitution adjacent to the hydroxyl group increased lipophilicity and oxidation potential whilst substitution adjacent to the amide had little effect on lipophilicity but led to a greater increase in oxidation potential. Lack of coplanarity and conjugation of the amide group and aromatic ring was also apparent with the analogues that had fluorine in the 2 and 6 positions. Introduction of fluorine into the amide group of paracetamol increased the lipophilicity 4-fold and also increased the oxidation potential of paracetamol. ED50 values for analgesic activity in the phenylquinone-induced abdominal constriction test on male Swiss White mice showed that ring substitution by fluorine reduced activity, especially at the 2,6-positions. Introduction of fluorine into the amide group enhanced activity significantly. Correlation of the analgesic activity with the physicochemical properties indicated that conjugation (and planarity) of the amide group with the aromatic ring is essential for activity and that ease of oxidation may also be an important factor.
Potent Antinociceptive Activity of a Hydroalcoholic Extract of Phyllanthus corcovadensis
Authors: Gorski Franco , Corrêa Clovis R , Filho Valdir C , Yunes Rosendo A , Calixto João B
Published: April 2011

This study analyses the analgesic effect of a hydroalcoholic extract (HE) from Phyllanthus corcovadensis in several models of pain in mice. HE (3–60 mg kg−1, i.p.) or (100–500 mg kg−1, p.o.) caused a graded and potent analgesic effect against the abdominal constriction response caused by acetic acid and acetylcholine with an ID50 of about 3 and 100 mg kg−1, respectively. In the tail-flick model HE (up to 500 mg kg−1, p.o.) was without effect, while morphine (1–10 mg kg−1, s.c.) caused a graded increase in pain latency (ID50, 3 mg kg−1). HE (1–300 mg kg−1) given both intraperitoneally and orally caused a potent and graded inhibition of the second phase of formalin-induced persistent pain in mice with an ID50 of 1 and 80 mg kg−1, respectively. In contrast, morphine (1–5 mg kg−1, s.c.) inhibited both phases of formalin-induced pain with an ID50 of 2·5 mg kg−1. Indomethacin (1–10 mg kg−1, i.p.) only inhibited the second phase of formalin-induced pain with an ID50 of about 3 mg kg−1. The analgesic effect of indomethacin, but not that caused by morphine and HE was accompanied by a graded inhibition of formalin-induced mouse paw oedema. In addition, HE up to 1 g kg−1 failed to prevent carrageenan- and dextran-induced rat hindpaw oedema. It is concluded that HE exhibits a potent antinociceptive profile, either when given intraperitoneally or orally. The mechanisms that underly its analgesic effect are unclear at present, but appear to be unrelated to inhibition of synthesis of arachidonic acid via cyclo-oxygenase or to activation of opioid receptors.
Pharmacokinetic Study of Loprinone Hydrochloride, a New Cardiotonic Agent, in Beagle Dogs
Authors: Uemura Yuji , Tanaka Shigeru , Ida Satoshi , Yuzuriha Teruaki
Published: April 2011

Pharmacokinetic parameters and bioavailability of a new cardiotonic agent, loprinone hydrochloride, in beagle dogs were determined by measuring plasma levels of loprinone after intravenous bolus and oral administration. The plasma half-life after intravenous administration of loprinone varied among individuals over the range 2·65–15·40 h. The bioavailability after oral administration of loprinone as a solution was 37·1%. Effects of enterohepatic circulation on the time-course of plasma levels after intravenous administration of the drug were also studied in bile-duct-cannulated beagle dogs. The amounts of loprinone and its glucuronide excreted in bile during 8 h after administration were 25·4 and 8·6% of the dose, respectively, indicating the possibility of enterohepatic circulation. The plasma half-life in bile-ductcannulated beagle dogs was 1·98 h. These results indicate that the variation in the half-life in beagle dogs resulted from enterohepatic circulation and that the true half-life is about 2 h. The relative bioavailability after oral administration of the drug as a powder in a capsule compared with a solution was 95·7%. In addition, the amounts of loprinone and its glucuronide excreted in bile, and the AUC of plasma level after infusion for 30 min into the portal vein in bile-duct-cannulated beagle dogs were similar to those after bolus intravenous administration. These results show that the low bioavailability reflects incomplete absorption.
Rolipram inhibits airway microvascular leakage induced by platelet-activating factor, histamine and bradykinin in guinea-pigs
Authors: Ortiz José L , Cortijo Julio , Vallés José M , Bou Josep , Morcillo Esteban J
Published: April 2011

Rolipram (0·1–1000 μg kg−1, i.v.) reduced the increase in microvascular permeability induced by platelet-activating factor (PAF; 50 ng kg−1, i.v.) at different sites of the guinea-pig airways. Rolipram (1–100μg kg−1, i.v.) inhibited histamine (30μg kg−1, i.v.)-and bradykinin (0·3 μg kg, i.v.)-induced airway microvascular leakage. These effects of rolipram were obtained at doses which inhibit histamine (7–20 μg kg−1 min−1)-induced bronchoconstriction (IC50 = 3 ± 1 μg kg, i.v.) without depressing arterial blood pressure in the guinea-pig. Aminophylline (50 mg kg−1) did not change the effect of PAF. The anti-exudative effect of rolipram is of potential therapeutic value in asthma.
Protection from reperfusion-induced arrhythmias by polyethylene glycol 600
Authors: Hoffmann P , Klapperstü M , Scholz J , Weise M , Döpfer K-P
Published: April 2011

The effects of polyethylene glycol (PEG) 600 on cardiovascular parameters and reperfusion-induced arrhythmias were investigated using a 5-min period of ligation of the left anterior descending coronary artery followed by reperfusion in an anaesthetized open-chest rat model. PEG 600 was effective in reducing reperfusion arrhythmias, such as ventricular fibrillation and ventricular tachycardia. Mortality was decreased from 29.4%) (5/17) in the saline-control to 0% (0/14) in the PEG-treated group (P < 0.05). Biochemical investigations during the ischaemia/reperfusion period revealed that PEG infusion resulted in a reduction of cardiac lactate as well as a striking maintenance of the glutathione content of the heart.
Wide-angle X-ray Diffraction of Human Stratum Corneum: Effects of Hydration and Terpene Enhancer Treatment
Authors: Cornwell P A , Barry B W , Stoddart C P , Bouwstra J A
Published: April 2011

Wide-angle X-ray-diffraction experiments were used to investigate the molecular organization of barrier components of human stratum corneum. Diffraction lines related to the side-by-side lipid packing arrangements in the intercellular bilayers were identified as were patterns arising from secondary protein structures in intracellular keratin. Reflections were also identified which may be produced by proteins in the corneocyte envelopes. The effects of hydration on stratum corneum structure were monitored using 0, 20–40, 40–60, 60–80 and approximately 300% hydrated samples. The packing arrangements in the intercellular lipid bilayers remained the same over the entire hydration range, as did keratin structures. A new diffraction ring, attributable to liquid water, was produced by 300% hydrated samples with a repeat spacing of 0.35 to 0.30-0.29 nm. The effects of three terpene enhancers, (+)-limonene, nerolidol and 1,8-cineole, on stratum corneum structure were monitored. Treatment with each of the terpenes produced additional reflections which were attributed to the presence of the respective liquid enhancers within the stratum corneum. (+)-Limonene produced an additional reflection at 0.503-0.489 nm, nerolidol, an additional reflection at 0.486-0.471 nm and 1,8-cineole, an intense reflection at 0.583–0.578 nm. Reflections characteristic of gel-phase lipids and crystalline lipids also remained after all terpene treatments. These results provide no clear evidence of lipid bilayer disruption by the terpenes and suggest that areas of liquid terpene exist within the stratum corneum. The mechanisms underlying propylene glycol synergy with terpene enhancers were investigated. Treatment of stratum corneum with each terpene mixed with propylene glycol gave rise to two additional reflections. One reflection, always positioned at 0.452–0.448 nm, had been observed in control studies following propylene glycol treatment and may have been associated with bilayer structures disrupted by propylene glycol or altered keratin structures. The second reflection was developed by the respective terpene enhancer. For example, treatment with a 1,8-cineole/propylene glycol mixture produced reflections at 0.457—0.451 nm (propylene glycol-disrupted lipids or altered keratin) and 0.591—0.578 nm (liquid 1,8-cineole). Since the reflection at 0.452—0.448 nm was unaffected by co-application of propylene glycol with terpene enhancers, this study offers no evidence to support the theory that propylene glycol synergy with the terpenes occurs through enhanced lipid disruption.
Absorption Enhancement of Intrapulmonary Administered Insulin by Various Absorption Enhancers and Protease Inhibitors in Rats
Authors: Yamamoto Akira , Umemori Shinji , Muranishi Shozo
Published: April 2011

The effects of absorption enhancers and protease inhibitors on the pulmonary absorption of insulin were examined by means of an in-situ pulmonary absorption experiment. Absorption enhancers used in this study were sodium glycocholate, linoleic acid-surfactant mixed micelles and N-lauryl-β-d-maltopyranoside whereas aprotinin, bacitracin and soybean trypsin inhibitor were used as protease inhibitors. The absorption of insulin from the lung was evaluated by its hypoglycaemic effect. In the absence of these additives, a slight hypoglycaemic effect was obtained following intrapulmonary administration of insulin. However, we found significant and continuous hypoglycaemic effects after the insulin administration with these additives. N-Lauryl-β-d-maltopyranoside and bacitracin appeared to be more effective for enhancing the pulmonary absorption of insulin than the other adjuvants. These findings suggest that the use of these two adjuvants would be a useful approach for improving the pulmonary absorption of insulin.
Effect of Terfenadine on Substance P and Vasoactive Intestinal Polypeptide Concentrations in Nasal Secretions from Patients with Nasal Allergy
Authors: Takeyama Masaharu , Mori Kazuo , Morikawa Norifumi , Asakura Shunji , Chaen Tokuo , Watanabe Noritake , Mogi Goro
Published: April 2011

Before terfenadine treatment, the mean substance P and vasoactive intestinal polypeptide (VIP) concentrations in nasal secretions from nasal allergy patients tended to be higher than the values of healthy subjects. During terfenadine treatment, the mean substance P concentrations in nasal secretions from patients allergic to house dust or pollen were significantly decreased to 62 and 39% of the initial values, respectively. The mean VIP concentrations in nasal secretions from the house dust allergy patients and the pollen allergy patients were significantly decreased to 52 and 18% of the initial values, respectively. Plasma substance P and VIP concentrations were not affected by nasal allergic symptom and terfenadine treatment.
Pharmacokinetics and Cardiovascular Effects of YM-21095, a Novel Renin Inhibitor, in Dogs and Monkeys
Authors: Shibasaki Masayuki , Usui Takashi , Inagaki Osamu , Asano Masaharu , Takenaka Toichi
Published: April 2011

The pharmacokinetics and cardiovascular effects of YM-21095 ((2 RS), (3S)-3-[Nα-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)-butyl]-l-histidylamino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thio]-2-butanol), a potent renin inhibitor, have been studied in beagle dogs and squirrel monkeys. Plasma levels of YM-21095 after 3 mg kg−1 intravenous dosing to dogs declined biphasically and fitted a two-compartment model. Kinetics were as follows: t½α = 4·9±0·2 min, t½β = 2·76±0·79 h, Vdss = 3·86±1·04 L kg−1, plasma clearance = 2·22 ± 0·39 L kg−1, and AUC= 1445 ± 266 ng h mL−1. After 30 mg kg−1 oral dose, maximum plasma concentration, tmax and AUC of YM-21095 were 28·8 ± 9·6 ng mL−1, 0·25 h and 23·6 ± 7·7 ng h mL−1, respectively. Systemic bioavailability as determined on the basis of the ratio of AUC after intravenous and oral dose was 0·16 ± 0·04%. In conscious, sodium-depleted monkeys, YM-21095 at an oral dose of 30 mg kg−1 lowered systolic blood pressure and inhibited plasma renin activity without affecting heart rate and plasma aldosterone concentration. Maximum plasma concentration of YM-21095 after 30 mg kg−1 oral dose to monkeys was 71·8 ± 41·5 ng mL−1, which was reached 0·5 h after the dose. At equihypotensive doses, captopril and nicardipine increased plasma renin activity markedly and slightly, respectively. These results suggest that oral absorption of YM-21095 is low in dogs and monkeys, and YM-21095 shows a blood pressure lowering effect by inhibiting plasma renin activity in sodium-depleted monkeys.