bluuebunny/crossref_metadata_2025_split huggingface dataset:
Digoxin-specific Fab fragments impair renal function in the rat
Authors: Moran Robert J , Struthers Allan D , Hewick David S 
Published: April 2011

Abstract
The effect on renal function, and the plasma and urinary disposition, of digoxin-specific antibody fragments (DSFab), were studied using the rat as an experimental model. After 24 h, DSFab (2 mg kg−11, i.v.) caused decreases in urine volume and creatinine clearance of 34 and 33%, respectively, when measured in the same rats. However, only the creatinine clearance was significantly changed when compared with a separate saline-treated control group. Plasma and urinary creatinine concentrations were unaffected by DSFab treatment. Since creatinine clearance approximates to glomerular filtration rate (GFR), it appears that a dose of DSFab equivalent to about one-fifth of the usual clinical dose, causes a reduction in GFR of about one-third. In patients undergoing digitalis therapy, a degree of renal impairment is common and it is possible that this may be exacerbated by treatment with DSFab. DSFab had an elimination half-life of 178 min, an apparent volume of distribution (Vd) of 106 mL kg−1 and a plasma clearance of 0·42 mL kg−1 min−1. If it is assumed that the plasma volume of a rat is approximately 35 mL kg−1, the measured Vd suggests appreciable penetration of DSFab into the extracellular fluid at this dose. Seventy-two hours after injection, only 7·6% of the administered dose of DSFab was found in the urine.
Distribution and Protein Binding of FK506, a Potent Immunosuppressive Macrolide Lactone, in Human Blood and Its Uptake by Erythrocytes
Authors: Nagase Kazuko , Iwasaki Kazuhide , Nozaki Katsuko , Noda Kohsei 
Published: April 2011

Abstract
The distribution of FK506 in the blood was estimated in-vitro. At a drug level of 5 ng mL−1, FK506 mainly distributed in erythrocytes (95–98%) in dog, monkey and human blood, and its distribution was affected by drug concentration, temperature, and haematocrit values. In erythrocytes most of FK506 was distributed in cytoplasmic components and was bound strongly to a protein having a molecular weight of 10–11 kDa. The molecular weight of this protein agrees with FK506-binding protein found in various cells. Greater than 98·8% of FK506 was bound to the plasma proteins in all species studied. FK506 bound to various plasma proteins such as lipoproteins, globulins, α1-acid glycoprotein and albumin.
The Protective Effect of Nimodipine, a Calcium Antagonist, and Its Influence on Soman Clearance in the Anaesthetized Rabbit
Authors: Karlsson Britt , Fredriksson Sten-Åke , Sellström Åke , Algers Güran 
Published: April 2011

Abstract
The effect of pretreatment with a vasoactive compound, nimodipine, on soman intoxication in peripheral organs of rabbits was studied by measuring changes in the cholinesterase and acetylcholinesterase activity and by measuring clearance of soman in blood using gas chromatography/high resolution mass spectrometry. In animals receiving soman only, initial blood concentrations were approximately 100 ng mL−1 and were still detectable after 5 min. The clearance rate of soman in blood markedly increased following nimodipine pretreatment such that soman was below the detection limit (0·002–0·003 ng mL−1) in all samples. Soman injection caused a significant inhibition of the acetylcholinesterase activity in serum, and in brain. In rabbits pretreated with nimodipine, no significant inhibition of acetylcholinesterase activity occurred after soman injection. In view of the effects of nimodipine on soman clearance and on the acetylcholinesterase and cholinesterase inhibition during soman intoxication, we suggest that nimodipine has profound circulatory effects, which during soman intoxication, increase the vascular perfusion through the body and thereby increase the detoxifying capacity.
The effect of Ca2+ antagonists on spontaneous motility from sheep duodenum
Authors: Murillo María Divina , Plaza Miguel Angel , De Pedro María José , Arruebo María Pilar 
Published: April 2011

Abstract
Longitudinal smooth muscle of the sheep duodenum showed a rhythmic spontaneous activity with an average frequency of 5·6 ± 0·55 phasic movements min−1 and a mean value of the amplitude of phasic contractions of 0·956 ± 0·1 g. When the strips were incubated in Ca2+-free medium, the spontaneous motility amplitude (SMA) was reduced to 37 ± 8·2% of control values. In Ca2+-free medium plus EDTA (1 or 2 Mm), the SMA was strongly reduced to 21·9 ± 8·3 and 1·8 ± 1·8%, respectively. Verapamil, nifedipine and diltiazem diminished the SMA. The EC50 value for verapamil was 10−9 M., whereas that for diltiazem was 2 × 10−9 M and for nifedipine was 3 × 10−14 M. Trifluoperazine and TMB-8 reduced the SMA with EC50 values of 7 × 10−6and 3 × 10−5 m, respectively. The spontaneous activity in the sheep duodenum seemed to be mediated by influx extracellular Ca2+, which enters through potential-dependent channels and intracellular Ca2+ release.
Effects of Nω-nitro-l-arginine and capsaicin on neurogenic vasomotor responses in isolated mesenteric arteries of the monkey
Authors: Tsuchiya Kimiyuki , Urabe Masanobu , Yamamoto Ryuich , Asada Yujiro , Lee Tony J-F 
Published: April 2011

Abstract
Monkey isolated mesenteric arterial rings denuded of endothelium constricted upon transmural nerve stimulation (TNS) in the absence of active muscle tone. The constriction was potentiated by Nω-nitro-l-arginine (3 × 10−5 m), but not by the d-enantiomer (3 × 10−5 m). The potentiation was reversed by l-arginine (3 × 10−4 m). The neurogenic vasoconstriction of mesenteric arteries was also augmented by capsaicin, but to a lesser extent than that induced by Nω-nitro-l-arginine. Indomethacin (10−5 m) did not affect TNS-induced vasoconstriction. These findings suggest that nerve-derived nitric oxide or a related substance may play a greater role than do capsaicin-sensitive vasodilator transmitters in neurogenic regulation of mesenteric arterial tone in the monkey. The transmitter mechanisms for vasodilation in mesenteric circulation vary among species.
Comparative Study of Buccoadhesive Formulations and Sublingual Capsules of Nifedipine
Authors: Save Tanuja , Shah Meena U , Ghamande A R , Venkitachalam Padma 
Published: April 2011

Abstract
The pharmacodynamics of nifedipine administered via the oral mucosa was investigated in hypertensive patients. The effect of two buccoadhesive formulations, tablets and films, was compared with the commercially available sublingual capsule in a complete cross-over study in six patients. All three formulations elicited onset of action 10 min after administration. The sublingual capsule and the buccoadhesive film revealed peak response at 30 min. The buccoadhesive tablet, however, exhibited a delayed peak response at 45 min. Analysis of variance indicated that, although time-dependent differences in the formulations were suggested, there was no significant difference in the overall effect produced by the three formulations. The results of the study suggest that the buccoadhesive formulations of nifedipine were comparable in performance with the sublingual capsule.
Diltiazem Facilitates Endothelin Clearance from the Blood Stream to Reduce Toxic Elevation of Plasma Endothelin Level in Rodents
Authors: Ashizawa Naoki , Okumura Hiroshi , Matsuura Akihiro , Kobayashi Fujio 
Published: April 2011

Abstract
Pretreatment with diltiazem at a dose of 2 mg kg−1 intravenously protected against sudden death induced by intravenous administration of endothelin-1 (ET-1, 5 nmol kg−1), with an apparent decrease in the plasma immunoreactive-ET-1 (IR-ET-1) in mice. These effects, which were also observed in anaesthetized rats, disappeared in rats with bilateral ligation of the renal arteries. In the latter, the exogenous ET-1-induced elevation of plasma IR-ET-1 tended to be higher than that in the sham-operated controls. Furthermore, in anaesthetized rats, diltiazem inhibited ET-1-induced decreases in renal blood flow and increased renal accumulation of IR-ET-1. These results indicate that part of the clearance of ET-1 from the bloodstream occurs in the kidney, and that diltiazem enhances the elimination of the peptide, presumably by improvement in the renal circulation, this action leading to alleviation of the toxic effects of ET-1.
Sesquiterpene Components of Volatile Oils as Skin Penetration Enhancers for the Hydrophilic Permeant 5-Fluorouracil
Authors: Cornwell P A , Barry B W 
Published: April 2011

Abstract
Twelve sesquiterpene compounds, derived from natural volatile oils, were investigated as putative skin penetration enhancers for human skin. Pretreatment of epidermal membranes with sesquiterpene oils, or solid sesquiterpenes saturated in dimethyl isosorbide, increased the rate of absorption of the model hydrophilic permeant, 5-fluorouracil (5-FU). Enhancers with polar functional groups were generally more potent than pure hydrocarbons. Furthermore, enhancers with the least bunched structures were the most active. The largest effect was observed following pretreatment with nerolidol, which increased pseudo-steady-state 5-FU flux over 20-fold. Molecular modelling suggested that terpenes with structures suitable for alignment within lipid lamellae were the most potent enhancers. Sesquiterpene enhancers had long durations of action implying that they did not wash out of the skin easily. This study attempted to improve enhancer clearance by replacing the aqueous donor and receptor phases by ethanol: water (1:1) solutions. Ethanol increased the permeability coefficient for 5-FU 13-fold, demonstrating that, in aqueous solution, it is a moderately potent penetration enhancer. Sesquiterpene and ethanol enhancement effects were approximately additive. Sesquiterpene effects were almost fully maintained for at least 4·5 days following pretreatment, illustrating poor reversibility. Stratum corneum/water drug partitioning studies suggested that an important mechanism of action of the enhancers was to increase the apparent drug diffusivity in the stratum corneum. Increases in drug partitioning into the entire stratum corneum following enhancer pretreatment were relatively small. Diffusivity increases were directly related to overall rises in permeability. This study has shown that sesquiterpene compounds, which are of low toxicity and cutaneous irritancy, can promote 5-FU absorption across human skin. Sesquiterpene compounds, therefore, show promise as clinically-acceptable skin penetration enhancers.
Effect of Policosanol on Isoprenaline-induced Myocardial Necrosis in Rats
Authors: Noa Miriam , Herrera M , Magraner J , Más Rosa 
Published: April 2011

Abstract
Policosanol is a mixture of higher aliphatic primary alcohols isolated from sugar cane (Saccharum officinarum L.) and octacosanol represents its main component. This study was conducted to examine the effects of policosanol on myocardial necrosis induced by subcutaneous injection of isoprenaline in rats. A significant reduction (P &lt; 0·01) of infarct size, polymorphonuclear cells and mast cells was observed in animals treated with policosanol at 5 or 25 mg kg−1, while animals receiving only acetysalicylic acid pretreatment showed a significant decrease in the infarct area (P &lt; 0·05). No significant differences in polymorphonuclear and mast cells were obtained when compared with positive control data. It is concluded that policosanol delays the evolution of infarction, showing a protective effect on the myocardial necrosis induced by isoprenaline in this experimental model.
A Novel 11β-Hydroxysteroid Dehydrogenase Inhibitor Contained in Saiboku-To, a Herbal Remedy for Steroid-dependent Bronchial Asthma
Authors: Homma Masato , Oka Kitaro , Niitsuma Tomoyuki , Itoh Hisao 
Published: April 2011

Abstract
To identify the inhibitor of prednisolone metabolism contained in Saiboku-To, we conducted in-vitro experiments of 11β-hydroxysteroid dehydrogenase (11β-HSD), using rat liver homogenate and Cortisol as a typical substrate. We studied the effects often herbal constituents on 11β-HSD. Five herbal extracts showed inhibitory activity with Glycyrrhiza glabra &gt; Perillae frutescens&lt; Zizyphus vulgaris &gt; Magnolia officinalis &gt; Scutellaria baicalensis. This suggests that unknown 11β-HSD inhibitors are contained in four herbs other than G. glabra which contains a known inhibitor, glycyrrhizin (and glycyrrhetinic acid). Seven chemical constituents which have been identified as the major urinary products of Saiboku-To in healthy and asthmatic subjects were studied; magnolol derived from M. officinalis showed the most potent inhibition of the enzyme (IC50, 1·8 × 10−4 m). Although this activity was less than that of glycyrrhizin, the inhibition mechanism (non-competitive) was different from a known competitive mechanism. These results suggest that magnolol might contribute to the inhibitory effects of Saiboku-To on prednisolone metabolism through inhibition of 11β-HSD.
Effect of cardiopulmonary bypass on plasma concentrations of diltiazem and its two active metabolites
Authors: Boulieu R , Bonnefous J L , Lehot J J , Durand P G , Chassignolle J F , Ferry S 
Published: April 2011

Abstract
Diltiazem is often used to prevent myocardial ischaemia during the perioperative period of coronary artery bypass surgery. The purpose of this study was to investigate the effect of cardiopulmonary bypass (CPB) on plasma concentrations of diltiazem and of its two main and active metabolites (N-monodemethyldiltiazem (N-desmethyldiltiazem) and desacetyldiltiazem). The patients were administered their usual treatment during the preoperative days. The last dose was administered immediately before anaesthesia. At the onset of CPB, a significant decrease in the plasma concentrations of diltiazem and its metabolites was observed, whereas the variation was slight and not significant when the plasma concentrations were corrected for haemodilution. These results confirm that the decrease observed at the initiation of the bypass procedure can be ascribed to the haemodilution induced by the CPB. During CPB, the concentrations of diltiazem and its metabolites remained constant suggesting that the rate of metabolism and excretion of the drug was altered during the bypass procedure. At the end of CPB, there was no increase of drug plasma concentrations suggesting that no redistribution of diltiazem from tissues to plasma occurred. Furthermore, this study shows that only 33% of subjects have therapeutic levels of diltiazem before anaesthesia, and that all subjects have subtherapeutic levels during and after the CPB. These results suggest that a higher chronic oral dose of the drug should be given in patients undergoing cardiac surgery with CPB.
Adipose tissue storage of drugs as a function of binding competition. In-vitro studies with distribution dialysis
Authors: Minder S , Daniel W A , Clausen J , Bickel M H 
Published: April 2011

Abstract
Distribution dialysis was used to study binding competition between homogenates of adipose tissue and of lean tissues. The concentration ratios adipose/X (X = blood, muscle, lung, liver) of eight lipophilic drugs were determined in the absence and in the presence of a competing binding system X. With drugs which do not undergo storage in adipose tissue in-vivo, yet have a high volume of distribution, such as imipramine or desipramine, there was strong binding competition, and the balance of distribution was shifted from adipose to lean tissues. In the case of indomethacin with a low volume of distribution this shift was from adipose tissue to blood. With diazepam there was a marked binding competition which was not, however, sufficient to shift the balance of distribution away from adipose tissue. Binding competition was negligible with thiopentone. In contrast, with the equally lipophilic hexethal a moderate binding competition was observed. This is consistent with a decreased adipose tissue storage of the latter barbiturate. It is concluded that binding competition exists not only between blood and tissues but also among individual tissues. It is suggested that occurrence and extent of adipose tissue storage of drugs are determined by binding competition between lean and adipose tissues and, more generally, that distribution of lipophilic drugs is largely a function of binding competition.
Effect of lignocaine on eicosanoid synthesis by pieces of human gastric mucosa
Authors: Goel R K , Tavares I A , Nellgard P , Jonsson A , Cassuto J , Bennett A 
Published: April 2011

Abstract
Lignocaine can affect prostaglandin synthesis in various tissues, and it has anti-inflammatory activity. No studies have been made previously on human isolated gut tissues. When concentrations of 5, 50 and 250 μg mL−1 lignocaine were incubated with human gastric mucosa/submucosa at 37°C for 30 min, only the highest concentration reduced the levels of prostaglandin E, thromboxane B2 and 6-keto-PGF1α in the incubates, and leukotriene C4/D4 was unaffected. Therapeutically relevant amounts of lignocaine given parenterally would therefore seem unlikely to alter gastric mucosal prostanoids, but high doses can be given orally because of extensive first-pass metabolism in the liver.
The In-vitro Effects of Insulin and the Effects of Acute Fasting on Cardiac β-Adrenoceptor Responses in the Short-term Streptozotocin-diabetic Rat
Authors: Austin Clare , Chess-Williams Russell 
Published: April 2011

Abstract
This study demonstrates that in-vitro incubation with insulin results in a reduction of the sensitivity of cardiac tissues from streptozotocin-diabetic rats to isoprenaline. Following incubation with insulin, the sensitivity of left atria and papillary muscles from diabetic animals was not significantly different from those of control animals. Insulin incubation had no effect on the sensitivity of diabetic tissues to forskolin or on ventricular β-adrenoceptor number. Reduction of blood glucose in the absence of insulin by fasting, did not affect the sensitivity of tissues from diabetic animals to isoprenaline. These results suggest that insulin itself can directly reduce β-adrenoceptor sensitivity without altering receptor number.
Vasorelaxant Effects of Oxpentifylline and Theophylline on Rat Isolated Aorta
Authors: Marukawa Seishiro , Hatake Katsuhiko , Wakabayashi Ichiro , Hishida Shigeru 
Published: April 2011

Abstract
The mechanism of the relaxation response of rat aorta to the phosphodiesterase inhibitors oxpentifylline and theophylline was studied. Oxpentifylline induced a greater vasorelaxation response in the intact strips than in those without endothelium. The endothelium-dependent relaxation response to oxpentifylline was inhibited by nitro-l-arginine but not by indomethacin, and the endothelium-independent relaxation response was potentiated by the combination with isoprenaline but not sodium nitroprusside. Theophylline induced a similar relaxation response in vascular strips with and without endothelium. The relaxation response to theophylline was not inhibited by indomethacin or nitro-l-arginine in intact strips, but was potentiated by combination with isoprenaline or sodium nitroprusside in the denuded strips. These results suggest that the two phosphodiesterase inhibitors oxpentifylline and theophylline induce vasorelaxation by different mechanisms. Oxpentifylline can induce both endothelium-dependent relaxation, which is probably mediated by an endothelium-derived relaxing factor, and endothelium-independent relaxation, which may be due to an inhibitory action on phosphodiesterase of vascular smooth muscle. In contrast, theophylline can induce endothelium-independent relaxation alone, without modulation by the endothelium.
Lack of Circadian Variation in the Sensitivity of Rat Terminal 5-HT1B Autoreceptors
Authors: Singh Ashish , Redfern Peter 
Published: April 2011

Abstract
The sensitivity of terminal 5-HT1B autoreceptors in the cerebral cortex and hippocampus to both agonist and antagonist was determined at four different time points in the light: dark cycle of the rat to evaluate whether changes in their responsiveness underlie the circadian rhythm in 5-hydroxytryptamine (5-HT) release. No significant circadian differences were evident in the apparent pIC50 values calculated for 5-HT to inhibit K+-evoked tritium effiux or in the apparent pA2 values calculated for methiothepin to antagonize the effect of 5-HT, at the different time points, in either brain region. These findings suggest that the sensitivity of terminal 5-HT1B autoreceptors in rat cerebral cortex and hippocampus does not change in a circadian pattern, during the light: dark cycle, and argues against such a change influencing the circadian variation in 5-HT release.
SR 48968 selectively prevents faecal excretion following activation of tachykinin NK2 receptors in rats
Authors: Croci Tiziano , Emonds-Alt Xavier , Manara Luciano 
Published: April 2011

Abstract
We tested the ability of SR 48968, (S)-N-methyl-N(4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl)benzamide, a non-peptide antagonist highly selective for tachykinin NK2 receptors, to prevent defecation induced in rats by several agents. The tachykinin agonists substance P, [MePhe7]neurokinin B and [β-Ala8]neurokinin A (4–10) all promoted defecation and increased faecal water content, the last compound being over ten times more potent than the other two (intraperitoneal dose inducing the excretion of I g faeces dry weight = 6·7 μg kg−1). SR 48968 given either orally (p.o.) or subcutaneously (s.c.) was similarly potent in dose-dependently inhibiting faecal output stimulated by the selective NK2-agonist [β-Ala8]neurokinin A (4–10) (doses causing 50% inhibition 0·4 μg kg−1, p.o. and 0·3 μg kg−1, s.c). This inhibition was long-lasting (more than 18 h after 1 μg kg−1 SR 48968 either s.c. or p.o.). At the higher doses tested, SR 48968 also significantly prevented the increase in faecal water content produced by [β-Ala8]neurokinin A (4–10). In rats treated with SR 48968, stimulation of faecal output by the α2-adrenergic antagonist idazoxan and by salmonella endotoxin (LPS), but not by the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin, 5-HT, carbachol or platelet-activating factor, was partially prevented. The present results suggest that activation of intestinal NK2 receptors, either directly by the selective agonist [β-Ala8]neurokinin A (4–10) or indirectly through the release of endogenous neurokinin A (by idazoxan or LPS), promotes defecation, presumably as a consequence of increased gut motility or secretion, or both. SR 48968 should therefore be useful for studying the role of neurokinin A-dependent mechanisms in health and disease, including those of the gastrointestinal system, and possibly for developing new therapeutic agents.
Involvement of nitric oxide in the response to 5-hydroxytryptamine in the rat in-vivo
Authors: Franks C M , Hardcastle J , Hardcastle P T 
Published: April 2011

Abstract
The involvement of nitric oxide (NO) in the effects of 5-HT on intestinal secretion and cardiovascular function in anaesthetized rats was investigated using NG-nitro-l-arginine methyl ester (l-NAME), a specific NO-synthase antagonist, and its optical isomer d-NAME. l-NAME significantly reduced the prolonged hypotensive response to 5-HT. It also caused a small rightward shift in the colonic 5-HT dose-response curve. This suggests that NO plays a significant role in the prolonged hypotensive response to 5-HT, and may make a small contribution to the secretory response of the colon, but not that of the jejunum, in the rat in-vivo.