bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of the Subtype of Presynaptic (α2-Adrenoceptors Modulating Noradrenaline Release in Cat and Bovine Cerebral Arteries
Authors: Arribas Silvia , Galvan Rosa , Ferrer Mercedes , Herguido Maria J , Marin Jesus , Balfagín Gloria
Published: April 2011

The possible existence of a heterogeneous population of α2-adrenoceptors (α2A and α2B, demonstrated by binding studies) in adrenergic nerve endings of cat and bovine cerebral arteries modulating noradrenaline release was investigated. Electrical field stimulation elicited an increase of tritium secretion from these vessels preincubated with (±)-[3H]noradrenaline, which was reduced by the α2-agonists, clonidine (1 μM) and B-HT 920 (0·01 and 0·1 μm), in cat cerebral arteries but only by B-HT 920 in bovine cerebral arteries. This reduction was inhibited by the antagonist of the α2B-subtype, prazosin, and the antagonists of α2A- and α2B-subtypes yohimbine and particularly rauwolscine. The effect of B-HT 920 was partially inhibited by clonidine in bovine, but not in cat cerebral arteries. In both types of arteries, prazosin, yohimbine and the α1-agonist methoxamine (all at 1 μm) failed to modify the stimulated radioactivity liberation, whereas it was increased by 1 μm rauwolscine, and by yohimbine plus prazosin in cat cerebral arteries. The basal tritium release was enhanced by rauwolscine and prazosin in cat cerebral arteries but only by the latter in bovine cerebral arteries. These results suggest: (1) the existence of presynaptic α2-adrenoceptors, mainly of the α2B-subtype, in these vessels negatively modulating noradrenaline release, their activity being greater in cat than in bovine cerebral arteries, and (2) clonidine has no agonistic but a weak antagonistic action in the latter vessels.
The blood binding of cefotiam and cyclohexanol, metabolites of the prodrug cefotiam hexetil, in-vitro
Authors: Querol-Ferrer V , Zini R , Tillement J-P
Published: April 2011

The binding of cefotiam and cyclohexanol to human serum, isolated proteins and erythrocytes has been studied in-vitro by equilibrium dialysis. The two molecules are 50% bound to serum proteins and the free fraction for both compounds remained constant within the therapeutic concentration range. Human serum albumin (HSA) was exclusively responsible for the cefotiam binding (48%) with a saturable process characterized by one binding site (n=1·00±0·14) with a very weak affinity (Ka=1457 ± 352 m−1). Like other cephalosporins, cefotiam showed no binding to α1-acid glycoprotein, lipoproteins or γ-globulins. Cyclohexanol is mainly bound to HSA with a weak affinity (Ka ∼ 1 800 m−1) but lipoproteins and α1-acid glycoprotein bind about 30% of bound cyclohexanol in serum. Interactions with free fatty acids (FFA) or bilirubin were studied at physiopathological concentrations. HSA-bound cefotiam was displaced by FFA (1260 μM) and bilirubin (330 μM), whereas the cyclohexanol binding was inhibited only by FFA. The cefotiam binding site seems to be close to the warfarin site (site I) whereas cyclohexanol probably shares the diazepam site (site II) on HSA. There is no mutual inhibition of binding between cefotiam and cyclohexanol at therapeutic levels. The binding of both compounds to erythrocytes is low and restricted when measured in the presence of plasma.
The negative inotropic effect of diazepam in rat right ventricular strips
Authors: Hernández Jesús
Published: April 2011

The effect of diazepam on cardiac contractility was investigated in electrically-driven right ventricular strips of the rat. Diazepam produced a concentration-dependent negative inotropic effect which was antagonized by either flumazenil, a benzodiazepine central-type receptor antagonist, or PK 11195, a benzodiazepine peripheral type receptor antagonist. The results suggest that the inhibitory effect of diazepam on cardiac contractility in the rat is mediated by both central and peripheral benzodiazepine receptors.
Investigations into the Pharmacodynamic Effects of Dermally Administered Microemulsions Containing β-Blockers
Authors: Kemken J , Ziegler A , Müller B W
Published: April 2011

Water uptake from the skin changes dermally applied near-saturated solutions of β-blockers in microemulsion-bases into supersaturated microemulsions. Due to an enhanced thermodynamic activity, high absorption rates are expected from these preparations. The pharmacodynamic effect after dermal administration of such preparations has been evaluated using rabbits as a suitable in-vivo model. The dose dependency, influence of lipophilicity and of the thermodynamic activity of the drug is described. Assessment of dermal doses which were therapeutically equivalent to i.v. doses as, for example, shown with carazolol is possible. Although not all observed pharmacodynamic effects were due to these influences but rather due to the numerous other skin-vehicle-drug interactions which could not be explained with this model, the presented in-vivo model is helpful in evaluation of β-blockers which were suitable candidates for transdermal administration.
The role of the gastric mucosal sulphydryls in the ulcer-protecting effects of sulphasalazine
Authors: Garg G P , Cho C H , Ogle C W
Published: April 2011

The role of gastric mucosal sulphydryls in gastric ulceration, produced by restraint at 4°C (stress) for 2 h, and in the ulcer-protecting effects of sulphasalazine and its constituents (sulphapyridine and 5-aminosalicylic acid), have been studied in rats. Stress significantly raised the mucosal sulphydryl content, but sulphasalazine and sulphapyridine did not influence these changes; only 5-aminosalicylic acid decreased the mucosal sulphydryl concentration. These results indicate that depletion of mucosal sulphydryls does not occur in stress-induced ulceration, in contrast to what has been shown in other experimental ulcer models. The antiulcer effects of sulphasalazine or of any of its constituents may, therefore, not involve the sulphydryl mechanism.
Decrease of Gastrointestinal Mucosal Damage by Salicyluric Acid Compared with Salicylic Acid in Rabbits
Authors: Nakamura Junzo , Katayama Michihiro , Kido Mitsuhiko , Nishida Koyo , Sasaki Hitoshi
Published: April 2011

The gastrointestinal mucosal damage following the oral administration of salicylic acid or salicyluric acid was examined in rabbits using a scanning electron microscope. Six and 24 h after treatment with salicylic acid, morphological changes of gastric mucosa were recognized. In rabbits treated with salicyluric acid, however, severe damage in the gastric mucosa was not found after 24 h compared with the treatment with salicylic acid. Following the treatment with salicylic acid, some mucosal damage in the duodenum, jejunum and ileum was observed after 24 h. The surface character of the duodenal, jejunal, ileal, caecal and colonic mucosa were almost identical compared with the control following the treatment with salicyluric acid. It was reported that salicyluric acid is metabolized to salicylic acid by the intestinal microorganisms. From these results, it was suggested that prodrugs utilizing the metabolism of salicyluric acid to salicylic acid by intestinal microorganisms may be useful in reducing gastrointestinal mucosal damage.
Lysophosphatidic Acids Induce Contraction of Rat Isolated Colon by Two Different Mechanisms
Authors: Tokumura Akira , Yube Nobuyuki , Fujimoto Hiroaki , Tsukatani Hiroaki
Published: April 2011

Lysophosphatidic acids (1-linoleoyl-, 1-linolenoyl, 1-arachidonoyl- and 1-O-hexadecyl-sn-glycero-3-phosphate) induced rapid contraction of rat isolated colon which was dependent on external Ca2+, 1-linolenoyl-lysophosphatidic acid having the greatest effect. The contraction induced by 1-linolenoyl-lysophosphatidic acid was reduced considerably by nifedipine and verapamil, but not by atropine or indomethacin. Phosphatidic acids with two short-chain acyl groups induced a small, atropine-sensitive contraction at 100 μM, but phosphatidic acids with two long-chain acyl groups were inactive. These results suggest that unlike phosphatidic acids, lysophosphatidic acids act directly on extracellular sites of the plasma membrane of smooth muscle cells in rat colon, mainly through activation of voltage-sensitive Ca2+ channels.
Human Albumin Binding of Tamoxifen in the Presence of a Perfluorochemical Erythrocyte Substitute
Authors: Shah I G , Parsons D L
Published: April 2011

The binding of tamoxifen (an HSA site IV ligand) to human serum albumin (HSA) in the presence of a perfluorochemical (PFC) erythrocyte substitute has been examined. Standard centrifugation followed by supernatant ultrafiltration was used to study the binding of 0·1 and 0·5 μg mL−1 tamoxifen at ambient conditions. Tamoxifen was extensively bound (>99%) to the PFC emulsion through an association with the emulsifiers of the droplets. Tamoxifen was also extensively bound (> 99%) to HSA. The percent free tamoxifen increased upon HSA dilution. Tamoxifen was extensively bound by various mixtures of HSA and the PFC emulsion and the percent free drug was similar to those obtained with HSA alone. However, the position of drug binding (PFC emulsion vs HSA) varied significantly with changes in the ratio of PFC emulsion to HSA. This could be important in terms of the different distribution of HSA and PFC emulsion in the body. Studies with PFC emulsion components indicated that any displacement of HSA-bound tamoxifen by the PFC emulsion was due to the oleic acid and, to a much smaller degree, Pluronic F-68 components. Other HSA site IV ligands are expected to be similarly displaced.
Influence of Ion-pair Formation on the Pharmacokinetic Properties of Drugs. Pharmacokinetic Interactions of Bretylium and Hexylsalicylic Acid in Rabbits
Authors: Amlacher Reinhard , Härtl Albert , Neubert Reinhard , Stöckel Ursula , Wenzel Kerstin
Published: April 2011

The simultaneous i.v. administration of equimolar doses of bretylium and hexylsalicylic acid results in an increase in plasma area under the curve value of both substances in comparison with their separate administration. The higher plasma levels of both compounds were associated with a reduced renal excretion and an increased biliary elimination. However, the increase in biliary excretion did not compensate for the reduced elimination of bretylium and hexylsalicylic acid via the kidney. The results presented in this paper give further evidence that ion-pairing in-vivo may result in altered pharmacokinetics of drugs particularly due to changes in biliary or renal excretion.
Ulcerogenic Mechanism of Ethanol and the Action of Sulphanilyl Fluoride on the Rat Stomach In-vivo
Authors: Cho C H , Pfeiffer C J , Misra H P
Published: April 2011

The effects of ethanol alone and in combination with sulphanilyl fluoride on some of the antioxidant defences in the stomach of rats have been examined. These effects were correlated with lesion formation in the gastric mucosa. Oral administration of ethanol induced gastric lesions which were prevented by sulphanilyl fluoride pre-treatment. N-Ethylmaleimide antagonized the anti-lesion action of sulphanilyl fluoride. Ethanol administration lowered the glucose-6-phosphate dehydrogenase activity in the gastric mucosa, an effect potentiated by N-ethylmaleimide pre-treatment. The total superoxide dismutase activity was unaffected by the drugs used in the present study. Ethanol, however, markedly increased mucosal catalase activity which was reduced by sulphanilyl fluoride pretreatment and reversed by N-ethylmaleimide. It is concluded that the ulcerogenic mechanism of ethanol is mediated at least in part by the depression of the hexose monophosphate shunt and the production of active oxygen species, whereas the anti-lesion action of sulphanilyl fluoride is probably not mediated through these mechanisms.
One-point Feedback Control Method for Phenytoin Dosage Adjustment
Authors: Yukawa Eiji , Higuchi Shun , Aoyama Toshinobu
Published: April 2011

Routine clinical pharmacokinetic data collected from patients receiving phenytoin have been analysed to propose a new and simple equation to aid the dosage adjustment of this drug. The data were analysed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. The rate equation for the elimination of phenytoin can be written as Do = kCssn, which fits the steady-state serum concentration (Css) and daily dose data (Do). The parameter n is the kinetic order and the parameter k is an arbitrary rate constant. From the above equation, D2 = D1C1  −nC2n can be derived, which forms the basis of predicting the dosage, D2, to obtain a desired Css, Q2, using one initial Css, C1, obtained with an initial dose, D1 and using a population value of n. The value of n for phenytoin was estimated to be 0·312 in this study. The predictive performance of this equation was compared with the Richens and Dunlop nomogram and Bayesian feedback method using two or more steady-state concentration/dose pairs from each of 78 outpatients. This equation allowed the prediction of a dose needed to produce a desired steady-state concentration with errors comparable with the Bayesian feedback method for therapeutic drug monitoring.
Effect of Crude Extracts from Leonotis nepetaefolia (Labiatae) on Rat and Guinea-pig Smooth Muscle and Rat Cardiac Muscle
Authors: Calixto João B , Yunes Rosendo A , Rae Giles A
Published: April 2011

The actions of hydroalcoholic and tea extracts of stems of Leonotis nepetaefolia on agonist-induced and electrically-evoked contractions have been analysed in-vitro in rat uterus and left atrium and in guinea-pig ileum and trachea. The tea extract (500–2000 μg mL−1) caused parallel and graded rightward shifts of concentration-response curves to bradykinin and BaCl2 in the rat isolated uterus, but antagonized responses to prostaglandin F2α in a typically non-competitive manner. The hydroalcoholic extract also caused rightward displacements of the curves to bradykinin, acetylcholine (ACh), angiotensin II, oxytocin and BaCl2 and reduced their maximal contractile effects. Both extracts (30–3000 μg mL−1) relaxed uterine preparations precontracted with KCl (80 Mm), the hydroalcoholic extract being about 2-fold more potent than the tea extract. The relaxant response to the former was unaffected by propranolol (1 μm) or forskolin (10 Nm), but was potentiated 2-fold by 3-isobutyl-1-methylxanthine (10 μm). In the guinea-pig ileum the hydroalcohplic extract shifted the ACh- and bradykinin-induced contractile curves to the right and markedly inhibited their maximal effects, whereas the tea extract caused a typical non-competitive antagonism of ACh-induced contractile responses. In field-stimulated ileal strips, both extracts (3–3000 μg mL−1) caused contractions and inhibited twitch responses. Guinea-pig tracheal rings precontracted with carbachol (0·3 μm) were relaxed only by concentrations of either extract in excess of 1000 μg mL−1, an action that was unaffected by propranolol (0·1 μm) or by indomethacin (1 μm). Prior incubation of tracheal rings with the hydroalcoholic extract (1000 μg mL−1), which failed to affect responses to ACh, significantly potentiated the relaxations induced by isoprenaline or theophylline (3-fold) of preparations contracted with carbachol. Finally, the hydroalcoholic extract (0·1–1000 μg mL−1) caused a graded long-lasting inotropic effect in the rat electrically-stimulated left atrium. Altogether, these findings provide some experimental support for the reputed folk medicinal anti-asthmatic and anti-diarrhoeal properties of this plant. It is suggested that the pharmacological effects of the extracts of L. nepetaefolia may result from potentiation of the cAMP system.
Protective Effect of Cimetidine on Tannic Acid-induced Gastric Damage in Rats
Authors: Hung Chen-Road , Lee Chau-Hwei
Published: April 2011

The effect of cimetidine on the acidified tannic acid-induced back diffusion of gastric acid and mucosal damage was investigated in the vagotomized rat. After intragastric irrigation for 1 to 3 h, tannic acid (20–500 mg kg−1) produced a dose-related increase in gastric volume and the loss of luminal H+. The change of mucosal permeability to the electrolyte, either the loss of H+ or the gain of Na+, K+, and Ca2+, induced by tannic acid was significantly diminished by the combination with intragastric cimetidine. However, intravenous injection of cimetidine did not protect this damage and back diffusion of acid neutralized intragastric cimetidine did not reduce the back diffusion of acid and Na+, K+, and Ca2+ output provoked by acid solution. Thus, the neutralizing action of cimetidine seems responsible.
Cepharanthine (biscoclaurine alkaloid) treatment in endotoxic shock of suckling rats
Authors: Goto Masakatsu , Zeller W Patrick , Hurley R Morrison
Published: April 2011

Gram-negative sepsis/septic shock causes significant mortality in newborns. However, there has been no established method for newborn endotoxic shock treatment. Prostaglandins play a role in endotoxic shock. Cepharanthine is a biscoclaurine alkaloid that primarily inhibits phospholipase A2. Therefore, the effects of cepharanthine have been studied on endotoxic shock in newborn rats. Cepharanthine decreased the 24 h mortality of endotoxic shock in a dose-related manner. At the dose of 0·2 mg kg−1 it effectively reduced the mortality from 90 to 21 % in newborn rats. It also induced hyperglycaemia in control rats and blunted the hypoglycaemia of endotoxic shock. Cepharanthine did not suppress body weight gain nor did it delay death as seen with glucocorticoid treatment. We conclude that cepharanthine is beneficial in the treatment of newborn endotoxic shock.
The effect of dihydropyridine calcium channel agents on 5-HT metabolism in the CNS of the rat
Authors: Colado M I , Alfaro M J , López F , Del Val V , Martín M I
Published: April 2011

The effects of dihydropyridines on the levels of 5-hydroxytryptamine (5-HT) and 5-hydroxy-3-indole acetic acid (5-HIAA) in the spinal cord and various brain regions of the rat have been studied. Nimodipine, nitrendipine and nifedipine (10 mg kg−1), nisoldipine (5 mg kg−1), and BAY K8644 (0–2 and 2 mg kg−1) were administered i.p. 1 h before killing. The administration of nifedipine and nitrendipine increased 5-HT turnover in all of the areas studied except for the spinal cord. Nisoldipine increased 5-HT turnover in midbrain, hippocampus and cortex, while the effect of nimodipine was restricted to midbrain. BAY K8644 at 2 mg kg−1 produced the same effects as nifedipine and nitrendipine; however, at low doses (0·2 mg kg−1), this compound increased 5-HT turnover only in midbrain and medulla oblongata. These results indicate that both dihydropyridine calcium channel agonist and antagonists are able to activate the 5-HT-ergic system in the central nervous system of the rat in-vivo. Therefore, it seems likely that such effects could be due to indirect actions or to interactions of the compounds with receptors other than the voltage-sensitive calcium channels.
Effects of khellin on contractile responses and 45Ca2+ movements in rat isolated aorta
Authors: Ubeda Amalia , Tejerina Teresa , Tamargo Juan , Villar Angel
Published: April 2011

The effects of khellin on contractile responses and 45Ca2+ flux have been studied in rat isolated aortae. Khellin (10−5- 3.2 times 10−4M) produced a concentration-dependent inhibition of noradrenaline (10−6 M) and high K+ (80 mM)-induced contractions. At 3.2 times 10−4 M, khellin increased cAMP levels and reduced 45Ca2+ influx in resting tissues and in tissues stimulated by noradrenaline (10−5 M) and high K+ without affecting basal 45Ca2+ efflux or noradrenaline induced 45Ca2+ efflux. It is concluded that in rat isolated aorta, khellin caused a non-specific inhibition of Ca2+ influx but may also exhibit intracellular actions, thus decreasing the availability of Ca2+ required for activation. One or more of these mechanisms may be related to an increase in intracellular cAMP levels.
Solid tumour chemotherapy using implantable collagen-poly (HEMA) hydrogel containing 5-fluorouracil
Authors: Jeyanthi R , Nagarajan B , Panduranga Rao K
Published: April 2011

Implantable collagen-poly(HEMA) hydrogels containing the anticancer drug 5-fluorouracil (5-FU) have been prepared and evaluated for their efficacy towards a solid tumour fibrosarcoma in Wistar rats. The tumour was developed by inoculation of a 10% tumour-cell suspension in the anterior aspect of the hind limb. Four groups were studied—untreated control, intratumoural injection of free 5-FU, subcutaneous implantation of placebo and implantation of 5-FU-bearing hydrogel pellets (10 mm diameter × 1 mm thick) containing the drug in close proximity to the tumour. The hydrogel showed an improved antitumour activity over free 5-FU as evidenced by the gross tumour weight assessments and by [3H]thymidine incorporation in-vitro. This was attributed to the controlled and slow release of 5-FU compared with free 5-FU over the same period of treatment. The implantation of hydrogel could thus be a potential alternative to free 5-FU therapy in the treatment of solid tumours such as fibrosarcoma.
Duration of action and effect on baroreflex function of the anti-arrhythmic α1 antagonist UK-52,046
Authors: Spiers James P , Harron Dean W G , Wilson Richard
Published: April 2011

The effects of acute and chronic oral administration of UK-52,046 (25 μg kg−1) on baroreflex function and its duration of action, were studied in conscious dogs. It was found that UK-52,046 had no effect on blood pressure and heart rate following acute and chronic administration. UK-52,046 shifted the phenylephrine dose response curve to the right, and the PE50 (measure of α1-adrenoceptor antagonism) was increased (P < 0.05) compared to placebo on day 1 (2, 4, 8 and 24 h) and day 8 (2, 4, 8 and 12 h). The antagonism was increased (P < 0.05) on day 8 (0,8 and 12 h) compared with day 1. Evaluation of the effects of UK-52,046 on baroreflex function using phenylephrine to increase blood pressure indicated no significant difference from placebo. It was concluded that at an antiarrhythmic dose, UK-52,046 has no effect on blood pressure, heart rate or baroreflex function. The pressor response curve was shifted to the right indicating a duration of action of at least 12 h on chronic oral administration.
Effects of Temperature and Pressure During Compression on Polymorphic Transformation and Crushing Strength of Chlorpropamide Tablets
Authors: Matsumoto Takahiro , Kaneniwa Nobuyoshi , Higuchi Shigesada , Otsuka Makoto
Published: April 2011

The effects of temperature on the polymorphic transformation of chlorpropamide during compression and on the physical properties of the tablet have been investigated. A heater and liquid nitrogen pool were mounted on the die of a single punch eccentric tableting machine, and the die temperature was controlled by a thermocontroller. A tableting machine with two load cells (upper and lower punches) and a non-contact displacement transducer were used to measure compression stress, distance and energy. The X-ray diffraction profiles of the deagglomerated compressed sample powder were measured to calculate the polymorphic content. The amount of form C transformed from form A at 45°C was about twice that at 0°C with the same compression energy. The amount of form A transformed from form C by compression at 45°C was almost the same as that at 0°C. This suggests that the mechanochemical effect of form A depended on the compression temperature, but that of form C was independent of temperature. The crushing strength of tablets of form A was about twice that of form C, even at the same porosity. The plots of log (crushing strength of tablet) against porosity of form A tablets compressed at 0 and 45°C were linear with the same slope; the slope for form C tablets compressed at 45°C was less than that at 0°C.
Dissolution and relative bioavailability of two carbamazepine preparations for children with epilepsy
Authors: Hartley R , Aleksandrowicz J , Bowmer C J , Cawood A , Forsythe W I
Published: April 2011

The in-vitro dissolution profiles of two carbamazepine formulations (Tegretol and a generic carbamazepine) have been assessed and the bioavailability of carbamazepine compared in 12 epileptic children at steady-state. Dissolution from the generic formulation (100 and 200 mg tablets) tended to be greater than for the proprietary tablets. However, the bioavailability and pharmacokinetics of carbamazepine when assessed at steady-state were similar for the two formulations. It appears, therefore, that the breakthrough seizures and higher incidence of neurological side-effects observed when children were given generic carbamazepine in place of the proprietary formulation cannot be accounted for by differences in bioavailability or pharmacokinetics.
Inhibition of contractions and 45Ca influx by adenosine in rabbit aorta
Authors: Parija S C , Raviprakash V , Mishra S K
Published: April 2011

The effects of adenosine on contractility and 45Ca-uptake in rabbit aorta have been examined and compared with those of nifedipine. Both adenosine (10−5 M) and nifedipine (10−8 M) inhibited contractions caused by CaCl2 (0.1–10 mM) in K+-depolarized preparations. Nifedipine (10−7 M) significantly inhibited the contractions of noradrenaline (NA) at all doses (10−8-10−4 M), while adenosine inhibited the contractions induced only by lower doses of NA (10−8 and 10−7 M) without affecting those at higher doses (> 10−7 M). Adenosine (10−8 M) and nifedipine (10−7 M) inhibited K+-stimulated 45Ca-uptake by aortic strips by 75 and 100%, respectively. Similarly, NA (10−4 M)-stimulated 45Ca influx was inhibited by about 70% by both these agents. The results suggest that adenosine inhibits inward Ca2+ movement involving both voltage-operated and receptor-operated calcium channels in rabbit aortic smooth muscle.
Opioid Properties of Some Derivatives of Pethidine Based on Tropane
Authors: Casy A F , Dewar G H , Pascoe R A
Published: April 2011

The preparation of some tropane analogues of pethidine and its reversed ester, chiefly with preferred 3α-m-hydroxyphenyl chair conformations, is described. The former were secured from tropan-3-one in a sequence of reactions involving cyanide attack, hydrolysis, Grignard attack and then rearrangements. The reversed ester was obtained by treating tropan-3-one with lithium phenyl, followed by acylation. Configurational and conformational assignments follow from NMR analysis. The antinociceptive potencies of these compounds in mice are reported, and discussed in relation to non-phenolic congeners and the 4-arylpiperidine moiety of morphine.
Comparison of the Effects of Cromakalim in Trachea Isolated from Normal and Albumin-sensitive Guinea-pigs
Authors: McCaig Dorothy J , Aitken Susan , De Jonckheere B
Published: April 2011

The effects of the K+-channel activator, cromakalim, on spontaneous tone and constrictor responses to vagal stimulation or acetylcholine were compared in trachea isolated from groups of guinea-pigs that were: untreated; sensitized and chronically exposed to inhaled albumin; or sham sensitized. Responses were assessed as changes in intraluminal pressure in the isolated, Krebs-filled trachea, increases and decreases in intraluminal pressure directly reflecting constriction and dilatation, respectively. Cromakalim reduced resting intraluminal pressure in normal trachea but in sensitized trachea mixed effects occurred, many preparations exhibiting increases in intraluminal pressure, particularly at lower concentrations of cromakalim. Cromakalim attenuated the frequency-dependent increases in intraluminal pressure evoked by stimulation of the vagus nerve in a concentration-dependent manner and to a similar degree in trachea from each of the three groups tested. The degree of attenuation was similar in the absence and presence of the cyclo-oxygenase inhibitor flurbiprofen. In untreated trachea, responses to a range of concentrations of applied acetylcholine were attenuated by cromakalim. In sensitized trachea the response to the lowest concentration of applied acetylcholine was attenuated by cromakalim but responses to higher concentrations of were unaffected. The results indicate that the direct relaxant effect of cromakalim is altered in sensitized trachea, which may indicate abnormal K+-channel behaviour in the smooth muscle cell membrane. Attenuation by cromakalim of vagal responses occurs in both normal and sensitized trachea, due chiefly to a pre-junctional effect on cholinergic neurotransmission which is independent of the generation of cyclo-oxygenase products.
The Interaction between Noradrenaline and ATP upon Polyphosphoinositide Metabolism and Contraction in Tail Arteries from Normo- and Hypertensive Rats
Authors: Guild S B , Jenkinson S , Muir T C
Published: April 2011

The effects of, and interaction between, noradrenaline and α,β-methylene ATP upon polyphosphoinositide (PPI) breakdown, investigated by measuring the accumulation of inositol phosphates, and contraction, were studied in tail arteries from normo- (WKY) and spontaneously-hypertensive (SHR) rats. Noradrenaline (10−7-10−3  m) evoked a prazosin (10−6  m)-sensitive, concentration-dependent increase in total inositol phosphate accumulation in both WKY and SHR rats. No significant differences were observed in either the maximal response or in the concentration range over which noradrenaline evoked this response, between these two populations. Noradrenaline (5 × 10−7-5 × 10−5  m) evoked a concentration-dependent contraction of arteries from both SHR and WKY rats. The responses to noradrenaline were about 2-fold greater at all effective concentrations of noradrenaline in SHR compared with WKY rats. α,β-Methylene ATP (10−6  m) did not alter noradrenaline-stimulated total inositol phosphate accumulation, in arteries from either SHR or WKY rats, measured either as the maximal response or as the EC50. α,β-Methylene ATP (5 × 10−6m), by itself, evoked a contractile response, which was quantitatively similar in SHR and WKY rats, and was additive with the contractile responses to noradrenaline (5 × 10−7–5 × 10−5  m). The maximum response produced by a combination of noradrenaline and α,β-Methylene ATP was quantitatively similar to that produced by noradrenaline alone. No evidence of synergism between α,β-Methylene ATP and noradrenaline upon contraction was observed. Nerve stimulation (50 V, 16 Hz, 0·5 ms for 5 min) evoked a prazosin (10−6  m)-sensitive significant (P < 0·001) increase in total inositol phosphate accumulation in arteries from WKY rats. α,β-Methylene ATP did not modulate noradrenaline-elicited increases in either contraction or PPI metabolism in either SHR or WKY rats. The postsynaptic modifications responsible for the previously reported enhanced contraction to sympathetic nerve stimulation in this tissue are not due to changes in purinergic influence upon either noradrenaline-stimulated PPI metabolism or upon contraction.
Effect of terfenadine on the plasma concentrations of substance P and vasoactive intestinal polypeptide in volunteers
Authors: Mori Kazuo , Asakura Shunji , Morikawa Norifumi , Takeyama Masaharu
Published: April 2011

The effect of terfenadine on the plasma concentrations of substance P and vasoactive intestinal polypeptide (VIP) was studied in 7 healthy subjects and 8 subjects with the common cold. Before terfenadine administration, the mean plasma substance P concentration of the subjects with the common cold was significantly higher than that of the healthy subjects. The increased mean plasma substance P concentration of the subjects with the common cold was decreased after terfenadine administration. In the healthy subjects, the mean plasma substance P concentration was unchanged by terfenadine administration. The mean plasma VIP concentration of the subjects with common cold was slightly higher than that of the healthy subjects before and after terfenadine administration, with no significant difference.
Digoxin-specific Fab fragments impair renal function in the rabbit
Authors: Timsina M P , Hewick D S
Published: April 2011

A 2 mg kg−1 intravenous bolus dose of digoxin-specific Fab fragments produced a 28% reduction in creatinine clearance in rabbits after 24 h. Urine output was reduced, while plasma and urinary creatinine concentrations were unaffected and increased, respectively. By 5 days the creatinine clearance had returned to normal. The fractional excretion of Na+ was nearly halved, indicating that the tubular reabsorption of Na+ increased to compensate for the reduced glomerular filtration rate, suggesting that tubular (as opposed to glomerular) function was not impaired.
Effect of Cromakalim on the Smooth Muscle of the Cat Gastric Antrum
Authors: Kortezova N , Bayguinov O , Boev K , Papasova M
Published: April 2011

The effect of the K+-channel opener cromakalim (BRL 34915) on the electrical and contractile activity of the smooth muscle of the cat gastric antrum has been studied. Cromakalim induced a concentration-dependent inhibition of the contractions and shortening of the sustained partial repolarization phase of the plateau action potential. High concentrations of cromakalim produced hyperpolarization and shortening of the repolarization and depolarization phases of the plateau action potential. The K+-channel blockers 4-aminopyridine (10−2  m) and tetraethylammonium (10−2  m) decreased the effect of cromakalim on the phasic contractions, while glibenclamide (5 × 10−5  m) completely abolished it. We suggested that the inhibitory effect of cromakalim on the electrical and contractile activity of the gastric antrum smooth muscle is due to the cromakalim-induced increase of the outward K+-current through glibenclamide-dependent K+-channels.
Effect of Fenbufen on the Entry of New Quinolones, Norfloxacin and Ofloxacin, into the Central Nervous System in Rats
Authors: Ichikawa Nobuhiro , Naora Kohji , Hayashibara Masakazu , Katagiri Yoshihiro , Iwamoto Kikuo
Published: April 2011

The entry of two new quinolone antibacterial agents, norfloxacin and ofloxacin, into the central nervous system (CNS) of rats, and the effect of fenbufen on this was investigated. At various times after the administration of a bolus intravenous dose of norfloxacin or ofloxacin (10 mg kg−1) with or without fenbufen (20 mg kg−1), serum and cerebrospinal fluid (CSF) samples and whole brain were collected from the rats and the concentration of norfloxacin or ofloxacin in each sample was determined. Serum concentrations of both quinolones declined biexponentially with time and were significantly elevated by coadministration with fenbufen at the terminal phase. The fractions of these quinolones bound to serum protein were not altered by coadministration with fenbufen. Coadministered fenbufen raised the brain concentrations of both quinolones but did not affect their brain to serum unbound concentration ratios. In contrast, CSF to serum unbound concentration ratios as well as CSF concentrations of norfloxacin and ofloxacin were elevated by coadministration with fenbufen. Apparent diffusional clearances between blood and CSF of norfloxacin and ofloxacin estimated by the physiological model analysis increased by 1·9 and 2·6 times, respectively, after coadministration with fenbufen. These findings suggest that coadministered fenbufen may facilitate the entry of norfloxacin and ofloxacin into the CNS.
Enantioselective Pharmacokinetics of α-Fluoromethylhistidine in Rats and Its Comparison with Histidine
Authors: Sakurai Eiichi , Yamasaki Seiji , Iizuka Yukisumi , Hikichi Noboru , Maeyama Kazutaka , Watanabe Takehiko
Published: April 2011

The enantiomer-specific pharmacokinetics of histidine and its analogue, α-fluoromethylhistidine (FMH), were investigated in rats. After bolus intravenous administration of each enantiomer of histidine or FMH at a dose of 40·3 mg kg−1 as free base equivalents, the plasma concentrations of l-histidine, d-histidine, (S)-FMH and (R)-FMH decreased biexponentially with half-lives of 39·2, 20·8, 32·8 and 25·0 min, respectively, in the elimination phase. Although the concentration of l-histidine in the plasma was lower than that of d-histidine, there was no large difference in plasma concentration-time curves of the enantiomers of FMH. The apparent total clearance of l-histidine from rat plasma was about 4 times that of d-histidine or the enantiomers of FMH. l-Histidine was quickly transferred to the peripheral tissues where the concentrations also decrease biphasically. l-Histidine penetrated more rapidly into the brain than either its d-enantiomer or a compound closely related in structure such as FMH. However, the disappearance of l-histidine from the various brain regions was very rapid. In contrast, brain/plasma ratios of d-histidine and (S)-FMH increased continuously after injection of these compounds, indicating that d-histidine or (S)-FMH partitioned into the brain and was very slowly removed from the brain; (R)-FMH was not distributed to the brain. These results suggested stereoselectivity in disposition of histidine and FMH enantiomers in rats.
Selective Inhibition of Calcium Entry Induced by Benzylisoquinolines in Rat Smooth Muscle
Authors: Anselmi Elsa , Fayos Gloria , Blasco Rafael , Candenas Luz , Cortes Diego , D'Ocon Pilar
Published: April 2011

The mechanism of relaxant activity of six benzylisoquinolines was examined in order to determine the minimal structural requirements that enable these compounds to have either a non-specific action like papaverine or an inhibitory activity on calcium entry via potential-operated channels. All the alkaloids tested totally or partially relaxed KCl-depolarized rat uterus and inhibited oxytocin-induced rhythmic contractions. Only glaucine and laudanosine inhibited K+-induced uterine contractions more than oxytocin-induced uterine contractions. In Ca+-free medium, sustained contractions induced by oxytocin or vanadate were relaxed by the alkaloids tested except for glaucine and laudanosine indicating no inhibitory effect on intracellular calcium release. Those alkaloids containing an unsaturated heterocyclic ring (papaverine, papaverinol, papaveraldine, N-methylpapaverine and dehydropapaverine) exhibited a more specific activity than those with a tetrahydroisoquinoline ring.
Postoperative course of plasma protein binding of lignocaine, ropivacaine and bupivacaine in sheep
Authors: Rutten Albert J , Mather Laurence E , Plummer John L , Henning Elke C
Published: April 2011

The plasma protein binding of the 2,6-xylidide local anaesthetic agents lignocaine, ropivacaine and bupivacaine enantiomers was determined by equilibrium dialysis in plasma obtained from chronically catheterized sheep before and up to 21 days after surgery. Three concentrations (1, 5 and 10 mg L−1), were used for each agent. Concentration-dependent binding was evident for each agent throughout the study period. R(+)-Bupivacaine was more extensively bound than S(–)-bupivacaine at the higher concentrations. Compared with pre-surgery, binding of each agent was less on the first postoperative day but did not differ significantly from days 8 to 21.
The cytoprotective effect of zinc l-carnosine on ethanol-induced gastric gland damage in rabbits
Authors: Cho C H , Hui W M , Chen B W , Luk C T , Lam S K
Published: April 2011

The effects of zinc l-carnosine on the damaging actions of ethanol were examined in rabbit isolated gastric glands. Ethanol (8%, v/v) incubation produced a 50% viability of the gland populations and released a significant amount (38%) of the total lactate dehydrogenase (an index of membrane injury) of the glands. Zinc l-carnosine pre-incubation for 15 min markedly prevented these actions of ethanol; however, l-carnosine by itself did not have these effects. These findings indicate that zinc ion but not carnosine in the zinc l-carnosine molecule possesses cytoprotective action against ethanol-induced gastric gland damage in rabbits.
Effects of the Mucoadhesive Polymer Polycarbophil on the Intestinal Absorption of a Peptide Drug in the Rat
Authors: Lehr Claus-Michael , Bouwstra Joke A , Kok Wouter , De Boer Albertus G , Tukker Joseph J , Verhoef J Coos , Breimer Douwe D , Junginger Hans E
Published: April 2011

The absorption across rat intestinal tissue of the model peptide drug 9-desglycinamide, 8-arginine vasopressin from bioadhesive formulations was studied in-vitro, in a chronically isolated internal loop in-situ and after intraduodenal administration in-vivo. A controlled-release bioadhesive drug delivery system was tested, consisting of microspheres of poly(2-hydroxyethyl methacrylate) with a mucoadhesive Polycarbophil-coating, as well as a fast-release formulation consisting of an aqueous solution of the peptide in a suspension of Polycarbophil particles. Using the controlled-release system, a slight improvement of peptide absorption was found in-vitro in comparison with a non-adhesive control system, but not in-situ or in-vivo. In contrast, bioavailability was significantly increased in all three models from the Polycarbophil suspension in comparison with a solution of the drug in saline. The effect appeared to be dose-dependent, indicative of intrinsic penetration-enhancing properties of the mucoadhesive polymer. A prolongation of the absorption phase in-vitro and in the chronically isolated loop in-situ suggested that the polymer was able to protect the peptide from proteolytic degradation. This could be confirmed by degradation studies in-vitro. The duration of the penetration enhancing/enzyme inhibiting effect was diminished with increasing complexity of the test model, in the same way as was previously found for the bioadhesive effect. This interrelationship suggests that the observed improvement in peptide absorption and the mucoadhesive properties of this polymer are associated. The development of a fast-release oral dosage form for peptide drugs on the basis of Polycarbophil appears to be possible.
In-vitro Evaluation of 5-Lipoxygenase and Cyclo-oxygenase Inhibitors using Bovine Neutrophils and Platelets and HPLC
Authors: Dannhardt Gerd , Lehr Matthias
Published: April 2011

Inhibition of 5-lipoxygenase has been determined by monitoring the formation of leukotriene B4 and 5-hydroxyeicosatetraenoic acid in bovine polymorphonuclear leucocytes. For evaluating the inhibition of cyclo-oxygenase two different test systems are presented: the first uses 12-hydroxyheptadecatrienoic acid produced by bovine platelets as an indicator of the cyclo-oxygenase activity; the second test system monitors the prostaglandin E2 formation by bovine platelets. All arachidonic acid metabolites are quantified by reverse-phase HPLC with UV-detection.
A Comparative Study on Desipramine Pharmacokinetics in the Rat Brain after Administration of Desipramine or Imipramine
Authors: Daniel Wladyslawa , Melzacka Miroslawa
Published: April 2011

Chronic intraperitoneal administration of desipramine led to an extensive cumulation of the drug in brain and blood compared with that after a single dose treatment, while chronic treatment with desipramine by the oral route produced a brain concentration comparable with its level after a single oral dose. Comparison of the present results with the corresponding data of published imipramine pharmacokinetics indicated that the cumulation of desipramine in the rat brain was nearly the same when rats received desipramine or imipramine twice a day for two weeks at a dose of 10 mg kg−1 orally, or imipramine, twice a day for two weeks at a dose of 10 mg kg−1 intraperitoneally. It is suggested that these three experimental paradigms may be used as models for differentiation of the pharmacological effects of imipramine and desipramine in-vivo.
Elimination of non-reactive and weakly reactive human α1-acid glycoprotein after induction of the acute phase response in rats
Authors: Parivar Kourosh , Tolentino Lorna , Taylor Glyn , øie Svein
Published: April 2011

The disposition of concanavalin A (Con A)-non-reactive and Con A-reactive human α1-acid glycoprotein (AAG) was studied in normal male rats and in acute phase response-activated male rats. Activation of the acute phase response was made using a subcutaneous administration of ethynyloestradiol in sesame oil. This technique increased the endogenous AAG concentration 7-fold. In control rats the two forms of human AAG showed identical kinetics with an average clearance of 5·4 mL h−1 kg−1, terminal half-life of 13·5 h and a volume of distribution (steady state) of 91 mL kg−1. In the acute phase response-activated animals, both the clearance and volume of distribution were larger: the average clearance of the Con A-non-reactive AAG was 10·2 mL h−1 kg−1, the volume of distribution (steady state) 152 mL kg−1 and the terminal half-life 11·7 h. The Con A-reactive AAG had a clearance of 14·7 mL h−1 kg−1, a volume of distribution (steady state) of 262 mL kg−1 and a half-life of 15·8 h. The results indicate that not only does activation of the acute phase response alter the kinetics of AAG but that the change is different for the different types of AAG.
In-vitro assessment of a matrix system of levobunolol
Authors: Ghosh Tapash K , Gokhale Rajeev D , Chiao Charles S
Published: April 2011

In order to study the feasibility of systemic delivery of levobunolol transdermally, a matrix-type delivery system was fabricated using a silicone elastomer. The relationship between loading dose and skin permeation rate was evaluated in-vitro using hairless mouse skin mounted on the stirred receptor compartment of the Keshary–Chien glass diffusion cell maintained at 37°C. The concentration of levobunolol in the receptor compartment was determined by HPLC. A similar study without using the skin was carried out to determine the effect of loading dose on the release of levobunolol from discs. It was observed that the release of drug from disc followed a matrix-diffusion controlled (Q) vs square root of time relationship at different loading doses. In contrast, the results of skin permeation of levobunolol from transdermal discs containing different loading doses showed a linear Q vs time relationship indicating a constant zero order skin permeation rate at each loading dose. Skin permeation of levobunolol appeared to reach a plateau at a 5% (w/w) loading dose in the disc indicating the attainment of equilibrium concentration of levobunolol in the skin.
Improvement of Large Intestinal Absorption of Insulin by Chemical Modification with Palmitic Acid in Rats
Authors: Hashizume Minoru , Douen Takayuki , Murakami Masahiro , Yamamoto Akira , Takada Kanji , Muranishi Shozo
Published: April 2011

The intestinal absorption of 125I-labelled palmitoyl insulin was examined following administration into in-situ closed large intestinal loops of rats. When mono- and dipalmitoyl insulins (Palins-1 and Palins-2, respectively) were administered in polyoxyethylene hydrogenated castor oil (HCO 60) micellar system into intestinal loops, a marked increase in plasma radioactivity and a corresponding disappearance of residual radioactivity in the intestinal lumen were observed in the following rank order: Palins-2 > Palins-1 > native insulin. In addition, the derivatives were more stable than native insulin in the mucosal tissue homogenates of the large intestine. These results suggest that chemical modification of insulin with palmitic acid may not only increase the lipophilicity of insulin but also reduce its degradation, resulting in the increased transfer of insulin across the large intestinal mucous membrane. The linoleic acid-HCO 60 mixed micelles system did not have a significant effect on the large intestinal absorption of radioactivity associated with the lipophilic insulin analogues.