bluuebunny/crossref_metadata_2025 huggingface dataset:
Di-iodo-l-tyrosine-labelled Dextrans as Molecular Size Markers of Nasal Absorption in the Rat
Authors: Fisher A N , Illum L , Davis S S , Schacht E H
Published: April 2011

A series of fractionated di-iodo-l-tyrosine-labelled dextrans (DIT dextrans), with a narrow range of number average molecular weights from 1260 to 45 500 Da, was administered intranasally and intravenously to anaesthetized rats. The nasal absorption of these compounds ranged from 0·6 to 52·7%. There was an inverse relationship between molecular size and the proportion of an intranasal dose absorbed. The study demonstrated the usefulness of DIT dextrans as molecular weight markers and confirmed the relationship between molecular size and nasal absorption for highly water soluble compounds. These results also supported the proposition that there is a continuous range of aqueous pores in the nasal mucosa.
Interaction Between Cicletanine and the Eicosanoid System in Human Subcutaneous Resistance Arteries
Authors: Calder J A , Schachter M , Sever P S
Published: April 2011

In human subcutaneous resistance arteries in-vitro, the relaxation produced by the novel furopyridine compound cicletanine (30 μm) was inhibited by 51% (P < 0·0001) in the presence of 20 μm of the cyclo-oxygenase inhibitor indomethacin. Maximal cicletanine-induced relaxation was reduced by both the cyclo-oxygenase inhibitor mefenamic acid and the relatively specific blocker of prostacyclin synthetase, tranylcypromine by 55% (P < 0·0005) and 43% (P < 0·01), respectively. The potassium channel blocker, glibenclamide (100 μm), did not affect the relaxation produced by cicletanine but did inhibit the relaxation produced by the potassium channel blocker cromakalim (P < 0·0001). Cromakalim-induced relaxation was inhibited in the presence of indomethacin; relaxation induced by cromakalim (30 μm) was reduced by 22% (P < 0·02). The relaxation produced by the hypotensive agonists sodium nitroprusside, hydrochlorothiazide, bumetanide and nicardipine was unaffected by incubation with indomethacin. The results suggest that the vascular eicosanoid system, specifically prostacyclin, may be involved in the mechanism of the acute vasodilator action of cicletanine. Although at high doses, cicletanine is a diuretic, in this model it did not act like either a thiazide or a loop diuretic. The acute vasodilator action of the thiazide diuretic, hydrochlorothiazide was a novel finding of this study. Cromakalim showed a reduced response in the presence of indomethacin suggesting an involvement of the eicosanoid system in its mechanism of action.
Enhancement of the stability of thrombin by polyols: microcalorimetric studies
Authors: Boctor Amal M , Mehta Surendra C
Published: April 2011

Glycerol increased the transition temperature (Tm) of thrombin in a concentration-dependent fashion up to a concentration of 50% glycerol in aqueous buffer solution. Glycerol showed a comparable effect on Tm of trypsin. This effect on Tm of thrombin was not seen in the presence of excess sodium chloride (1·2 m) in aqueous buffer solution. The stabilizing effect of glycerol may be due to increased energy demand to unfold the protein molecule, as reflected by an increase in Tm. This stabilizing effect, as measured by Tm, was seen for other polyols, including sucrose, and was also dependent on the concentration of the stabilizing agent. Micro-calorimetry may be used as an effective tool to screen for the protective action of compounds in enzyme stabilization studies before conducting the time-consuming and expensive stability studies of proteins in the presence of additives under different storage conditions.
Effect of exogenous copper on lipid peroxidation in rat hepatocytes. Possible involvement of protein kinase C
Authors: Mudassar S , Andrabi K I , Khullar M , Ganguly N K , Walia B N S
Published: April 2011

We have investigated the direct effect of copper on malondialdehyde formation in rat isolated hepatocytes. Copper was found to decrease the cell viability with concomitant production of ujalondialdehyde in a time related manner. In addition the protein kinase C activator, PMA, was found to have a synergistic effect with copper on rat hepatocytes. These results indicate that protein kinase C may be important in mediating hepatotoxicity after exposure to copper.
An in-vitro comparison of controlled release aminophylline tablets: phyllocontin Continus and Pecram
Authors: Smart J D , Barnes M S , Norris M J
Published: April 2011

It has been suggested that two controlled release preparations containing aminophylline, Phyllocontin Continus and Pecram, are clinically equivalent and are therefore interchangeable. In this study, an in-vitro evaluation of the two preparations was completed using the British Pharmacopoeia dissolution apparatus, initially using water and then an acid/buffer medium to provide a similar pH environment to that within the gastrointestinal tract. Similar release profiles were found when water was used as the dissolution medium, with very little variation between tablets within each group. Good fits were obtained for dissolution-controlled release and diffusion-controlled release models. When the acid/buffer solution was used as the dissolution medium a reduction in the rate of release was observed with Phyllocontin. It was predicted that if this was repeated in-vivo then differences in the peak plasma levels between the two formulations would be seen, although these may be masked by the other variables encountered.
Transport Characteristics of Cephalosporin Antibiotics Across Intestinal Brush-border Membrane in Man, Rat and Rabbit
Authors: Sugawara Mitsuru , Toda Takaki , Iseki Ken , Miyazaki Katsumi , Shiroto Hiroshi , Kondo Yukifumi , Uchino Jun-Ichi
Published: April 2011

The uptake of orally active cephalosporins, ceftibuten and cephradine, by intestinal brush-border membrane vesicles isolated from man, rat and rabbit was studied. In the presence of an inward H+ gradient, ceftibuten but not cephradine was taken up into intestinal brush-border membrane vesicles of man and rat against the concentration gradient (overshoot phenomenon). In rabbit jejunal brush-border membrane vesicles, the uptake of both cephalosporins in the presence of an inward H+ gradient exhibited the overshoot phenomenon. In human and rat vesicles, the initial uptake of ceftibuten was strongly inhibited by compound V, an analogue of ceftibuten, but the uptake of cephradine was not affected by any of the cephalosporins tested, whereas in the rabbit brush-border membrane vesicles, initial uptake of both ceftibuten and cephradine were markedly inhibited by all cephalosporins and dipeptides used. These results suggest that the transport characteristics of human and rat intestinal brush-border membrane for cephalosporins are comparable, and that rabbit is an inadequate animal for investigating the transport characteristics of β-lactam antibiotics.
Transport of Paraquat and Mexiletine from the Blood into the Rat Intestinal Lumen and Peritoneal Cavity
Authors: Arimori Kazuhiko , Deshimaru Megumi , Furukawa Emiko , Nakano Masahiro
Published: April 2011

Transport of paraquat and mexiletine from the blood into the intestinal lumen and the peritoneal cavity was examined after their intravenous administration (paraquat: 20 mg kg−1, mexiletine: 10 mg kg−1) to rats. The average amounts of paraquat transferred into the intestinal lumen and the peritoneal cavity were 1·39 and 22·8% of the dose in 120 min, respectively. The average amounts of mexiletine transferred into the intestinal lumen and the peritoneal cavity were 6·1 and 2·5% of the dose in 120 min, respectively. The transfer rate of 3H2O into the peritoneal cavity after intravenous administration (1·85 MBq) was greater than that into the intestinal lumen. In view of the hydrophilic nature of paraquat cation, a solvent drag effect due to movement of water might contribute to transport of paraquat from the blood to the peritoneal cavity. Differences in transport behaviour across the two membranes could be due to differences in the geometrical factors such as the surface area and the distribution of blood vessels. Differences might also be due to differences in physicochemistry and pharmacological effects of both substances.
L-Dopa-like Regulatory Actions of l-threo-3,4-Dihydroxyphenylserine on the Release of Endogenous Noradrenaline Via Presynaptic Receptors in Rat Hypothalamic Slices
Authors: Yue Jin-Liang , Goshima Yoshio , Nakamura Shinichi , Misu Yoshimi
Published: April 2011

Effects of l-threo-3,4-dihydroxyphenylserine (l-threo-DOPS) on the spontaneous release and the stimulus(2 Hz)-evoked release of endogenous noradrenaline were studied in rat hypothalamic slices with functioning l-aromatic amino acid decarboxylase (AADC) and with AADC inhibition. In non-inhibited slices, spontaneous release was not modified by l-threo-DOPS at 1 Pm-100Nm, tended to increase at 1–10 μm and increased at 100 μm. Noradrenaline tissue content slightly increased at 100 μm. Stimulated release was concentration-dependently facilitated at 1–1000 Pm and tended to decrease gradually from a maximum at 10 Nm-10 μm. Under AADC inhibition, spontaneous release concentration-dependently increased at 10–100 μm by 60% of the increase seen in slices without AADC inhibition. Increase in noradrenaline tissue content was abolished. l-threo-DOPS produced a triphasic pattern on stimulated release; concentration-dependent facilitation at 1–1000 Pm similar to that seen in slices with functional AADC, no facilitation at 10–1000 Nm, and a concentration-dependent increment at 10–100 μm. The facilitation at 1 Nm was stereoselective and was antagonized by (–)-propranolol 10 Nm, and no facilitation at 100 Nm was restored to the maximum by yohimbine 10 Nm, DG-5128 10 Nm or S-sulpiride 1 Nm. Furthermore, l-threo-DOPS (1–1000 Pm)-induced facilitation was competitively antagonized by l-dopa methyl ester, a competitive antagonist for l-dopa, with a pA2 value of 13·6, whereas it was noncompetitively antagonized by (–)-propranolol.
Cardiac Function in Rats with Acute Renal Failure
Authors: Robinson S C , Bowmer C J , Yates M S
Published: April 2011

Inotropic responses of isolated cardiac preparations from rats with glycerol-induced acute renal failure (ARF) were recorded, following a range of cardiac stimulants. Left atria of rats with ARF showed diminished inotropic responses only to the calcium agonist Bay K 8644 (methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethyl-phenyl)-pyridine-5-carboxylate) whilst right ventricular strips exhibited reduced responses to isoprenaline, 3-isobutyl-1-methylxanthine, Ca2+ and Bay K 8644. Investigations of cardiac mitochondrial respiration indicated that there is a site-unspecific ‘pseudo’ uncoupling of oxidative phosphorylation in ARF but that electron transport is unaffected. This uncoupling of oxidative phosphorylation did not have any detectable effect on either levels of total adenine nucleotides and creatine phosphate or cellular energy charge. Measurements were also made of the activity of pyruvate dehydrogenase which provides an index of mitochondrial Ca2+ levels. The proportion of pyruvate dehydrogenase in its active form was threefold higher following isoprenaline injection in hearts of rats with ARF compared with controls. The results suggest that in hearts of rats with ARF there is a change in the number, affinity, efficacy or coupling of the dihydropyridine receptor on the L-type calcium channel. Moreover, in the ventricle, a defect in cellular Ca2+ control, resulting in an increase in mitochondrial Ca2+ uptake, may contribute to the depression of inotropic response to the range of cardiac stimulants tested.
Spectrophotometric Method for the Determination of Carbidopa Using Neotetrazolium Chloride
Authors: Issopoulos Prodromos B , Economou Pantelis T
Published: April 2011

A new high-sensitive spectrophotometric method for the determination of microquantities of carbidopa is described. The method is based on the reduction of neotetrazolium chloride by carbidopa in an alkaline ethanolic medium. The formazan formed exhibits an absorption maximum at λ = 507 nm, with an apparent molar absorptivity of = 6·63 × 104  m−1 cm−1 and a corresponding Sandell's sensitivity of 3·68 ng cm−2. Beer's law is obeyed over the range of 0·10–6·0 μg mL−1 while the optimum concentration range is 0·125–5·0 μg mL−1. The regression line equation was calculated as: A = 0·271C +0·0023 with a correlation coefficient of 1·0000 (n = 28). The accuracy and the precision of the method were considered as very satisfactory. The results obtained from the determination of carbidopa using both the described procedure and the corresponding USP. XXII and BP 1988 official methods were statistically compared by means of Student's t-test as well as by the variance ratio F-test, and no significant difference was observed.
Effect of Humidity on Solid-state Isomerization of Various Kinds of Lactose During Grinding
Authors: Otsuka Makoto , Ohtani Hiro , Otsuka Kuniko , Kaneniwa Nobuyoshi
Published: April 2011

The effect of humidity on isomerization during grinding of α-monohydrate, α-anhydrate and β-anhydrate of lactose was investigated. Samples were ground in an agate centrifugal ball mill at 270 rev min−1 at room temperature (21°C) and at 5 and 60% relative humidity. Crystallinity of the ground lactose was measured by Hermans' method from the powder X-ray diffraction profiles. The α- and β-lactose content of the ground lactose was measured by using angular rotation spectrophotometry. The crystalline lactose samples were transformed into noncrystalline solids by mechanical stress during grinding. After grinding, the adsorbed water content of all ground lactose samples increased, and the isomerized amount increased with increase of the water content during grinding at 5 and 60% relative humidity. The results suggest that the isomerization rate of α-monohydrate during grinding may depend on the crystallinity, but those of α-and β-anhydrate depend on the content of adsorbed water.
Investigation of Potential Genotoxic Effects of Low Frequency Electromagnetic Fields on Escherichia coli
Authors: Chahal R , Craig D Q M , Pinney R J
Published: April 2011

Exposure of growing cells of Escherichia coli strain AB1157 to a frequency of 1 Hz with field strengths of 1 or 3 kV m−1 did not affect spontaneous or ultraviolet light (UV)-induced mutation frequencies to rifampicin resistance. Neither did growth in the presence of charge alter the sensitivities of strains AB1157, TK702 umuC or TK501 umuC uvrB to UV. Similarly, although the resistance of strains TK702 umuC and TK501 umuC uvrB to UV was increased by the presence of plasmid pKM101, which carries DNA repair genes, pregrowth of plasmid-containing strains in electric fields did not increase UV resistance. Finally, growth in a low frequency field in the presence of sub-inhibitory concentrations of mitomycin C did not affect mitomycin C-induced mutation frequencies. It is concluded that low frequency electromagnetic fields do not increase spontaneous mutation, induce DNA repair or increase the mutagenic effects of UV or mitomycin C.
Inhibition of drug-induced contractions of guinea-pig ileum by Annona crassiflora seed extract
Authors: Weinberg Maria De Lourdes Duarte , Pires Virginia , Weinberg Julio , De Oliveira Alaide Braga
Published: April 2011

A hydro-alcoholic extract of dried Annona crassiflora seeds (AR.1) showed a non-specific inhibitory effect on drug-induced contractions of guinea-pig ileum. Maximum responses to histamine, acetylcholine and bradykinin were reduced increasingly with increasing doses of AR.1. Affinities of the gut to the above agonists, expressed as respective pD2 values were not changed by AR.1. Dose-response curves of calcium-induced contractions in depolarized preparations were shifted to the right but maximum responses were not changed by AR.1. It is suggested that the inhibitory effect of AR.1 is due to a decrease in membrane permeability to calcium. This inhibitory effect may be responsible for the effect of Annona crassiflora as a remedy against snake venom.
Anti-nociceptive activity of nitric oxide synthase inhibitors in the mouse: dissociation between the effect of l-NAME and l-NMMA
Authors: Babbedge R C , Hart S L , Moore P K
Published: April 2011

The anti-nociceptive effect of selective inhibitors of nitric oxide synthase has been assessed in a formalin-induced paw-licking model in mice. l-NG-Nitro arginine methyl ester (l-NAME) but not l-NG-monomethyl arginine (l-NMMA) exhibited anti-nociceptive activity in both the early and late phases of paw licking following intraperitoneal administration. The effect on the late phase response was more pronounced. l-NAME (0·1–100 μg) and l-NG-nitro arginine base (l-NOARG; 10 μg) but not d-NAME (10 μg) were also anti-nociceptive following intracerebroventricular administration. l-NAME (10 μg) administered by this route did not influence locomotor activity. l-NMMA was inactive at doses up to 40 μg by this route. At higher doses (75–200 μg) l-NMMA produced a similar and non-dose related reduction in early/late phase paw-licking time. d-NMMA (100 μg) was inactive. The greater anti-nociceptive effect of l-NAME in this model accords with recently published biochemical data indicating that l-NAME is several orders of magnitude more potent than l-NMMA as an inhibitor of brain nitric oxide synthase. These data support the use of l-NAME as a selective tool to investigate the central pharmacological effects of nitric oxide.
The Effect of Carbohydrate Additives in the Freeze-Drying of Alkaline Phosphatase
Authors: Ford Annette W , Dawson Peter J
Published: April 2011

Alkaline phosphatase was used as a model in studies to assess the effects of lyophilization on biological activity and molecular integrity in the presence or absence of added carbohydrate. The stability of the activity of alkaline phosphatase, lyophilized in Tris buffer alone or in the presence of the carbohydrates mannitol, lactose or trehalose was examined. Enzyme activity in formulations with Tris buffer alone or with mannitol was considerably reduced by freeze-drying and further storage at elevated temperatures; freeze-drying with mannitol failed to maintain activity at a temperature of 37°C over 21 days, whilst the loss of activity was more gradual when freeze-dried in buffer alone and stored at higher temperatures. Lactose and trehalose maintained the alkaline phosphatase activity after freeze-drying and, furthermore, preparations containing trehalose retained activity even when the material was subjected to temperatures of up to 45°C for up to 84 days. At 56°C the alkaline phosphatase activity did not show a significant drop until 14 days with the lactose formulation or until 21 days with trehalose. After 84 days at 56°C, 30% of the activity still remained in the formulation containing trehalose. In addition to the changes in the enzyme activity, FPLC chromatographic traces and SDS-PAGE gels demonstrated compositional differences between each formulation after storage.
Effect of Bicarbonate-free Balanced Salt Solutions on Fluid Pump and Endothelial Morphology of Rabbit Corneas In-vitro
Authors: Doughty Michael J , Newlander Kflly , Olejnik Orest
Published: April 2011

Corneas from young adult albino rabbits were exposed, in-vitro, to various bicarbonate-free balanced salt solutions under an applied hydrostatic pressure of 20 cmH2O at 35°C for up to 4·5 h. The solutions were buffered with a HEPES-MOPS mixture, phosphate salts or acetate-citrate salts (pH 7·1–7·4). All of these solutions support a net fluid pump activity attributed to the corneal endothelium although the net fluid pump rates were less than those measurable with a bicarbonate-buffered, CO2-equilibrated Ringer solution. Evaluation of the endothelia by scanning electron microscopy revealed no evidence of any acute toxic effect of the balanced salt solutions. Morphometric analyses of cell size and shape revealed a normal mosaic for endothelia exposed to commercial balanced salt solution for 5 h. The results further indicate that exogenous bicarbonate is not required for the net fluid pump function of the mammalian corneal endothelium.
Host Reaction against Empty Alginate-polylysine Microcapsules. Influence of Preparation Procedure
Authors: Vandenbossche Geert M R , Bracke Marc E , Cuvelier Claude A , Bortier Hilde E , Mareel Marc M , Remon Jean-Paul
Published: April 2011

Microcapsules, prepared with alginate and polylysine, were injected intraperitoneally into mice and the number of peritoneal leucocytes as well as the cells sticking to the capsule wall were counted after 4–28 days. A significant increase in host reaction was observed when the microcapsules contained an outer layer of polylysine as compared with calcium alginate beads without polylysine or microcapsules coated with an outer layer of alginate. The alginate sources influenced the host reaction significantly. After an intraperitoneal residence of 4 days, the microcapsules were mainly surrounded by macrophages. After 28 days, several cell layers surrounded the microcapsules; macrophages, multinucleate giant cells, fibroblasts and mesothelial cells.
Host Reaction against Alginate-polylysine Microcapsules Containing Living Cells
Authors: Vandenbossche Geert M R , Bracke Marc E , Cuvelier Claude A , Bortier Hilde E , Mareel Marc M , Remon Jean-Paul
Published: April 2011

Syngeneic and nude mice were injected intraperitoneally with saline, empty microcapsules, aggregates of tumourogenic MO4 cells, encapsulated non-tumourogenic MO cells and encapsulated MO4 cells. The host reaction 4 days after injection, was evaluated by counting the leucocytes in the peritoneal cavity and the cells sticking to recovered microcapsules. A significantly lower number of peritoneal leucocytes was found in mice injected with empty microcapsules or encapsulated MO cells as compared with encapsulated MO4 cells. Histological evaluation showed a significantly higher number of cells sticking to microcapsules containing cells as compared with empty microcapsules. These observations showed that the cellular host reaction against intraperitoneal implants can be evaluated by counting the leucocytes in the peritoneal lavage and histology of recovered capsules.
Bromhexine plus Oxytetracycline: the Effect of Combined Administration Upon the Rheological Properties of Mucus from the Mini-pig
Authors: Martin Gary P , Loveday Bernard E , Marriott Christopher
Published: April 2011

Three adult mini-pigs were employed to assess the effects of a twice daily dosage (40 mg kg−1) of oxytetracycline hydrochloride (OTC) and a combination of OTC with (0·5 mg kg−1) bromhexine hydrochloride (BHC) on the rheological properties and wet weight of secreted tracheal mucus. Mucus was collected daily from open-ended tracheal pouches established surgically in the mini-pigs. After a five day control period, either OTC or OTC plus BHC was administered twice daily with the normal diet. Each study period was followed by a five day washout period when mucus was collected but no drug given. The viscoelastic properties of each mucus sample were determined using creep compliance analysis. OTC was shown to increase the residual shear viscosity (P < 0·01) and increase the instantaneous compliance (P < 0·01). An increase in the wet weight of the collected mucus occurred in one pig only (P < 0·01). When BHC was co-administered with OTC, all of these changes were abolished. Evidence was obtained to suggest that BHC increased the concentration of OTC within the secreted mucus. BHC appeared to reverse the mucospissic activity of OTC in-vivo.
Effects of LP-805, a Newly Developed Vasodilator, on Myocardial Metabolism in Ischaemic Dog Hearts
Authors: Ichihara K , Morimoto T , Tsujitani M , Abiko Y
Published: April 2011

The effects of LP-805, a newly developed vasodilator, on changes in the myocardial energy and carbohydrate metabolism induced by ischaemia were studied in open-chest anaesthetized dogs. Ischaemia was induced by ligating the left anterior descending coronary artery for 3 min. The myocardial energy stores were depleted, and the levels of glycolytic intermediates were altered 3 min after the onset of ischaemia. Energy change potential was decreased, and ([G6P] + [F6P])/[FDP] and [lactate]/[pyruvate] ratios were increased by ischaemia. These findings indicated that the myocardial metabolism was converted from an aerobic to an anaerobic type by ischaemia. LP-805 (10, 30, or 100 μg kg−1) was injected intravenously 5 min before the onset of ischaemia. LP-805 prevented the myocardial energy depletion and alterations of myocardial carbohydrate metabolism due to ischaemia, indicating that it appeared to convert the anaerobic metabolism back to aerobic metabolism in the ischaemic myocardium. In conclusion, LP-805 may reduce the ischaemic influence on the myocardium.
A comparison of the incorporation of model steroids into non-ionic micellar and microemulsion systems
Authors: Malcolmson Carole , Lawrence M Jayne
Published: April 2011

The incorporation of testosterone and two of its esters, and progesterone and one of its esters (log Poct varying from 3·3 to 6·9) into 2% w/w soybean oil/Brij 96 microemulsions and Brij 96 surfactant systems has been examined. Possible sites of incorporation have been investigated. The drug carrying improvement of an oil-in-water microemulsion over a micellar system appears to depend on the solubility of the drug in the dispersed oil phase and is significant only for very lipophilic drugs.
Reduced kallikrein excretion by liposome-encapsulated cyclosporin in the rat
Authors: Akbarieh Mostafa , Adam Albert , Legris Fabien , Tawashi Rashad
Published: April 2011

Different phospholipids and methods of preparation were used to produce cyclosporin encapsulated in liposomes. The optimal formulation of cyclosporin-liposome was compared to the oily cyclosporin after intraperitoneal administration of 25 mg kg−1 body weight to rats. Urinary kallikrein excretion was significantly reduced with the liposomal form. The abrupt increase of kallikrein excretion after the tenth day with the control oil preparation suggests that cyclosporin toxicity could be present at the tubular level, and the encapsulation of cyclosporin in liposomes reduces tubular damage.
Influence of intravenous infusion of ethanol on regional blood flow in conscious rats
Authors: Tabrizchi Reza , Pang Catherine C Y
Published: April 2011

The effects of intravenous infusions of ethanol and saline (0·9% NaCl) on mean arterial pressure (MAP), heart rate (HR), total peripheral resistance (TPR), cardiac contractility (dP/dtmax) and systemic haemodynamics were studied in conscious, unrestrained rats by the radioactive microsphere technique. Saline (0·03 and 0·06 mL min−1 kg−1 for 12 min each dose) in the time-control group did not affect MAP, HR, TPR, dP/dtmax or vascular conductances in any organs or beds. While the low dose ethanol (2·4 mg min−1 kg−1) did not alter MAP, HR, TPR, systemic haemodynamics or dP/dtmax, the high dose (4·8 mg min−1 kg−1) slightly reduced MAP and TPR but did not affect HR, cardiac output or dP/dtmax. Both doses of ethanol vasodilated the intestine and spleen, but vasoconstricted the skin. The high dose caused additional vasodilatation in the heart and testes and the low dose also constricted the skeletal muscle bed. Our results show that ethanol, at non-hypotensive or slightly hypotensive doses, has marked vasodilator effects in the heart, intestine, spleen and testes.
Structural Requirements for the Direct and Cytochrome P450-dependent Reaction of Cyclic α,β-Unsaturated Carbonyl Compounds with Glutathione: a Study with Coumarin and Related Compounds
Authors: Fry Jeffrey R , Fentem Julia H , Salim Alena , Tang S P Anna , Garle Michael J , Whiting Donald A
Published: April 2011

The interaction of glutathione (GSH) with coumarin, or one of a series of compounds related to coumarin, was assessed in the absence and presence of liver microsomes (direct reaction and indirect reaction, respectively) to determine the structural requirements for direct and mono-oxygenase-mediated reaction of cyclic α,β-unsaturated carbonyls with GSH. Acrolein was used as a positive control for the direct reaction, and produced complete or nearly complete depletion of GSH under all assay conditions. 5,6-Dihydro-2H-pyran-2-one and 2-cyclohexen-1-one also produced substantial depletion of GSH in the direct reaction, which was not increased by the addition of liver microsomes. Coumarin, 2H-pyran-2-one and precocene I (a substituted pyran lacking the 2-one structure) were not substrates for the direct reaction but did cause depletion of GSH when incubated in the presence of rat or human liver microsomes. These depletions were dependent on a functioning mono-oxygenase system as judged by the effects of omission of cofactors, addition of competitive or inactivating inhibitors of cytochrome P450, and induction. Dihydrocoumarin, ∂-valerolactone, cyclohexanone and 4H-pyran-4-one were not substrates for either the direct or indirect reaction. These findings are rationalized on the basis of a direct nucleophilic attack of GSH on the α,β-centre of the α,β-unsaturated carbonyl compounds, which is hindered by benzenoid resonance in coumarin and 2H-pyran-2-one, for which enzyme-mediated reaction with GSH, probably via a 3,4-epoxide, is the favoured mechanism.
In-vitro permeation of some β-blockers across the hairless mouse skin
Authors: Ghosh Tapash K , Chiao Charles S , Gokhale Rajeev D
Published: April 2011

To support the development of a suitable transdermal dosage form for β-blockers, in-vitro, skin permeation studies of nine β-blockers were conducted at 37°C across the excised abdominal skin of hairless mouse mounted on the receptor compartment of a two-chambered Valia-Chien glass diffusion cell. The drugs varied in lipophilicity, whereas pKa values were comparable. Permeability coefficients were calculated from the steady-state flux values. Agreement was found between the permeability coefficient and the drug lipophilicity, expressed as the octanol-bufter distribution coefficient.
Effect of Bay K 8644 on the synthesis and metabolism of dopamine and 5-hydroxytryptamine in various brain areas of the rat
Authors: Colado M I , Ormazabal M J , Alfaro M J , Martin M I
Published: April 2011

The effects of Bay K 8644 (1,2 and 4 mg kg−1, i.p.) on the synthesis and metabolism of dopamine and 5-hydroxytryptamine (5-HT) in rat brain after m-hydroxybenzylhydrazine administration were studied. Bay K 8644 (2 and 4 mg kg−1, i.p.) caused an increase in the synthesis of both dopamine in the striatum and 5-HT in the midbrain and striatum, measured as the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan, respectively. Moreover, Bay K 8644 at the dose of 4 mg kg−1 increased the turnover of dopamine in the striatum and of 5-HT in midbrain and striatum. These neurochemical changes were antagonized by the calcium channel antagonist nimodipine (10 mg kg−1, i.p.). It is concluded that dihydropyridine receptors may mediate the brain region-specific changes in the dopaminergic and 5-HT-ergic neurotransmission which occur following activation of neuronal calcium channels.
Stereoselective binding of β-blockers to purified rat α1-acid glycoprotein
Authors: Murai-Kushiya Mami , Okada Satoshi , Kimura Toshio , Hasegawa Ryuichi
Published: April 2011

The stereoselectivity of binding of four β-blockers, pindolol, propranolol, oxprenolol and acebutolol, to purified rat α1-acid glycoprotein (AAG) was examined using equilibrium dialysis. Pindolol and propranolol were bound stereoselectively to AAG, whereas binding of oxprenolol was non-stereospecific. Neither of the enantiomers of acebutolol bound to either AAG or any other plasma protein. The affinity of (+)-pindolol was 25 times that of (–)-pindolol, as determined in a single enantiomer experiment. Both enantiomers of propranolol demonstrated two classes of binding sites in AAG, the total binding for the high affinity site for (+)-propranolol being double that of (–)-propranolol, which could explain the higher binding of the (+)-enantiomer in racemate experiments. These results further showed that stereoselective binding to a rat AAG is not a property common to all β-blockers.
Centpropazine affinity to cortical noradrenergic receptors and effect on their responsiveness in the rat
Authors: Dikshit M , Chalecka-Franaszek E , Nalepa I
Published: April 2011

We have studied the in-vitro effect of centpropazine on cerebral cortical noradrenergic receptors measured as the accumulation of second messengers, cyclic AMP and inositol phosphate, stimulated by noradrenaline, and the binding to α1- and β-adrenoceptors. Centpropazine inhibited inositol phosphate, but not the cyclic AMP accumulation in the cerebral cortical slices of the rat. It moderately antagonized the specific binding of [3H]prazosin but did not affect the specific binding of the β-adrenoceptor ligand, [3H]CGP 12177, to cerebral cortical membranes.
A new aspect of tolbutamide metabolism in the rabbit: the role of 1-butyl-3-(p-formylphenyl)sulphonylurea
Authors: Washio Kanetoshi , Makaya Osami , Sasaki Hitoshi , Nishida Koyo , Nakamura Junzo , Shibasaki Juichiro
Published: April 2011

We investigated the metabolism of tolbutamide by using synthetic 1-butyl-3-(p-formylphenyl)sulphonylurea (ATB), an intermediate in the metabolic pathway of tolbutamide. ATB (40 mg kg−1) administered intravenously to rabbits was oxidized to 1-butyl-3-(p-carboxyphenyl)sulphonylurea (CTB) and also reduced to 1-butyl-3-(p-hydroxymethylphenyl)sulphonylurea (HMTB). Therefore, it is likely that in the metabolism of tolbutamide, the oxidation of HMTB to ATB involved the reverse reaction, suggesting the reduction of ATB to HMTB. The oxidation of ATB to CTB was inhibited by disulfiram pretreatment. ATB was detected in the blood following intravenous administration of HMTB in rabbits pretreated with disulfiram. These results, confirm that ATB is an intermediate in the oxidative metabolism of tolbutamide in the rabbit.
Contraction Induced Either by Iso-osmolar or Hyper-osmolar Potassium-rich Solutions Influences Relaxant Responses to Pinacidil and Verapamil in Rat Isolated Aorta
Authors: Nielsen Claus Brøsckner
Published: April 2011

Relaxant responses of pinacidil and verapamil were studied in rat isolated aorta contracted by either iso-osmolar or hyper-osmolar potassium-rich solutions. Relaxant response profiles of pinacidil and verapamil in rat isolated aorta contracted by 124 mm K+ hyper-osmolar Krebs solutions showed marked reductions in inhibiting Emax values and substantial increases in corresponding IC50 values in comparison with results obtained at iso-osmolar conditions. Changes in the slopes of the fitted log concentration-relaxation curves were also observed, whereas pinacidil relaxation curves obtained after initial contraction induced by 30 mm K+ Krebs solutions were only slightly influenced by osmolarity, a definite decrease in Emax occurred for verapamil at hyper-osmolar conditions. Initial tension development was much slower and maximal tension lower when induced by 124 mm K+ in hyper-osmolar compared with iso-osmolar Krebs solutions. After incubation in Ca2+-deprived EGTA-containing Krebs solutions the maximal tension produced by 124 mm K+ iso-osmolar Krebs solution in rat aorta was nearly 95% reduced, whereas it was only reduced by 50% at hyper-osmolar conditions. Hyper-osmolarity as established by direct addition of potassium chloride to Krebs solutions in order to induce contraction in vascular smooth muscle could influence the in-vitro action profile, potency and intrinsic activity of the two vascular relaxant drugs.
Effects of Dopamine on the Gastrointestinal Tract of Chicks
Authors: Lot Theodore Y
Published: April 2011

The effects of dopamine on the gastrointestinal tract of chicks have been investigated. Dopamine caused concentration-related contractions of the upper oesophagus, crop or lower oesophagus but relaxed the duodenum, ileum, large intestine or caecum in a concentration-related fashion. By means of specific antagonists, the presence of muscarinic, histamine (H1), α-adrenergic, 5-HT-ergic and dopaminergic receptors were established in the lower oesophagus and their stimulation caused contraction while β-adrenergic-receptor stimulation caused relaxation. Contraction of the lower oesophagus induced by dopamine was abolished by lysergic acid diethylamide and was antagonized by moderate concentrations of haloperidol or pimozide. Tachyphylaxis developed to repeated administration of a large concentration of dopamine. These findings suggest that contraction of the lower oesophagus of chicks by dopamine is largely mediated by 5-hydroxytryptamine release and that stimulation of dopaminergic receptors contributes to a lesser extent.
The Adverse Effect of Glycation of Human Serum Albumin on its Preservative Activity in the Freeze-Drying and Accelerated Degradation of Alkaline Phosphatase
Authors: Ford Annette W , Allahiary Zahra
Published: April 2011

The effects of a glycated protein additive on the stability of freeze-dried biological standards were studied using alkaline phosphatase as a model. Alkaline phosphatase was formulated with artificially glycated albumin, freeze-dried, sealed into glass ampoules and subjected to accelerated degradation studies at temperatures from —20 to 56°C. Alkaline phosphatase, freeze-dried without an additive in neutral buffer, lost over 95% of its activity, but when freeze-dried with human serum albumin it retained approximately 70% of the initial activity. Both deliberately glycated and native albumin protected approximately 70% of the initial activity on freeze-drying and this protection was maintained during storage of the freeze-dried product at temperatures of 20°C or below for up to 16 weeks. At 37°C or above, alkaline phosphatase activity was lost in a time- and temperature-related manner with changes appearing in the SDS-PAGE gels and FPLC chromatograms but, with the artificially glycated albumin formulations, this loss of activity and the changes in the gels and chromatograms happened earlier and at lower temperatures. Formulations with trehalose at 1% w/v and 15% w/v, but without albumin, preserved some 40% of alkaline phosphatase activity following freeze-drying. Further, approximately half of that activity was maintained after 16 weeks' storage at all temperatures up to 56°C by the 15% trehalose without albumin. This study indicates that, in the formulation of freeze-dried biological standards, if albumin is to be used, the initial degree of glycation should be kept to a minimum and combinations of albumin and reducing sugar should be avoided. Trehalose 15% provides an acceptable alternative where exposure to high temperature is likely to occur.
The effect of silymarin and gamma radiation on nucleic acids in rat organs
Authors: Haková H , Mišúrová E
Published: April 2011

The influence of silymarin on radiation-induced changes in concentrations of RNA and DNA was followed in male Wistar rats. The liver, spleen and bone marrow were examined at 30 h, 7, 14 and 21 days after 6 Gy whole-body gamma irradiation or 30 h and 7 days after 3 Gy whole-body gamma irradiation. Following silymarin treatment, a mild increase in the concentration and total content of RNA and DNA in liver and bone marrow at days 7 and 14 after administration was found; in spleen, total content of DNA significantly increased at 30 h. Silymarin administered 1 h before irradiation, moderated radiation-induced changes in nucleic acids in its target organ, liver, and in spleen and bone marrow. We suggest that beneficial effects of silymarin on radiation injury to the membranes of liver cells resulted primarily from its antioxidative ability and its ability to act as a radical scavenger, thereby preventing membrane permeability changes.
Characterization of the α1-adrenoceptors of the rat prostate gland
Authors: Couldwell Caroline , Jackson Andrea , O'Brien Helen , Chess-Williams Russell
Published: April 2011

The α1-adrenoceptor-mediated responses of the rat prostate to phenylephrine have been examined in-vitro. Phenylephrine induced concentration-dependent contractions of the isolated prostate gland which were antagonized by WB4101 (1–30 nm). Schild plot analysis of the antagonism yielded a straight line with a slope not significantly different from unity. The pKB value of 9·2 was similar to that obtained for WB4101 on the rat vas deferens (9·4) but was greater than that obtained on the rat spleen (8·4). Chloroethyl-clonidine depressed responses to phenylephrine of the rat spleen but not the prostate or the vas deferens. These results indicate that the rat prostate gland possesses a typical α1A-adrenoceptor similar to that found in the vas deferens.
The purely chronotropic effects of relaxin in the rat isolated heart
Authors: Thomas G Roger , Vandlen Richard
Published: April 2011

The endogenously occurring protein relaxin was evaluated for its cardiac effects in the rat isolated heart. Relaxin caused a dose-dependent tachycardia without positive inotropic effects in intact preparations and in preparations where the atria had been removed. It is concluded that relaxin acts on both the atrial and ventricular pacemakers to increase heart rate, but the precise mechanism of action remains unknown.
Partitioning and thermodynamics of dipyridamole in the n-octanol/buffer and liposome systems
Authors: Betageri G V , Dipali S R
Published: April 2011

The thermodynamics of partitioning (K) of dipyridamole has been determined in n-octanol/buffer and liposome-buffer systems at pH 7·4. Dimyristoylphosphatidylcholine (DMPC) and dipalmitoylphosphatidylcholine (DPPC) were used to prepare multilamellar liposomes. Partitioning of dipyridamole did not depend on the amount of n-octanol employed, however, partitioning was dependent upon the quantity of DMPC employed to prepare liposomes. Plots of log K vs 1/T were linear in the n-octanol and liposome systems. Partitioning was generally greater in liposomes than in the n-octanol/buffer system. Among liposomes, the partitioning was greater in DMPC liposomes at all temperatures. The values of enthalpy (ΔH) and entropy (ΔS) were positive in both the n-octanol and liposome systems. These values were lower in DMPC liposomes and were comparable in the n-octanol and DPPC liposomes. Thus, the interaction of dipyridamole depends on the rigidity of lipid bilayers and liposomes constitute a more selective partitioning system than the n-octanol/buffer system.
Anomalous parameter estimates in the one-compartment model with first-order absorption
Authors: Purves R D
Published: April 2011

A difficulty sometimes encountered in least-squares fitting of a one-compartment model with first-order absorption is that estimated values (ka and ke) of the rate constants of absorption and elimination are almost identical, are highly correlated and have very large standard deviations. This anomaly is explained by the existence of a class of data sets for which least-squares estimates of the rate constants are complex quantities. Such data sets may arise either from an unfortunate combination of random (e.g. assay) errors in the concentration values if ka and ke are sufficiently similar in magnitude, or from delayed absorption.
Sennoside-induced Secretion is Not Caused by Changes in Mucosal Permeability or Na+,K+-ATPase Activity
Authors: Leng-Peschlow Elke
Published: April 2011

The effect of sennosides (50 mg kg−1) on the rat colon in-situ was studied 6 h after oral treatment when the laxative effect was maximal. In a second experiment, rhein (4 × 10−3  m), an active sennoside metabolite, was administered into the lumen of the colon for 1 h. Both sennosides and rhein reduced net H2O and Na+ absorption or reversed it to net secretion. Paracellular permeability, as measured using erythritol as a small marker molecule, was increased 2- to 3-fold; permeability to a large molecule, PEG 1000, was unchanged. The activity of Na+, K+-ATPase in the colon mucosa was not affected. There was no damage of the epithelial cells as determined by lactic acid dehydrogenase release. These results indicate that neither inhibition of Na+, K+-ATPase nor damage of the colon epithelium are involved in the secretory effect of sennosides or rhein. The increased paracellular permeability of small molecules fits into the concept of stimulation of active chloride secretion by sennosides, which is electrochemically and osmotically balanced by an increase in Na+ and H2O flow via the paracellular pathway.
The Role of Cyclic AMP and Phosphodiesterase Activity in the Mechanism of Action of Tetramethylpyrazine on Human and Dog Cardiac and Dog Coronary Arterial Tissues
Authors: Lin Cheng-I , Wu Shiou-Ling , Tao Pao-Luh , Chen Hsing-Ming , Wei Jeng
Published: April 2011

The aim of the present experiments was to explore the underlying cellular mechanisms responsible for the actions of tetramethylpyrazine (TMP) on atrial, ventricular and coronary arterial tissues. Transmembrane potentials of cardiac tissues were detected by means of the glass microelectrode technique and contractile tension by a force transducer. Tissue cyclic (c) AMP level was determined by protein binding assay. Results show that in human atrial and dog Purkinje fibres, high concentration of TMP (3 Mm) induced a persistent positive inotropic effect only in the presence of adrenaline. Also, 3 Mm TMP increased the cAMP level of the atrial muscle fibres, especially in the presence of adrenaline. Determination of the activity of cAMP-phosphodiesterase revealed that 0·3 and 3 Mm TMP inhibited the phosphodiesterase activity of dog coronary artery and human atrial tissues in a concentration-dependent manner. When compared at the lower concentration (0·3 Mm), the inhibitory effect of TMP was about 60% that of theophylline. The above findings indicate that the cardiovascular effects of TMP are related to the inhibition of phosphodiesterase activity and the subsequent elevation of the cAMP concentration.
Sex-related Differences in Rat Liver Microsomal Enzymes and Their Induction by Doxapram
Authors: Ozaki Masayasu , Ishikawa Masaaki , Takayanagi Yoshio , Sasaki Ken-Ichi
Published: April 2011

The effects of doxapram on the hepatic microsomal mono-oxygenase system of male and female rats were investigated. Male and female rats were administered doxapram (10–120 mg kg−1 day−1, i.p.) for 4 days. In female rats, administration of doxapram (20, 40, 60, 80, 100 and 120 mg kg−1) elevated the parameters in a dose-dependent manner while doxapram (100 and 120 mg kg−1) elevated the levels of cytochrome P450 and hexobarbitone hydroxylase in male rats. Doxapram (40 mg kg−1) caused induction of hepatic drug metabolism typified by an increase of hepatic microsomal cytochrome P450 content and activities of hexobarbitone hydroxylase, benzphetamine N-demethylase and ethylmorphine N-demethylase in female rats, but no change in male rats. These findings were supported by the results of SDS/polyacrylamide-gel electrophoresis. However, 7-ethoxycoumarin O-de-ethylase and arylhydrocarbon hydroxylase activities were significantly increased in male rats. NADPH-cytochrome c reductase and NADH-cytochrome c reductase activities, and cytochrome b5 content were unaffected in rats of both sexes. The sex-dependent cytochrome P450 species may be selectively sensitive to the action of doxapram.
Intestinal brush-border transport of the oral cephalosporin antibiotic, cefdinir, mediated by dipeptide and monocarboxylic acid transport systems in rabbits
Authors: Tsuji Akira , Tamai Ikumi , Nakanishi Masaru , Terasaki Tetsuya , Hamano Schoichiro
Published: April 2011

Intestinal absorption of the orally active cephalosporin, cefdinir, was investigated using brush-border membrane vesicles prepared from rabbit small intestine. The initial uptake of cefdinir was pH-dependent, with increased uptake at acidic pH, and was not influenced by either sodium gradient or membrane potential difference. Cefdinir uptake was saturable with an apparent Michaelis constant of 8·1 Mm. Initial uptake of cefdinir was inhibited by dipeptides (glycyl-l-proline and glycylsarcosine), β-lactam antibiotics (cephradine, cefixime and penicillin V), and monocarboxylic acids (acetic acid and l-lactic acid), whereas the uptake of cephradine and cefixime was not inhibited by monocarboxylic acids. Cefdinir significantly inhibited the initial uptake of cephradine, cefixime and [3H]acetic acid. From these results, it was suggested that cefdinir was transported across brush-border membranes by both dipeptide and monocarboxylic acid carriers.