bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of B-HT 920 and St 91 on venous haemodynamics in cats
Authors: Widdop Robert E
Published: April 2011

The present study reports the effects of 2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepin dihydrochloride (B-HT 920) and 2-(2,6-diethylphenylimino)-2-imidazolidine hydrochloride (St 91) in autoperfused cat hindquarters since we have previously shown that clonidine lowered blood pressure, heart rate and vena cava blood flow (VCBF) but not hindquarters perfusion pressure, indicating a selective venodilator action of this drug (Bentley et al 1986). It was found that intravenous (i.v.) and intracisternal (i.c.m.) administration of B-HT 920 caused essentially identical effects to those of Clonidine. St 91, given i.c.m. lowered blood pressure and VCBF but not perfusion pressure, while i.v. St 91 had little effect on these variables. Thus, parallel changes in blood pressure and VCBF occurred using both drugs, suggesting that these centrally-acting clonidine-like drugs also caused selective venodilatation.
QSAR study on species differences in microsomal N-oxygenation of N,N-dimethylalkylamines
Authors: Devínsky Ferdinand , Gorrod John W
Published: April 2011

The metabolic N-oxygenation of nine long chain N,N-dimethylalkylamines and tri-n-butylamine has been studied using hepatic microsomal homogenates from mice, dogs and guinea-pigs. The relative oxidizability of amines (ROA) was correlated with structure, lipophilicity and nucleophilicity parameters of substrates and corresponding amine oxides formed in this biological reaction. The highest conversion of amines to N-oxides was found with male guinea-pig, followed by dog (male, female) and the lowest amount of amine oxides has been produced with male mice microsomal homogenates. The analyses were carried out by GLC and the results quantified using QSAR methodology. ROA is parabolically dependent upon structure and physicochemical properties of the substrates and products which was proved by the high statistical significance of the regression equations. The biological N-oxygenation of these amines is controlled by lipophilicity, stereochemistry and electronic effects.
Doxorubicin is a potent inhibitor of interleukin 1 induced cartilage proteoglycan resorption in-vitro
Authors: Rainsford K D
Published: April 2011

Since interleukin 1 (IL-1) induces the transcriptional synthesis of enzymes responsible for cartilage resorption it was decided to examine the effects of the antitumour drug, doxorubicin, a DNA transcriptional inhibitor, on αIL-1-induced cartilage—resorption in-vitro. Doxorubicin inhibited the resorption in a concentration-dependent fashion, an effect which was shown to be reversible. Fine structure of the chondrocytes was preserved by the doxorubicin treatment with IL-1 in contrast to the extensive cellular destruction evident in cartilage treated with IL-1 alone. [14C]doxorubicin was bound to cartilage proteoglycans, and this effect was promoted by treatment of the cartilage with IL-1. This binding of the drug may prevent access of the proteoglycans to destructive enzymes during the resorptive process induced by IL-1.
Difference spectrophotometric assay of nitrazepam in tablet formulations
Authors: Davidson A G , Li H W
Published: April 2011

A difference spectrophotometric procedure is described for the assay of nitrazepam in tablet formulations. The method is based on the measurement of absorbance at 282 nm of a solution of the tablet extract in 0·1 M hydrochloric acid (pH 1) relative to that of an equimolar solution in 0·1 M sodium hydroxide (pH 13). The method is precise and selective for nitrazepam in the presence of the tablet excipients and 2-amino-5-nitrobenzophenone, the principal hydrolysis product of nitrazepam. The absence of a constant isosbestic point in the difference spectrum of nitrazepam during hydrolysis in alkaline solution indicates the presence of a previously unrecognized intermediate hydrolysis product.
SK&F 93574, a histamine H2-receptor antagonist, releases histamine in the dog
Authors: Jones C A , Conybeare G , Mortensen A , Catto L C , Atterwill C K
Published: April 2011

This study was designed to establish whether SK&F 93574 releases histamine in dogs. Three female beagle dogs each received single infusions (on separate days) of each of SK&F 93574 (2·5 mg kg−1), polyvinylpyrrolidone (PVP, 20 mg kg−1) and sterile saline. The treatments were given at 14 day intervals by rapid intravenous infusion at 0·5 mL kg−1 min−1 for 2 minutes. Dogs showed clinical signs of histamine release such as vasodilation, licking lips, head drooping and increased gut movement after treatment with the known histamine releaser PVP or the test compound SK&F 93574. These signs were of similar severity and duration for the two compounds. No such changes were observed when the dogs received vehicle alone. Treatment with PVP or SK&F 93574 also resulted in markedly elevated plasma histamine concentrations (> 10-fold increase over control). It is concluded that intravenous administration of SK&F 93574 to dogs is associated with histamine release.
Effects of the Mechanical Energy of Multi-tableting Compression on the Polymorphic Transformations of Chlorpropamide
Authors: Otsuka Makoto , Matsumoto Takahiro , Kaneniwa Nobuyoshi
Published: April 2011

The effects of the mechanical energy of tableting compression on the polymorphic transformation of chlorpropamide have been examined. A single-punch eccentric tableting machine with a load cell and a non-contact displacement transducer were used to measure compression stress, distance and energy. An amount of 100 mg of the stable form A or the meta-stable form C of the drug was loaded into the press and the sample compressed with a compression stress of 196 MPa at room temperature (20°C). The compression cycle was repeated from 1 to 30 times. The powder X-ray diffraction profiles of the deagglomerated compressed sample powder were measured to calculate the polymorphic content. The results on forms A and C suggested that both forms were transformed into each other in the solid state by mechanical energy during tableting. The contents of forms A and C reached equilibrium at a constant value above 100 J g−1 of compression energy after more than 10 cycles. After 30 tableting cycles of forms A and C., the contents of A, C and the non-crystalline solid were almost constant at about 45, 25 and 30%, respectively. The compression energies were estimated to be about 500–600 J g−1. From the results it seems that the transformation mechanism of forms A and C during tableting were as follows. The crystal form of A or C was converted to a non-crystalline solid by the mechanical energy, and the solid was then transformed into form A or C.
Thermodynamics of the Binding of Phenothiazines to Human Plasma, Human Serum Albumin and α1-Acid Glycoprotein: A Calorimetric Study
Authors: Aki Hatsumi , Yamamoto Magobei
Published: April 2011

A flow microcalorimetric study has been carried out to investigate the interactions between phenothiazine derivatives and human plasma, human serum albumin (HSA) and α1acid glycoprotein (AGP) at pH 7·4 and 37°C. The direct analyses of enthalpic titration curves allowed the determination of the binding enthalpy change (δH), the apparent binding constant (K), and the number of the binding sites (n), as well as the evaluation of the apparent free energy (δG), and entropy (δS) changes. The overall binding of phenothiazines was exothermic with negative δH, which was compensated for by changes in δS. The values of δG were relatively insensitive to variation in the molecular details of the binding reaction. HSA possessed two classes of binding sites for phenothiazines. The first (n1 = 1), with high affinity (K1 = 105–106 M−1) was characterized by small negative δH and positive δS values due to hydrophobic interaction. The second class of sites had a low affinity (K2 = 103-104 M−1) and high capacity (n2 = 3–8) and contributed to the negative δH and δS values. The binding and thermodynamic parameters were influenced by the aliphatic side chain moieties on the phenothiazine nucleus. On the other hand, the drugs were bound to AGP at a single common binding site with a binding affinity of the order of 104M−1, characterized by negative δH and δS values, which partially reflected the effect of a van der Waals' interaction. In plasma the drugs were bound as a result of an enthalpy-driven type of reaction having large negative δH and a large binding capacity resulting from the presence of AGP and HSA.
Use of Strips Containing Tetracycline Hydrochloride or Metronidazole for the Treatment of Advanced Periodontal Disease
Authors: Deasy P B , Collins Augusta E M , Maccarthy Denise J , Russell R J
Published: April 2011

Strips containing tetracycline hydrochloride or metronidazole 25% in polyhydroxybutyric acid as a biodegradable polymer matrix, showed sustained release in simulated gingival fluid pH 6·6 at 37°C. When evaluated in patients suffering from advanced periodontal disease, the greatest response to therapy was observed with tetracycline hydrochloride strips inserted into periodontal pockets at four-day intervals for 16 days, compared with an untreated control group. A reduction in plaque index, gingival index and pocket depth was observed. A favourable alteration occurred in the microbial flora of treated pockets with an increase in the proportion of cocci and decrease in gram-negative rods, fusiforms and spirochetes. Metronidazole strips or root-planing tended not to be as effective. The clinical improvement produced by each treatment was not maintained when treatment was terminated.
The influence of changes in buccal potential difference on the buccal absorption of propranolol
Authors: Hitoglou-Makedou A , Hedges A , Turner P
Published: April 2011

A buccal potential difference (b.p.d.) exists across the mucous membrane of the mouth, which can be made less negative by contact with aspirin. The influence of changing the b.p.d. with aspirin on the buccal absorption of propranolol from a series of buffers of pH5–10 has been studied in eight volunteers. The study confirmed that the buccal absorption of propranolol was markedly pH dependent, but pretreatment of the buccal membrane with aspirin had no influence on the absorption of propranolol.
α1-Adrenoceptors: the ability of various agonists and antagonists to discriminate between two distinct [3H]prazosin binding sites
Authors: Hanft G , Gross G , Beckeringh J J , Korstanje C
Published: April 2011

Recently, it has been demonstrated that two distinct α1-adrenoceptor binding sites showing high and low affinity for WB-4101 (2-(2,6-dimethoxyphenoxy)ethyl-aminomethyl-1,4-benzodioxane) and 5-methyl-urapidil can be distinguished. In the present study we examined the ability of several agonists and antagonists to discriminate between these α1-adrenoceptor binding sites. [3H]Prazosin binding to membranes of rat liver, heart, cerebral cortex and hippocampus was inhibited monophasically by butanserine, I-BE 2254 (2-(3-(4-hydroxy-3-iodophenyl)ethylaminomethyl)tetralone-hydrochloride), prazosin, rauwolscine and verapamil. In contrast, competition curves of adrenaline, oxymetazoline, amidephrine and YM-12617 (5-[2-[[2-(o-ethoxy-phenoxy)ethyl]-amino]propyl]-2-methoxybenzenesulfonamide HCl)were best described by a model of two binding sites. Chloroethylclonidine (CEC), a compound shown to irreversibly eliminate binding sites with low affinity for WB-4101, increased the proportion of high affinity binding sites for oxymetazoline and amidephrine, whereas the binding data for prazosin and adrenaline remained unchanged. These results indicate that amidephrine, oxymetazoline and YM-12617, but not the other drugs tested discriminate between different α1-adrenoceptor recognition sites labelled by [3H]prazosin.
Assessment of topical non-steroidal anti-inflammatory drugs
Authors: Poelman M C , Piot B , Guyon F , Deroni M , Leveque J L
Published: April 2011

A new non-invasive technique for assessing the efficacy of topical non-steroidal anti-inflammatory drugs (NSAID) in man is proposed. The NSAID are initially applied to the skin under occlusion before inflammation is induced by a methyl nicotinate solution. The inflammatory response is quantified in terms of cutaneous blood flow by a laser Doppler velocimeter (LDV). The efficacy of NSAID preparations is calculated by comparing the responses of the LDV to the methyl nicotinate challenge on the pretreated and the non-treated skin sites. This protocol has been used to investigate the effect of three different NSAID preparations (indomethacin, niflumic acid, palmitoyl collagenic acid) and the influence of the vehicle on the efficacy of indomethacin. The three preparations tested gave positive results but with different amplitudes in response. The efficacy of indomethacin varied with the vehicle used.
Amino acids dilate resistance blood vessels of the perfused rat mesentery
Authors: Al-Swayeh O A , Moore P K
Published: April 2011

The vasodilator effect of several L-amino acids in the perfused, noradrenaline-preconstricted rat mesentery preparation has been investigated. N-α-Benzoyl-L-arginine ethyl ester (BAEE) (ED50, 1·4 ± 0·09 μmol) and L-alanine methylester (ED50, 0·9 ± 0·007 μmol) were the most potent although L-arginine methylester, hydroxamate and hydrochloride, N-α-benzoyl-L-arginine methyl ester (BAME), L-methionine methylester, L-lysine hydroxamate and L-glutamic acid methylester exhibited similar potency with ED50 values in the range 2·4–3·7 μmol. L-Homoarginine chloride was inactive at doses up to 20 μmol. D-Arginine hydrochloride and D-lysine hydroxamate were inactive at doses up to 50 μmol whilst D-methionine methylester (50 μmol) produced small falls in perfusion pressure in only 3 out of 7 preparations studied. Responses to BAEE, BAME, L-arginine hydrochloride, L-alanine methylester, L-methionine methylester, L-lysine hydroxamate and acetylcholine (but not nitroprusside) were significantly inhibited by CHAPS (4·7 mg mL−1, 30 s) de-endothelialization as well as pretreatment of mesentery preparations with gossypol (3 μM). Responses to BAEE, BAME, L-arginine hydrochloride, L-alanine methylester and acetylcholine were similarly selectively reduced by NDGA (10 μM) pretreatment. We propose that these L-amino acids exhibit vasodilator activity in the perfused rat mesentery by virtue of releasing endothelium-derived nitric oxide (EDNO).
An improved formulation of chloroquine for intramuscular administration: absorption kinetics in rabbits
Authors: Prakongpan S , Sirimai S , Edwards G , Mcgrath C S , White N J
Published: April 2011

Intramuscular chloroquine is rapidly absorbed, even in severe falciparum malaria, and may cause potentially lethal hypotension. Less rapidly absorbed formulations should be safer. A chloroquine phosphate solution containing 2% methylcellulose 1500 released chloroquine 2·6 times more slowly than a commercial aqueous solution in an in-vitro absorption simulator. There was a log linear relationship between viscosity and release rate. The absorption pharmacokinetics of the more viscous chloroquine phosphate solution were then compared with those of a commercial solution after intramuscular injection to eight rabbits in an open cross over comparison. The rate of absorption was over three times slower with the viscous solution; median time to peak whole blood concentration with the commercial aqueous solution was 10 (range 5–20) min compared with 30 (range 10–60) min for the more viscous formulation (P < 0·05). Peak whole blood concentrations were 66% (95% CI 50–82%) of those with the commercial preparation, but the acute bioavailability of the two solutions was similar. This simple new formulation may be safer than currently available chloroquine preparations and should now be evaluated in man.
Studies on the effects of omeprazole on thyroid function in the rat
Authors: Atterwill C K , Brown C G , Fowler K L , Jones C A
Published: April 2011

The effects of omeprazole (an H+, K+-ATPase inhibitor) on thyroid parameters in rats have been examined. SK&F Wistar rats were dosed orally with omeprazole (up to 500 mg kg−1) or vehicle. Treatment for 7 or 14 days resulted in generally decreased plasma T3 concentrations in males (with little change or slight increases in females) and increased serum TSH concentrations (22%–68% increases). No changes were detected in thyroid 125I uptake or organification. Liver 5′-deiodinase activity was decreased in male rats after 7 days treatment. Thyroxine clearance was not altered after a single dose of omeprazole. In-vitro studies showed omeprazole to be only a weak inhibitor of TSH-stimulated 125I organification in cultured porcine thyrocytes. It is concluded that omeprazole has weak effects on the pituitary-thyroid-liver axis, its main action being to inhibit the peripheral deiodination of thyroid hormones.
The In-vitro pH-Dissolution Dependence and In-vivo Bioavailability of Frusemide-PVP Solid Dispersions
Authors: Doherty C , York P
Published: April 2011

The dependence of the dissolution rate on the pH of the buffered medium, using constant surface area discs, has been examined for crystalline frusemide, a semi-crystalline frusemide-polyvinylpyrrolidone (PVP) solid dispersion and an X-ray amorphous frusemide-PVP dispersion. The marked changes observed in the pH-dissolution profiles indicate that differing dissolution mechanisms operate in the amorphous regions. This conclusion was further supported by the comparison of pH-dissolution and pH-equilibrium solubility profiles that suggested a supersaturation effect to be the relevant term in describing the dissolution enhancing effects of amorphous regions. A marked dissolution enhancement, relative to crystalline frusemide, was shown by the X-ray amorphous solid dispersion in weakly acidic solutions. A similar effect was observed in the dissolution characteristics of gelatin capsule formulations in simulated gastric and intestinal media. In a human bioavailability study, the X-ray amorphous frusemide-PVP solid dispersion exhibited a significant reduction in the time for maximum effect in comparison to crystalline frusemide and a semi-crystalline solid dispersion. This effect, demonstrated by the primary end organ response in seven healthy subjects, concurred with the in-vitro prediction of dissolution enhancement in weakly acidic media.
Topical Application of Penetration Enhancers to the Skin of Nude Mice: a Histopathological Study
Authors: Lashmar Ulla T , Hadgraft Jonathan , Thomas Norman
Published: April 2011

Eighteen potential penetration enhancers, some at concentrations that might be used for that purpose, have been examined to evaluate their irritancy potential on nude mouse skin. A biopsy technique was employed followed by histological examination. Up to 50% glycerol, 10% hydroxyethyl lactamide (HELA), 10% oleyl alcohol, 10% Solketal, 10% glycofurol, 100% tetrahydrofurfuryl alcohol (THFA) and 10% urea induced no discernible change in the histological appearance of the skin whereas 100% dimethyl sulphoxide (DMSO), 100% dimethyl formamide (DMF), 100% N-methyl-2-pyrrolidone, 10% Azone, 10% oleic acid, 10% methyl laurate, 10% benzyl alcohol and 10% glycerol formal caused severe skin irritation.
Thermodynamics of the binding of salicylate to human serum albumin: evidence of non-competition with imidazole
Authors: Matias I , Ceballos A , Gonzalez-Velasco F , Cachaza J M
Published: April 2011

The thermodynamic characteristics of the binding of salicylate to human serum albumin have been studied using a technique based on the variation of the quantum yield of fluorescence of salicylate when it binds to the protein. The binding constants, number of sites and the values of ΔG°, ΔH° and Δ° were determined. The results are consistent with a model that proposes two equal and independent types of binding site with a predominantly ionic interaction and an important hydrophobic contribution in one of the sites. The technique was also used to demonstrate that imidazole and salicylate (that can be found simultaneously in plasma following administration of imidazole-2-hydroxybenzoate) do not compete for the same binding sites on the protein.
Enhancement of phenytoin binding to tissues in rats by heat treatment
Authors: Kato Yoshiteru , Hirate Junji , Sakaguchi Kazuo , Horikoshi Isamu
Published: April 2011

Phenytoin binding to heat-treated tissue homogenates has been examined to characterize the phenytoin binding to tissues. The binding to the heat-treated tissue homogenates was enhanced in all tissues studied compared with controls. The heating might produce the changes in conformation of proteins in tissues and then enhance phenytoin binding to tissue homogenates.
Effect of some penicillins on the sensitivity of limulus amoebocyte lysate test
Authors: Al-Khalifa Issa J , Naidu N V , Nallari V R , Raut H I
Published: April 2011

A group of penicillins have been tested for their effect on the sensitivity of limulus amebocyte lysate test (LAL). Cloxacillin, cephalothin and cefuroxime inhibited the gel formation at concentrations above 2 mg mL−, while ampicillin, methicillin and mecillinam showed no inhibitory effects upto concentrations of 10 mg mL−1. For benzylepenicillin the maximum non-inhibitory concentration was 10,000 units mL−1. However, the dilutions required to overcome inhibition were within the limits of maximum valid dilutions computed for each product showing that LAL test is valid for these products at their non-inhibitory concentrations.
Determination of cephalosporin-C amidohydrolase activity with fluorescamine
Authors: Reyes F , Martinez M-J , Soliveri J
Published: April 2011

A spectrophotometric procedure for the assay of cephalosporin-C amidohydrolase activity, based on the determination of the 7-aminocephalosporanic acid (7-ACA) produced in the hydrolysis of cephalosporin-C by the enzyme, is described. This procedure can be used to detect 7-ACA over a range of 10 to 200 μg mL−1. The same method can be used as a fluorometric procedure with a 100-fold greater sensitivity. At pH 4·5 7-ACA produces a strong fluorophor with fluorescamine, detectable spectrophotometrically at 378 nm and fluorometrically at an excitation of 378 nm and emission of 495 nm. At this pH the fluorophors formed with cephalosporin-C, proteins and aminoadipic acid present minimal absorbance values. The conditions for maximal detection of 7-ACA in the presence of proteins, cephalosporin-C and aminoadipic acid have been determined.
The Effect of Some Preservatives Used in Nasal Preparations on Mucociliary Clearance
Authors: Batts A H , Marriott C , Martin G P , Bond S W
Published: April 2011

The effect of methyl-ρ-hydroxybenzoate, propyl-ρ-hydroxybenzoate, chlorbutol, chlorocresol, EDTA, benzalkonium chloride, chlorhexidine, phenylmercuric nitrate and phenylmercuric borate on mucociliary transport rate of the frog palate has been examined. Following a variable number of applications all these preservatives halted transport, the first three reversibly. However, applications of thiomersal (0·01%) were well tolerated. The frog palate possesses a ciliated epithelium protected by mucus, since some of our findings are at variance with those previously reported results where the protective effect of mucus was negligible in the in-vitro model (usually trachea) employed, it would appear that the contribution of mucus to effective mucociliary clearance should not be underestimated.
Phorbol Esters of Different Biological Activities May Preferentially Act as Mitogens of Human Suppressor T-Cells and are Equi-effective Mitogens of IL-2 Dependent Cells
Authors: Edwards Mary C , Tudor Evans A , Evans Fred J
Published: April 2011

The actions of tetradecanoylphorbolacetate (TPA) and 12-deoxyphorbolphenylacetate-20-acetate (DPPAA) together with a phytohaemagglutinin (PHA) have been examined on the proliferative responses of human mononuclear cells (MNC) depleted of specific cell subsets by the use of monoclonal antibodies. PHA-induced proliferation was found to be reduced when monocytes/macrophages and T-helper cells were depleted from MNC, but enhanced compared with MNC responses when T-suppressor cells were depleted. In contrast, TPA- and DPPAA-induced proliferation was unchanged or slightly enhanced following macrophage/monocyte depletion, and whereas TPA-induced proliferation was largely independent of subtype constitution, the non-tumour promoting DPPAA appeared to selectively enhance proliferation of the T8+ suppressor subset. Indomethacin increased the proliferative MNC responses of phorbol esters whilst having little effect upon the PHA response, an effect antagonized by addition of PGE2. The addition of interleukin-2 (IL-2) increased the proliferative response, as well as resistance to inhibition induced by cyclosporin A and dexamethasone and partially abolished the selective actions of DPPAA and PHA. In IL-2 dependent cultures PHA induced stimulation was more sensitive to inhibition by cyclosporin than were the phorbol esters. The results suggest that, although induction of lymphocyte proliferation by phorbol esters is not a correlate for tumour promotion itself, non-promoting phorbol esters may have a more restricted ability to induce proliferation than TPA.
Effects of Urapidil on Catecholamine Turnover and Release in the Central Nervous System of the Rat
Authors: Singer Ernst A , Cichini G , Valenta B , Kraupp O
Published: April 2011

The actions of urapidil, prazosin, idazoxan, and haloperidol on the turnover of noradrenaline in the hypothalamus and dopamine in the nucleus accumbens of the rat were investigated using changes in the ratios of 3-methoxy-4-hydroxyphenyl-glycol/noradrenaline (MHPG/NA) and 3,4-dihydroxyphenylacetic acid/dopamine (DOPAC/DA), respectively, as measures for drug-induced effects. Urapidil (2·5–30 mg kg−1 i.v.) increased the ratios of MHPG/NA and DOPAC/DA. Its effects on NA turnover were maximal at 60 min (160% of control at 30 mg kg−1), and on DA turnover at 30 min (138% of control at 30 mg kg−1). Prazosin (0·5–2·5 mg kg−1 i.v.) had no effect, but the high dose of 5 mg kg−1 i.v. significantly increased the ratio of MHPG/NA in the hypothalamus. Idazoxan (2–50 mg kg−1 i.v.) and haloperidol (0·02–0·5 mg kg−1 i.v.) selectively enhanced turnover of NA and DA, respectively. In experiments on field-stimulated overflow of tritium from slices of hypothalamus and nucleus accumbens labelled with [3H]NA or [3H]DA, respectively, urapidil (1 μmol L−1) facilitated the evoked responses in both regions. Prazosin (0·1 μmol L−1) had no effect in either of the two areas. Idazoxan (0·1 μmol L−1) increased stimulated overflow of [3H]NA from the hypothalamus but not of [3H]DA from the nucleus accumbens. Conversely, haloperidol (0·1 μmol L−1) greatly enhanced evoked overflow of [3H]DA but not of [3H]NA. From the present results it is concluded that urapidil has an antagonistic effect at central α2-adrenoceptors and also a weak antagonistic action at central dopamine D2-receptors.
Non-linear Intestinal Absorption Kinetics of Cefadroxil in the Rat
Authors: Sánchez-Picó Antonio , Peris-Ribera José-Esteban , Toledano Coral , Torres-Molina Francisca , Casabó Vicente-Germán , Martín-Villodre Adela , Plá-Delfina José M
Published: April 2011

Absorption of Cefadroxil in a selective intestinal absorption area (the proximal third of the small intestine) of the anaesthetized rat, at seven initial perfusion concentrations, ranging from 0·01 to 10·0 mg mL−1, is shown to be a non-linear transport mechanism. With the aid of computer-fitting procedures based on differential and integrated forms of Michaelis-Menten equation, Vm and Km values of 36·7–37·3 mg h−1 and 12·0–13·0 mg, respectively, were found. The statistical parameters were better than those obtained both for first-order and for combined Michaelis-Menten and first-order kinetics. There is no evidence for substantial passive diffusion processes. The results reported here, together with allometric considerations and literature data analysis, may help to explain some particular non-linear features of plasma level curves associated with the administration of fairly high oral doses of Cefadroxil to humans.
The transport of microspheres from the gastro-intestinal tract to inflammatory air pouches in the rat
Authors: Alpar H O , Field W N , Hyde R , Lewis D A
Published: April 2011

The distribution of latex microspheres (1·1 μ diam) has been investigated in-vivo, as a potential passive targeted system for the treatment of inflammation. Microspheres administered orally were found in the circulation and in inflamed tissues and exudates of inflammatory air pouches in rats. Oral absorption was also found in a rabbit. Particles administered directly into the circulation also penetrated into the air pouch tissues and fluids. The possibility of using microspheres as a passive targeted system for the treatment of inflammation is discussed.
Sustained release ophthalmic formulations of pilocarpine
Authors: Deshpande S G , Shirolkar Satish
Published: April 2011

The bioavailability of drugs from conventional ophthalmic formulations is low. To optimize the therapy, sustained release ophthalmic dosage forms are warranted. Hydrogels such as sodium-carboxymethyl cellulose, hydroxypropylmethyl cellulose, Carbopol-940, Carbopol-941 and Lutrol-FC-127 increase the duration of action of various drugs. Gels containing pilocarpine were prepared and evaluated by measuring the intensity and duration of miotic response in albino rabbits. Carbopol-940 gels, being the best of those used, were studied further for the effect of its concentration and of additives (benzalkonium chloride, phenylmercuric nitrate, chlorbutol and disodium edetate), autoclaving at 121°C for 30 min and irradiation with gamma rays (2·5 Mrad), on the end product.
Comparative effects of ouabain on isolated papillary muscle from tree shrews, guinea-pigs and rats
Authors: Koga Takaki , Shiraki Yasuyuki , Sakai Kazushige
Published: April 2011

Inotropic effects of ouabain were investigated in the isolated papillary muscle preparations of the tree shrew (Tupaiaglis), guinea-pigs and rats. In the guinea-pig and shrew papillary muscles, ouabain at concentrations of 10−8 to 3 × 10−7 M caused a concentration-dependent positive inotropic response in a similar magnitude, while in the rat, ouabain at concentrations of 10−7 to 3 × 10−6 M elicited negative inotropic one. Either phentolamine or pindolol in a concentration sufficient to block the α- and β-adrenoceptors did not antagonize the positive inotropic effect of ouabain in the papillary muscle preparation of the shrews.
Nasal absorption of 17α-ethinyloestradiol in the rat
Authors: Bawarshi-Nassar R N , Hussain A , Crooks P A
Published: April 2011

The bioavailability of 17α-ethinyloestradiol was determined after intravenous, nasal, and intraduodenal, administration in the rat. The results showed that the bioavailability of nasally-administered and intraduodenally-administered drug was 80–85, and 15–25%, respectively, of that following intravenous administration. The study demonstrates that the nasal route for the administration of 17α-ethinyloestradiol is superior to the oral route in this species, and may thus provide an alternative for the administration of this drug at lower doses.
Inhibition of Na+, K+ -ATPase Activity by Phospholipase A2 and Several Lysophospholipids: Possible Role of Phospholipase A2 in Noradrenaline Release from Cerebral Cortical Synaptosomes
Authors: Nishikawa Takashige , Tomori Yuichi , Yamashita Sukehide , Shimizu Shin-Ichiro
Published: April 2011

p-Bromophenacyl bromide (PBPB), quinacrine and indomethacin, which inhibit phospholipase A2 (PLA2; EC 3.1.1.4) activity in several tissues, caused a dose-dependent inhibition of prelabelled [3H]noradrenaline ([3H]NA) release evoked by high concentrations of K+ from rat cerebral cortical synaptosomes. Release of prelabelled [3H]NA was caused by natural lysophosphatidic acid (LPA; 10−6-10−5 gmL−1) and lysophosphatidylcholine (LPC; 10−6-10−5 g mL−1) and synthetic LPA (6 × 10−6, 2 × 10−5 M) and LPC (6 × 10−6, 2 × 10−5 M), but not by natural lysophosphatidylserine (LPS; 10−5 g mL−1), lysophosphatidylethanolamine (LPE; 10−5 g mL−1) and lysophosphatidylinositol (LPI; 10−5 g mL−1). The release evoked by natural LPA and LPC could be inhibited only marginally by PBPB and quinacrine. Phosphatidic acid (PA)-specific and phosphatidylcholine (PC)-specific PLA2 activities from rat cerebral cortical synaptosomes were stimulated in incubation medium containing high concentrations of K+ or calcium ionophore A23187. Low concentrations of PLA2 (10−6–10−8 g mL−1, from bee venom) inhibited the synaptic membrane Na+, K+-ATPase activity in incubation media with intracellular levels of free Ca2+. Several lysophospholipids (LPLs), metabolites of the PLA2 type, also inhibited the synaptic membrane Na+, K+-ATPase activity in a dose-dependent manner. The minimum effective concentrations of natural LPA, LPC, LPS, LPI and LPE were 10−6, 4·7 × 10−6, 10−5,4·7 × 10−5 and 4·7 × 10−5 g mL−1, respectively. These results suggest that PLA2 and/or its metabolites, LPLs, especially LPA and LPC, may play partial roles in the depolarization and/or release of noradrenaline through their inhibitory action on the Na+, K+-ATPase activity in the brain.
Involvement of Sialic Acid in High-affinity Binding of Quaternary Ammonium Compounds by Brush Border Membrane from Rat Intestine
Authors: Saitoh Hiroshi , Ebina Mikiko , Fukuda Seiko , Iseki Ken , Miyazaki Katsumi , Arita Takaichi
Published: April 2011

As one approach to clarify the absorption mechanisms of quaternary ammonium compounds (QACs), their binding characteristics have been studied using brush border membrane vesicles isolated from rat small intestine and liposomes composed of phospholipid and GM3 ganglioside. The binding of propantheline was significantly decreased when the vesicles were pretreated with neuraminidase. Propantheline and methochlorpromazine bound to the liposomes, the binding for the latter drug being significantly greater than that for propantheline. When GM3, isolated from rat small intestine, was incorporated into the liposomes their binding capacity for both drugs increased significantly. It is suggested that the binding of QACs to the lipid layer and sialic acid play a role in the high binding of drugs to the intestinal brush border membrane. Furthermore, a sensitive and reproducible high-performance liquid chromatographic method for sialic acid has been developed.
Assignment of the C-5 configuration of penicilloic acids
Authors: Bird A E , Cutmore E A
Published: April 2011

Penicilloates prepared by the method of Munro et al (1978) were examined by nuclear magnetic resonance spectroscopy and optical rotation to assign the configuration at C-5. The configuration was 5S for carbenicillin and ticarcillin penicilloates and 5R for the other seven penicilloates examined. The chemical shift and coupling constants of 5-H and 6-H showed consistent differences between the isomers and the optical rotation of the 5R- isomers is consistently more positive than that of the corresponding 5S-isomer.
Solute adsorption and concentration-dependent permeability in certain polymer films
Authors: Okor R S
Published: April 2011

Certain parameters (solute adsorption, permeability and swellability) of films of a cationic acrylatemethacrylate copolymer have been determined as functions of the solute (sulphacetamide sodium) concentrations. Both permeability coefficients and the free (unadsorbed fraction of solute increased almost proportionately during increase in solute concentration 1–5%, above 5%, further increase in the fraction of free solute was slight, while the permeability coefficients decreased slightly. The solute also reduced film swellability but the observed concentration-dependent permeability related more to the adsorption phenomenon.
The Effect of Gelatin Grade and Concentration on the Migration of Solutes Into and Through Glycerogelatin Gels
Authors: Gebre-Mariam Tsige , Armstrong N Anthony , Brain Keith R , James Kenneth C
Published: April 2011

The diffusion of 4-hydroxybenzoic acid and phenobarbitone through glycerogelatin gels was found to be independent of the type of gelatin used. Three types of gelatin, two acid-processed and one alkali-processed were studied, and the bulk viscosities of gels prepared from them was seen to vary considerably. However, the microviscosities of the gels, as measured by ESR, showed no significant differences. Thus microviscosity was the factor governing diffusion. Gelatin concentration in aqueous solutions without glycerol influenced microviscosity and hence diffusion. This is believed to be caused by dissolution of water-soluble fractions of the gelatin. Interstices in the gelatin matrix, though reduced in size when gelatin concentration is raised, are still too large to act as physical barriers to diffusing molecules. It is suggested that hydrated gelatin forms the matrix of glycerogelatin mixtures and that the interstitial fluid, through which migration occurs, consists almost entirely of glycerol and water.
Vascular Smooth Muscle Function in Rats with Acute Renal Failure
Authors: Douglas S A , Bowmer C J , Yates M S
Published: April 2011

Vascular smooth muscle function in rats with glycerol-induced acute renal failure (ARF) was investigated by recording both the contractile responses of portal vein segments and the relaxant responses of aortic ring preparations. The portal veins from rats with ARF showed depressed contractile responses to the (α1-agonist methoxamine, the α2-agonist B-HT 920 and to the calcium agonist BAY K 8644 when compared with controls. Both isoprenaline and nitroprusside produced 100% reversal of KCl induced tone in control aortic rings but in rings from rats with ARF complete reversal of tone could not be obtained with either dilator drug. It is suggested that a defect in mitochondrial function and hence energy supply may account for the diminished ability of vascular preparations from rats with ARF to constrict and relax.
Interactions of Apomorphine and a Novel Neuroleptic Dibenzodioxazocine Derivative, as Evidenced by Changes of Somato-autonomic Reflexes and Spontaneous Sympathetic Activity in Cats
Authors: Dóda Margit
Published: April 2011

The apomorphine-antagonistic effects of EGYT-2509, a novel neuroleptic compound, has been studied by two different methods suitable for investigating the dopaminergic modulation of sympathetic output. (1) In cats lightly anaesthetized with urethane (600 mg kg−1 i.p.), blood pressure (BP) reflexes evoked by electrical stimulation of the sciatic nerve were inhibited by apomorphine (0·2 mg kg−1 i.v.) at low frequencies of stimuli (2–8 Hz), while the BP reflexes were facilitated by apomorphine at higher frequencies of stimulation; the evoked contractions of the nictitating membrane were depressed in the entire range of frequencies applied. EGYT-2509 (1·5 mg kg−1 i.v.) antagonized both the inhibition and facilitation of pressor reflexes induced by apomorphine. EGYT-2509, given alone, in doses exceeding 1·5 mg kg −1 either did not influence or inhibited the responses of nictitating membrane and of BP; the inhibition could be antagonized by haloperidol. The apomorphine-induced sustained hypotension was inhibited by EGYT-2509 (18·5 mg kg−1): after EGYT-2509, higher doses of apomorphine (0·7 vs 0·2 mg kg−1) were required for the effect. Sustained hypotension could be elicited by EGYT-2509, too; after apomorphine, smaller doses of EGYT-2509 (8·5 vs 18·5 mg kg−1) were enough to decrease BP. (2) In cats anaesthetized with chloralose and urethane (50 and 400 mg kg−1 i.p., respectively), apomorphine (0·2 mg kg−1) inhibited the spontaneous activity of the postganglionic renal sympathetic nerve. EGYT-2509 (<1 mg kg−1) and chlorpromazine (0·2-0·5 mg kg−1) failed to antagonize the apomorphine-induced inhibition. Haloperidol (0·4 mg kg−1), however, restored the renal nerve activity. All three compounds, EGYT-2509, chlorpromazine and haloperidol, themselves, inhibited the sympathetic discharges. The results indicate that EGYT-2509, in addition to its potent anti-apomorphine activity, possesses some apomorphine-like features, too.
Repeated Administration of Antidepressants Enhances Agonist Affinity for Mesolimbic D2-Receptors
Authors: Klimek Violetta , Maj Jerzy
Published: April 2011

Studies have shown an increased responsiveness of the dopaminergic system after repeated administration of a variety of antidepressant drugs. In the present study, the effect of repeated administration (twice daily for 14 days) of imipramine and mianserin on the affinity of dopamine D2-receptors for quinpirole, a D2-agonist, and on the quinpirole-induced locomotor hyperactivity was examined in rats. Repeated doses of imipramine and mianserin increased the affinity of quinpirole for [3H]spiperone binding sites in membranes prepared from the limbic system but not the striatum. The locomotor hyperactivity induced by quinpirole was enhanced by chronic treatment with both antidepressants. The data indicate that the enhanced responsiveness of the dopaminergic system in rats, observed after chronic treatment with antidepressants, may result from an increased affinity of agonists at D2-receptors in the mesolimbic system.
High resolution electron microscopy study of sulphathiazole crystals
Authors: Luklinska Z H , Solanke O O , Summers M P
Published: April 2011

A high resolution electron microscopy study was undertaken on samples of sulphathiazole obtained by recrystallization at 0°C, 30°C and 70°C. Low magnification electron microscopy study of the crystals showed featureless morphology yet the resolved lattice images showed imperfections such as dislocations, lattice irregularities and regions of discontinuity.
Pharmacokinetic study of tempo carboxylic acid, a nitroxyl MRI contrast media, in control and streptozocin diabetic rats
Authors: Michel A , Fernandez J P , Subra G , Pull L , Bonnet P A
Published: April 2011

The pharmacokinetics of tempo carboxylic acid (TCA), a nitroxyl contrast medium have been evaluated in control and streptozocin-diabetic rats. Previous magnetic resonance imaging (MRI) studies in diabetic rats showed prolongation of contrast visualization in the renal cavities after injection of TCA. Diabetes induced only slight alterations to the pharmacokinetic parameters. Rate constants and half lives were unchanged after four months of diabetes. A significant decrease of the apparent total body clearance and volume of distribution was observed while the area under the curve was increased. These alterations are not sufficient to explain MRI abnormalities which have to be elucidated.
The protective mechanisms of paracetamol against ethanol-induced gastric mucosal damage in rats
Authors: Poon Y K , Cho C H , Ogle C W
Published: April 2011

The protective mechanisms of paracetamol against ethanol-induced gastric mucosal damage have been examined. The antiulcer action of subcutaneously (s.c.)-injected paracetamol, 250 mg kg−1, was attenuated by either subdiaphragmatic vagotomy or s.c. injection of N-ethylmaleimide, 10 mg kg−1. This attenuation was not seen in rats given paracetamol by the oral route (p.o.). Indomethacin pretreatment, 5 mg kg−1, did not influence the lesion-preventing action of paracetamol given s.c. or p.o. The findings suggest that the antiulcer effect of s.c.-administered paracetamol results from an action involving the vagal nerve and tissue sulfhydryls, but not prostaglandins. On the other hand, the protective mechanism of paracetamol p.o. is independent of the vagal system or tissue sulfhydryls and prostaglandins. It seems that paracetamol given p.o. exerts its antiulcer effect by acting directly on the mucosal cell to strengthen mucosal integrity.
Effects of metabolic inhibitors and incubation temperature on the saturable uptake of propranolol by isolated rat lung tissue
Authors: Iwamoto Kikuo , Watanabe Jun , Yonekawa Hina
Published: April 2011

The effects of several metabolic inhibitors (50 μM) on the initial uptake rate of propranolol (0·5 to 500 #mUg mL−1) by the minced lungs (0·4g) isolated from 7-week-old rats has been investigated in oxygenated, pH 7·4 Krebs-Ringer bicarbonate buffer solution (20 mL) containing 3% BSA at 37°C for 5 min. The effect of the incubation temperature was also examined. Metabolism of propranolol was almost insignificant (i.e. less than 1·3% of the initial load). The overall initial uptake rate was considered to be a combination of apparent linear transport and saturable processes. For the control uptake rate, the linear transport rate constant was 1·26 ± 0·16 g−1 mL−1 min−1, while Vmax and Km' of the capacity limited uptake process were estimated as 0·727 ± 0·074 mg g−1 min−1 and 24·8 ± 2·71 μg mL−1, respectively. No metabolic inhibitor tested had an effect on the linear transport rate of propranolol but 2,4-dinitrophenol and potassium cyanide inhibited saturable uptake rate (i.e. Vmax) of propranolol significantly (P<0·01) while ouabain, phloridine and iodoacetic acid did not do so significantly. Reduction of the incubation temperature to 15°C decreased and at 25°C tended to decrease, both linear transport and saturable uptake rates.
The effect of Miglyol 812 oil on the oral absorption of propranolol in the rat
Authors: Woolfrey S G , Palin K J , Davis S S
Published: April 2011

This work has examined the effect of Miglyol 812 oil and its composite fatty acids on the oral absorption of propranolol with reference to its intravenous (i.v.) pharmacokinetics. Propranolol hydrochloride, spiked with 4-3 H labelled compound, was administered i.v. or orally to male Wistar rats and blood concentrations of parent material determined by liquid scintillation counting after extraction into toluene. An i.v. dose-linearity study indicated dose-independent pharmacokinetics for propranolol at 1–2 mg kg−1, with a mean Cls, Vss, MRTi.v. and t0·5β of 0·076 L min−1 kg−1, 4·74 L kg−1, 57·81 min and 47·10 min, respectively. At 5 mg kg−1, there was evidence of non-linearity with MRTi.v. increased by about 250%, Vss by 170% and t0·5β by 230% compared with the lower doses. After oral administration of propranolol (10 mg kg−1) in aqueous solution, with or without Tween 80 (6%), the mean absorption time (MAT) and terminal half-life were approximately 55 min and 86 min, respectively. The MAT for propranolol administered in a 50% octanoic and lauric acid (1:1 by weight) oil-in-water emulsion, stabilized with 6% Tween 80 (129·90 min), was significantly longer compared with that for a 50% Miglyol 812 oil-in-water emulsion containing the same surfactant (16·55 min). The terminal half-life of propranolol administered in the fatty acid formulation (128·96 min), unlike that for the Miglyol emulsion (54·37 min), was significantly longer compared with that observed after i.v. administration (t0·5β = 47 min). The fraction available for propranolol was independent of formulation with mean values between about 16 and 24%. These results show that the absorption of propranolol in the fatty acid formulation was decreased possibly due to a reduced rate of gastric emptying.
The Inotropic Effect of 4−Aminopyridine and pH Changes in Rabbit Papillary Muscle
Authors: Shahid M , Rodger I W
Published: April 2011

The effects of 4-aminopyridine (4AP), and pH changes have been examined on tension responses and cyclic nucleotide levels in rabbit isolated right ventricular papillary muscles. 4AP augmented papillary muscle contractions in a concentration-dependent manner. However, this positive inotropic action was largely due to an increase in extracellular pH produced by 4AP, rather than an intrinsic activity of the drug. Increases in extracellular pH (from 5 to 9) produced graded and reproducible increases in contractile force which were not blocked by propranolol (1 ± 10−7M) but were inhibited by verapamil in a concentration-dependent manner. The positive inotropic effects of Ca2+ were enhanced and depressed by alkaline and acidic pH, respectively. Neither 4AP nor alkaline pH significantly changed cyclic AMP concentration in rabbit papillary muscles. The cyclic GMP content, however, was increased by 4AP only and this effect was blocked by atropine. The results suggest that the positive inotropic effect associated with a rise in pH from neutrality may be due to facilitation of translocation of membrane Ca2+ and/or to increase the release of Ca2+ from sources within the cell. They also illustrate that a major component of the inotropic effect of 4AP is a result of an increase in extracellular pH.