bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of non-ionic surfactants in a polyacrylic acid gel base on the rectal absorption of [Asu1,7]-eel calcitonin in rats
Authors: Morimoto Kazuhiro , Akatsuchi Hiroaki , Morisaka Katsuaki , Kamada Akira
Published: April 2011

The effect of non-ionic surfactants in a polyacrylic acid gel base on the rectal absorption of [Asu1,7]-eel calcitonin, a calcitonin analogue, was studied in rats. Absorption was enhanced by a microenema which used a polyacrylic acid gel base, but it was reduced by the incorporation of polysorbate 80 (0.1-5% v/v). The incorporation of polyoxyethylene 9 lauryl ether (0.1-5% v/v) in the polyacrylic acid gel base enhanced the absorption. Rectal administration in the base containing 0.5% v/v polyoxyethylene 9 lauryl ether required a dose of the calcitonin 2-3 times greater than an intramuscularly administered dose to achieve an equivalent hypocalcaemic effect.
Assessment of bioavailability of experimental single-unit sustained release tablets of verapamil hydrochloride using the stable isotope technique
Authors: Marvola Martti , Kannikoski Anneli , Taskinen Jyrki , Ottoila Pekka
Published: April 2011

A stable isotope technique has been used to assess the bioavailability of sustained release verapamil products. The test formulations were tablets with a core containing 90 mg of verapamil hydrochloride coated with ethylcellulose film, the permeability of which was controlled using different amounts of hydroxypropyl methylcellulose. A product containing ethylcellulose 75% hydroxypropyl methylcellulose 25% w/w gave a single-unit sustained release tablet of verapamil hydrochloride that allowed a dose interval of 24 h. There was no loss in bioavailability, even though verapamil had extensive first-pass metabolism.
Physicochemical characterization of the human nail: solvent effects on the permeation of homologous alcohols
Authors: Walters Kenneth A , Flynn Gordon L , Marvel John R
Published: April 2011

To assess how vehicles might influence permeation through human nail, the diffusion of homologous alcohols (methanol to decanol) administered as neat liquids through finger nail plate has been studied using in-vitro diffusion cell methods and compared with permeation data for the same compounds in aqueous media. Permeation rates of the homologous alcohols through lipid depleted nail plate have also been assessed and the influences of dimethylsulphoxide (DMSO) and isopropyl alcohol on permeation rates of methanol and hexanol have been examined. With the exception of methanol, permeability coefficients are uniformly about five-fold smaller when the alcohols are undiluted than when they are applied in water. Overall parallelism in the permeability profiles under these separate circumstances of application is an indication that the external concentrations of the alcohols themselves are a determinant of their permeation velocities through the nail plate matrix. The even separation of the profiles suggests a facilitating role of water within the nail matrix. Chloroform/methanol delipidization of the nail led to increased penetration rates of water, methanol, ethanol and butanol. On the other hand, it caused a six-fold decrease in the permeation rate of decanol. Application of methanol and hexanol in DMSO somewhat retards their rates of permeation. Isopropyl alcohol also slows the permeation rate of hexanol but has little influence on that of methanol. Thus it appears that solvents which tend to promote diffusion through the skin horny layer have little promise as accelerants of nail plate permeability.
The influence of native porcine gastric mucus gel on hydrogen ion diffusion: the effect of potentially ulcerogenic agents
Authors: Turner N C , Martin G P , Marriott C
Published: April 2011

Experiments were carried out to investigate the ability of native gastric mucus gels to retard hydrogen ion diffusion. Mucus held between two polycarbonate membrane filters in a diffusion cell, separating equimolar solutions of NaCl and HCl, significantly reduced the rate of hydrogen ion diffusion and increased the time for the mean hydrogen ion front to traverse the mucus compartment (lag time) when compared to an unstirred layer of saline (P <0.01). N-Acetylcysteine, sodium taurodeoxycholate and acetylsalicylic acid significantly increased the diffusion rate (P <0.025); the lag time was significantly reduced by N-acetylcysteine (P <0.001). In addition mucus gels were found to have buffering capacity at a pH > 2. These observations suggest that native gastric mucus gels can retard hydrogen ion diffusion and that this retardation of diffusion is reduced by agents which are potentially damaging to the gastric mucosa.
Detection of host-derived contaminants in products of recombinant DNA technology in E. coli: a comparison of silver-staining and immunoblotting
Authors: Gooding R P , Bristow A F
Published: April 2011

Contamination of medicines produced in E. coli by recombinant DNA methodology with host-cell proteins is considered a potential problem with this type of method. In this report techniques for the detection of trace quantities of host-cell proteins in SDS-gel electrophoretograms were examined. Detection of E. coli proteins by immunoblotting, using antisera raised in rabbits to lysates of E. coli, was compared with detection using the ultrasensitive silver stain. Silver staining detected a larger number of E. coli proteins in a one-dimensional electrophoresis system than did immunoblotting. Proteins that were markedly antigenic in the rabbit were detected at a greater sensitivity by the immunoblotting approach. Both techniques detected contaminant proteins in a preparation of methionyl human growth hormone produced in E. coli known to be contaminated with host-cell proteins. No contaminating proteins were seen by either technique in more rigorously purified preparations of growth hormone. A combination of these two approaches would provide useful evidence of purity of medicines produced by recombinant DNA technology, and is potentially applicable to a wide range of host-vector systems.
Metabolite inhibition of nitroglycerin metabolism in sheep tissue homogenates
Authors: Cossum Paul A , Roberts Michael S
Published: April 2011

The metabolism of nitroglycerin in sheep tissue homogenates has been examined using tritiated nitroglycerin and a HPLC separation procedure. Nitroglycerin was metabolized by liver, lung, muscle, arterial and venous tissue to its dinitrometabolites and subsequently to mononitroglycerin. Addition of the dinitrometabolites substantially inhibited the degradation of nitroglycerin in all tissue homogenates.
Effect of bile acids on the binding of drugs and dyes to human albumin
Authors: Bowmer Christopher J , Donoghue Paul G , Leong Chee F , Yates Michael S
Published: April 2011

Chenodeoxycholic, cholic, deoxycholic and taurodeoxycholic acids were found to inhibit the binding of 2-(4′-hydroxybenzeneazo)benzoic acid, methyl orange, sulphadimethoxine and warfarin to human albumin. In addition, glycodeoxycholic acid inhibited the binding of sulphadimethoxine and warfarin. In contrast, these bile acids did not inhibit the binding of phenylbutazone. The extent of displacement was in the rank order of: dihydroxy acids (chenodeoxycholic and deoxycholic) > trihydroxy acid (cholic) > conjugates (glycodeoxycholic and taurodeoxycholic). Thus the introduction of polar groups into the steroid nucleus of bile acids reduces their effectiveness as binding inhibitors. Displacement was usually accompanied by a decrease in the apparent association constant which suggests that the mechanism of displacement may be competitive.
Absorption of exaprolol from the in-situ gastrointestinal tract of rats and dogs
Authors: Motheová O , Zemánek M , Faberova V , Trnovec T , Gabauer I , Styk J , Ďurišová M , Nosáľová V
Published: April 2011

The absorption rate of the β-adrenoceptor blocking drug, exaprolol, from the gastrointestinal tract was studied using in-situ methods in the rat and dog. Exaprolol was rapidly absorbed from the small and large intestine of rats and from the ileum of dogs. The cardiac output and regional blood flow decreased in rats to approximately one half of the original values within 30 min of the in-situ experiment. The logarithm of the amount vs time plots from dogs were linear, whereas with rats a curvilinearity appeared apparently because of the blood flow-limited absorption kinetics of this highly lipophilic drug. The data obtained suggest that exaprolol is suitable for administration in sustained release form.
Modification of the inotropic effect of digoxin by diazepam in rat left atria
Authors: Castillo-Ferrando J R , Perez-Ojeda E , Encina J L , Serrano J S
Published: April 2011

There is a pharmacokinetic interaction between digoxin and diazepam that increases the elimination half-life of digoxin. It may be due to a reduction of digoxin tissue concentrations and to an enhanced effect of diazepam on digoxin binding to plasma albumin. Diazepam (10−5 M) also induces a positive inotropic effect in guinea-pig isolated atria. In a study of a possible pharmacodynamic interaction between both drugs, the inotropic response to digoxin has been examined in rat isolated atria in the presence of diazepam. The atria were kept in Tyrode at 37 X, bubbled with 95% O2 and 5% CO2 and electrically stimulated at twice the threshold voltage. The results indicate that diazepam induces an inotropic effect at 10−5 M (P <0.05) and reduces (P <0.05) at 10−9, 10−7 and 10−5 M the inotropic response to digoxin (10−5 M).
Effect of β-funaltrexamine on opioid side-effects produced by morphine and U-50, 488H
Authors: Hayes A G , Skingle M , Tyers M B
Published: April 2011

Pretreatment of rats with the irreversible μ-opioid receptor antagonist, β-funaltrexamine (β-FNA), 20–40 mg kg−1 s.c., produced a dose-related antagonism of the reduction in respiratory rate, gastrointestinal (GI) propulsion, rotarod reaction latencies and body temperature produced by morphine administration 24 h later, suggesting that these effects are mediated via μ-opioid receptors. The k-receptor agonist, U-50,488H, was without effect on respiratory rate at the doses tested, but produced hypothermia, sedation and low maximum inhibition of GI propulsion. These effects of U-50, 488H were not blocked by β-FNA suggesting that they are mediated via k-receptors.
The pharmacological characterization of 3,4-dihydroxyphenylimino-2-imidazolidine (DPI) as a potent mixed α1/α2-adrenoceptor agonist rather than as a dopamine receptor agonist
Authors: van Oene J C , Horn A S
Published: April 2011

In the past decade many studies have been carried out on the pharmacological actions of the imidazoline derivative DPI (3,4-dihydroxyphenylimino-2-imidazolidine) because it has been proposed as a selective agonist at a postulated subtype of dopamine (DA) receptor. According to the first publication on this concept of multiple DA receptors, authored by Cools & van Rossum (1976), mammalian DA receptors can be divided into excitation-mediating (DAe) and inhibition-mediating (DAi) receptors. DAe receptors appeared to coincide with ‘classical’ DA receptors i.e. those that can be selectively stimulated with apomorphine and inhibited with haloperidol, whereas the newly postulated DAi receptors could be selectively stimulated with DPI and inhibited with ergometrine (Cools & van Rossum 1976, 1980). Though interesting from a conceptual point of view, the idea of the existence of DAi receptors in the mammalian brain was rather speculative, and Cools and coworkers consequently put much effort into attempting to provide it with an experimental basis. They found that in some test models DPI and ergometrine had indeed opposing effects, and they explained these results as being in strong support of the presence of DAi receptors and thus of the validity of the DAe/DAi concept (Cools et al 1976; Cools 1977). In spite of the latter conclusion, however, these authors have repeatedly revised their original concept, i.e. by the additional postulations of the ‘alpha-like norepinephrine receptor’ (Cools & van Rossum 1980) and of the ‘DAi/e receptor’ (Cools 1981).
The accumulation of an aryloxylkylamidine (501C) and 5-hydroxytryptamine in human polymorphonuclear leucocytes: a quantitative electron microscopy study
Authors: Read N G , Beesley J E , Blackett N M , Trist D G
Published: April 2011

The uptake of anilino -N-2-m-chlorophenoxypropylacetamidine (501C) and 5-hydroxytryptamine (5-HT), in human polymorphonuclear leucocytes (PMN) was investigated by quantitative ultrastructural autoradiography. The major concentration of both drugs was in the cytoplasmic granules, 71.5 ± 6.8% for [3 H] 501C, and 68.75 ± 6.1% for [3 H]5-HT. Lesser quantities of both drugs were associated with the nucleus; 18.1 ± 4.8% for [3 H] 501C and 23.0 ± 4.2% for [3 H] 5-HT. Only small amounts of activity were recorded at other sites. The data suggests that there may be common binding sites for 501C and 5-HT in PMN. Furthermore the concentration of 501C in PMN granules may also account for the damaging effect of high concentrations of the drug on PMN.
Acute blood pressure and urinary responses to single dose combinations of captopril and diuretics in conscious spontaneously hypertensive rats
Authors: Chiu P J S , Vemulapalli S , Barnett A
Published: April 2011

The present studies involved oral administration of captopril alone or in combination with individual diuretics in conscious, freely-moving spontaneously hypertensive rats (SHR). Both blood pressure (BP) and urinary fluid and electrolyte excretion were concomitantly measured. Captopril, 10 mg kg−1, caused a decrease in BP (-18 ± 3 mm Hg) which was not significantly different from control (-10 ± 2 mm Hg). Diuretics alone also failed to alter BP. However the BP-lowering effect of captopril was readily potentiated by concomitant administration of a single oral dose of frusemide (10 and 30 mg kg−1) in proportion to the magnitude of urinary loss. Hydrochlorothiazide at 1 and 3 mg kg−1 oral and metolazone at 0.3 and 1 mg kg−1 oral induced fluid loss similar to frusemide at 10 mg kg−1 and all produced comparable BP reduction in combination with captopril (25-32 mm Hg). Triamterene did not increase fluid excretion and was ineffective. In SHR with bilateral ureteral ligation, the synergistic effect of frusemide was abolished while that of hydrochlorothiazide still occurred with a delayed onset. It is concluded that concomitant measurement of BP and urinary excretion in conscious, freely-moving SHR is a useful technique for studying new antihypertensive drugs. Using this preparation it was found that enhancement of the acute hypotensive response to captopril with concomitant diuretic therapy occurs within 10 min and is primarily related to the fluid and Na loss, regardless of the diuretic agent used.
Identification of adrenoceptors and dopamine receptors mediating vascular responses in the superior mesenteric arterial bed of the rat
Authors: Nichols A J , Hiley C R
Published: April 2011

The nature of the adrenoceptors and dopamine receptors mediating vascular responses in the in-situ blood perfused superior mesenteric arterial bed of the rat have been studied. α1-Adrenoceptor agonists produced vasoconstriction but α2-agonists had no significant effect on vascular resistance. The vasoconstrictor effects of noradrenaline were antagonized by low doses of prazosin (26nmol kg−1 i.v.). Isoprenaline and salbutamol produced vasodilation when the vasculature was preconstricted with arginine vasopressin. The responses to isoprenaline were potently antagonized by propranolol (1.69 μmol kg−1 i.v.) and weakly but significantly reduced by practolol (3.75 μmol kg−1 i.v.) whereas the responses to salbutamol were unaffected by the same dose of practolol. After preconstriction of the vasculature and α-adrenoceptor blockade, dopamine and apomorphine produced dilator responses with both compounds producing the same maximal response and apomorphine being 1.8 times more potent than dopamine. The dopamine responses were present after the animals had been pithed and were resistant to spiperone (506 nmol kg−1 i.v.) but were antagonized by cis-α-flupenthixol (460 nmol kg−1 i.v.). These results suggest that this vascular bed possesses vasoconstrictor α1- but not α2-adrenoceptors, vasodilator β1 and β2-adrenoceptors and vasodilator dopamine receptors which appear similar to the D1-type found centrally.
Postjunctional effects of mianserin and its metabolites on the rat isolated anococcygeus muscle
Authors: Doggrell Sheila A
Published: April 2011

After rat isolated anococcygeus muscle had been treated with 6-hydroxydopamine to abolish noradrenergic transmission, the effects of mianserin and its metabolites alone on tone and on the contractile responses to methacholine and phenylephrine were studied. Mianserin (> 3 times 10−5 M) and 8-hydroxymianserin (> 3 times 10−6 M), but not desmethylmianserin and mianserin -N-oxide, induced contractions. The contractions to mianserin were not altered by phentolamine, atropine, cyproheptadine, ouabain and verapamil but were reduced in tissues treated with indomethacin. Thus the responses to mianserin may, in part, be mediated by the synthesis of prostaglandins. Mianserin (10−5 M) and 8-hydroxymianserin 10−7 −10−5 M) potentiated, mianserin- N-oxide had no effect, and desmethylmianserin (10−7 −10−5 M) inhibited methacholine-induced contractions. The inhibition of responses to phenylephrine was concentration-related with desmethylmianserin (10−7 −10−5 M) and mianserin- N-oxide (10−6 −10−5 M) but not with mianserin or 8-hydroxymianserin (10−7 −10−5 M). The effects of mianserin and its metabolites on responses to methacholine and phenylephrine were similar in the absence and presence of indomethacin. These results suggest that mianserin and 8-hydroxymianserin increase the tissue's sensitivity to methacholine by an action at the level, or distal to, the muscarine receptor. In addition to blocking α1-adrenoceptors, mianserin and 8-hydroxymianserin may have another postjunctional action at, or beyond, the α1adrenoceptor.
Phenolic analogues of reversed esters of pethidine
Authors: Casy A F , Ogungbamila F O
Published: April 2011

The preparation and stereochemical characterization of phenolic analogues of the reversed ester of pethidine, α-and β-prodine and a 1-phenethyl congener are described. All the compounds were weakly active or inactive as agonists in rodent antinociceptive tests and failed to antagonize fentanyl in rats. The results substantiate the view that the morphine and 4-phenylpiperidine groups of analgesics differ in their modes of interaction with opiate receptors, except possibly when the piperidine derivative carries a C-4 carbon substituent.
Enhancement of nasal absorption of insulin and calcitonin using polyacrylic acid gel
Authors: Morimoto Kazuhiro , Morisaka Katsuaki , Kamada Akira
Published: April 2011

The effects of polyacrylic acid gel on the nasal absorption of insulin and [Asusup>1,7]-eel calcitonin were investigated in rats. The nasal administration of insulin (1 IU kgsup>−1) in polyacrylic acid gel at 0.1 and 1% w/v showed maximum hypoglycaemic effects at 30 min and 1 h after administration, respectively. However, the nasal administration of insulin in carboxymethyl cellulose (1% w/v) solution had no hypoglycaemic effect at the same dose. When [Asu1.7]-eel calcitonin (10 U kg−1) was administered nasally in polyacrylic acid gel (0.1% w/v), a prominent hypocalcaemic effect was observed during the first 30 min. Nasal administration of [Asu1,7]-eel calcitonin in saline had no hypocalcaemic effect at the same dose. The results indicate that the polyacrylic acid gel base significantly enhanced the absorption of insulin and [Asu1,7]-eel calcitonin via the nasal cavity.
The effect of 6-oxo-prostaglandin E1 on human platelet aggregation in whole blood in-vitro
Authors: Wilsoncroft P S , Lofts F J , Griffiths R J , Moore P K
Published: April 2011

The effect of PGI2, 6-oxo-PGE1 and PGE1 on ADP-induced human platelet aggregation has been assessed in whole blood and in blood centrifuged to prepare plateletrich plasma (PRP). PG12 was the most potent antiaggregatory agent in both media. The concentration of PGI2 required to produce 50% inhibition of platelet aggregation was approximately 0.3 ng ml−1 in each case. In contrast both E series prostaglandins exhibited significantly greater (400-700%) anti-aggregatory activity when tested in whole blood than when tested in PRP. Since whole blood presumably represents a truer reflection of platelet reactivity in-vivo, we believe that the potency of 6-oxo-PGE1 (and PGE1) as inhibitors of platelet aggregation has been underestimated in previous experiments using PRP. In human whole blood 6-oxo-PGE1 has approximately 40% the anti-aggregatory activity of PGI2. The reasons for the increased anti-aggregatory potency of E series prostaglandins in whole blood is not known. We suggest that 6-oxo-PGE1 and PGE1 (but not PGI2) may prevent the release of pro-aggregatory ADP from red blood cells thereby enhancing their ability to inhibit platelet aggregation.
Distribution coefficients of atenolol and sotalol
Authors: Taylor P J , Cruickshank J M
Published: April 2011

Our original publication (Taylor & Cruickshank 1984) was addressed to one simple specific point: the confusion that has been caused by apparently contradictory data for the same two compounds. It is now criticised on two counts (Day & Parr 1984): that we used a confusing nomenclature; and that our treatment of the data was technically incorrect.
Force-displacement measurements in tableting
Authors: Ragnarsson Gert , Sjögren John
Published: April 2011

The influence of particle interaction, i.e. friction and bonding, on the net work (NETW) during compaction and on Heckel plots was tested by varying the particle size, the lubrication or the moisture content. The NETW was found to be significantly affected by particle interaction. The yield pressure, calculated from Heckel plots, was far less dependent on particle interaction and appears to be more useful for the evaluation of the deformation properties of materials. The NETW may be useful as a test of inter-lot variations in compaction behaviour of materials, due to its high sensitivity to both inter- and intraparticle properties, good reproducibility and low dependence upon die wall conditions. However, it appears to be a poor measure of the plastic properties of the substance.
The compaction properties of polyethylene glycols
Authors: Al-Angari A A , Kennerley J W , Newton J M
Published: April 2011

The mechanical properties of polyethylene glycol (PEG) powders of different average molecular weights have been characterized in terms of their yield pressure, determined from the densification of compacts by the method of Heckel. The yield pressure was found to be proportional to the molecular weight of the PEG. The densification which occurred during compaction was greater the lower the molecular weight. In terms of compact tensile strength, PEG 10000 produced the greatest strength for a given pressure. This arises from its ability to deform plastically to form a compact and be of sufficient intrinsic strength to resist fracture during the diametral compression test. Higher molecular weights PEGs do not allow sufficient plastic flow during consolidation for their inherent higher strength to be used.
Effect of protein on the absorption of phenytoin through everted gut preparations
Authors: Rosen A , Macheras P
Published: April 2011

The transfer of phenytoin across everted gut membrane has been measured both from solutions and from media where the drug is dissolving at different pH. Introduction of protein into the mucosal medium caused varying effects. Protein binding in the mucosal solution causes a decrease in the apparent transfer rate. However, in accord with previous findings, at pH 4 both the solubility and dissolution rate of phenytoin increase in the presence of protein, and this can lead to increased transfer rates. Effects such as these may account for the effect of food on phenytoin bioavailability.
Comparison of the effects of sodium salicylate, disodium ethylenediaminetetraacetic acid and polyoxyethylene−23−lauryl ether as adjuvants for the rectal absorption of sodium cefoxitin
Authors: Nishihata Toshiaki , Tomida Hisao , Frederick Gregory , Rytting J Howard , Higuchi Takeru
Published: April 2011

Sodium salicylate, disodium ethylenediaminetetraacetic acid (EDTA) and polyoxyethylene−23-lauryl ether (POE) significantly enhanced the absorption of cefoxitin from the rectum but with the following differences. (1) The effectiveness of salicylate or EDTA was enhanced by sodium chloride, whereas the activity of POE was not. (2) Although the ratios of plasma cefoxitin peak values to cefoxitin dose were constant with POE or EDTA, the peak to dose ratios with salicylate decreased with increasing cefoxitin concentration. (3) Phlorizin and 4, 4′-diisothiocyanostilbene−2, 2′-disulfonic acid (DIDS) inhibited the effectiveness of salicylate, but did not influence the adjuvant action of either POE or EDTA. (4) Although treatment with salicylate resulted in slightly less protein release than treatment with NaCl, both POE and EDTA increased the release of protein from the rectal mucosa. It appears that the effects of salicylate occur at the protein fraction of the rectal mucosa through a saturable process whereas the adjuvant action of POE and EDTA appears to involve some irreversible disruption of the membrane.
The inhibitory effects of ranitidine and Cimetidine on propranolol elimination by the rat isolated perfused liver
Authors: Jones D Brian , Ching Michael S , Morgan Denis J , Anderson Jeanette D , Smallwood Richard A
Published: April 2011

The effect of low (50 μg) and high (1 mg) doses of the histamine H2-receptor antagonists cimetidine and ranitidine on the first pass extraction of propranolol was studied in the rat isolated perfused liver. Both low and high dose cimetidine increased the area under the perfusate propranolol concentration time curve (AUC) 4 to 5−fold. Although low dose ranitidine did not alter propranolol AUC, high dose ranitidine increased it to the same extent as cimetidine. These results indicate that ranitidine has a clear propensity for microsomal inhibition, but one which is unlikely to be manifest at therapeutic dosage.
The effect of indoramin on plasma lipids in hypercholesterolemic patas monkeys
Authors: Pierce Vanessa , Shepperson Nicholas B , West-Watson Andrew
Published: April 2011

In patas monkeys fed a high cholesterol diet, chronic dosing with the antihypertensive agent indoramin increases the cholesterol ratio by raising the plasma HDL-C concentration. Epidemiological evidence suggests that increasing HDL-C reduces the incidence of coronary heart disease (CHD). If, therefore, indoramin is able to evoke these changes in man it may be expected to favourably influence the progress of CHD.
Chronic lithium prevents REM sleep deprivation-induced increased responsiveness to apomorphine
Authors: Rodrigues Francisco Das Chagas , Zwicker AsteróIde Paulo , Calil Helena Maria
Published: April 2011

REM sleep deprivation of rats induces an increased responsiveness to dopaminergic agonists. Chronic lithium (Li) has been reported to prevent the development of dopamine receptor supersensitivity induced by other agents. The effects of chronic dietary Li administration (producing a mean serum level of 0.96 mequiv. litre−1) and 96 h REM sleep deprivation were studied. Chronic Li completely blocked the increased stereotypy, and partially prevented the aggressive behaviour induced, respectively, by 0.6 and 5 mg kg−1 of apomorphine in REM sleep deprived rats compared with the appropriate control groups. This study constitutes the first attempt to evaluate chronic lithium effects on rats undergoing REM sleep deprivation, chosen as another method of inducing alteration of dopaminergic sensitivity.
Dissolution rate measurements of sparingly soluble compounds with the Coulter Counter model TAII
Authors: Nyström C , Mazur J , Barnett M I , Glazer M
Published: April 2011

A Coulter Counter, Model TAII was used to determine both solubility and dissolution rate from suspensions of griseofulvin and hydrocortisone acetate, where the initial particle size and shape had been characterized. The method assesses the weights and surface areas of particles remaining undissolved as a function of time. A comparison with a conventional method, assessing dissolved quantities of materials, showed that solubility data of the same order of magnitude can be obtained. The TAII data fitted a previously established equation that linearly relates log solubility and log of the intrinsic dissolution rate and indicated that the dissolution process was not diffusion controlled. The TAII method described is a rapid and convenient means of estimating the solubility and dissolution rate where no adequate technique for analysing the dissolved fraction exists.
The effect of nifedipine and verapamil on the pendular movements of the rabbit isolated ileum
Authors: Beleslin D B , Samardẑić Ranka , Terzić Branka , Jovanović-mićić Danica
Published: April 2011

The inhibitory effect of calcium antagonists such as nifedipine and verapamil on the pendular movements of the rabbit isolated ileum was investigated. Nifedipine and verapamil depressed or abolished the pendular movements. The inhibitory effects of nifedipine and verapamil were concentration-dependent. Nifedipine is about 1000 times more potent than verapamil. Calcium ions failed to reverse the inhibitory effects of nifedipine and verapamil. Calcium antagonists which influence the motor activity of the digestive tract, therefore, could have therapeutic use independent of their action on the cardiovascular system.
Comparison of the potency of 8−phenyltheophylline as an antagonist at A1 and A2 adenosine receptors in atria and aorta from the guinea-pig
Authors: Collis M G , Palmer D B , Saville V L
Published: April 2011

The potency of 8−phenyltheophylline as an antagonist at A, adenosine receptors in guinea-pig atria and at A2 adenosine receptors in the guinea-pig aorta has been investigated. 8-Phenyltheophylfine was an apparently competitive antagonist of the negative chronotropic effect of adenosine, 2-chloroadenosine, L- N6 -phenyl-isopropyl adenosine (L-PIA) and 5′- N-ethylcarboxamide adenosine (NECA) on atria and of the relaxant effect of adenosine, 2−chloroadenosine and NECA on the aorta. The pA2 values for 8−phenyltheophylline ranged from 6.4 to 6.6 and were not significantly different, irrespective of the agonist or tissue used. These results indicate that 8−phenyltheophylline is a relatively potent antagonist at adenosine receptors but does not exhibit selectivity for either of the putative sub-types in isolated tissues.
The metabolic chiral inversion of 2−arylpropionic acids–-A novel route with pharmacological consequences–-a correction
Authors: Hutt Andrew J , Caldwell John
Published: April 2011

In our recent review (Hutt & Caldwell 1983) on the metabolic chiral inversion of the 2−aryl propionic acids, Fig. 1 presented flying wedge diagrams to depict the three-dimensional structures of the enantiomers, assigned according to Shen (1979). Close examination of the Figure, in the light of model building, reveals that the absolute configurational designation of these structures is incorrect and should be reversed, i.e. the enantiomer labelled by us as R(-) is in fact S(+) and vice versa. We apologise for this error, and would also point out that the diagram of Shen (1979) upon which our assignments were based is similarly incorrect.
Effects of composition, moisture and stearic acid on the plasto-elasticity and tableting of paracetamol-microcrystalline cellulose mixtures
Authors: Bangudu A B , Pilpel N
Published: April 2011

Measurements were made under various conditions of the stress relaxation (SR) and elastic recovery (ER) of mixtures of paracetamol and microcrystalline cellulose (Avicel) and of the tensile strengths (T) of their tablets. T was inversely proportional to ER/SR. Tablets laminated or capped when they contained less than 25% w/w of cellulose and the value of ER/SR measured at 20 kN over a compression/decompression/ejection cycle of 2 min, was greater than 9. Addition of between 2 and 4% w/w of water increased the tensile strengths of tablets, provided they contained less than 75% w/w of cellulose, but more water caused decreases in T. Additions of up to 10% w/w stearic acid also caused decreases in T. Explanations are provided for the results.
Intranasal drug delivery by spray and drops
Authors: Hardy J G , Lee S W , Wilson C G
Published: April 2011

A solution of 99m Tc-labelled human serum albumin was administered into the nose as a spray and as one or three drops. The patterns of deposition and the rates of clearance in normal subjects were monitored by gamma scintigraphy. The spray was deposited mainly in the atrium, and cleared slowly into the pharynx. The single drop spread more extensively than the spray, while the three drops were sufficient to cover most of the walls of the nasal cavity. Clearance was faster following administration of the drops. These factors have implications when designing dosage regimens for drugs administered by the intranasal route.
Prazosin binding to human α1-acid glycoprotein (orosomucoid), human serum albumin, and human serum. Further characterization of the 'single drug binding site' of orosomucoid
Authors: Brunner F , Müller W E
Published: April 2011

The plasma protein binding of the α1-adrenergic blocking agent prazosin was investigated by means of circular dichroism (CD) and equilibrium dialysis (ED) measurements. The interaction of prazosin with human α1-acid glycoprotein (α1-AGP) results in pronounced negative extrinsic Cotton effects at 255 nm and a smaller negative band at 285 nm which are associated with the binding of prazosin to only one site of the protein. Various basic drugs, and warfarin also, at 50μM displace prazosin 10 μM from its binding site on α1-AGP and reduce the CD-spectra at 255 nm by 26% (disopyramide), 52% (mepivacaine), about 70% (verapamil, biperiden), and 90–100% (trihexyphenidyl, warfarin). (±)-Propranolol reduces the CD-spectra by 76%, its (-)-isomer by 89%, and the (+)-isomer by 65%. ED experiments indicated that the binding of prazosin to α1-AGP is saturable with an association constant of 48 000 M−1 and 0.85 binding sites per protein molecule. Displacement of prazosin from α1-AGP by the same drug as used for the CD experiments at displacer/porazosin ratios of 5 resulted in comparable reductions of the fraction bound as obtained by the CD experiments. Prazosin was also highly bound to human serum albumin (600 μM) with about 80–85% bound at prazosin concentrations from 1–100 μM. Since prazosin binding to human serum is only slightly higher (80–90%) it is concluded that prazosin binding in serum is largely mediated by the albumin fraction. The results indicate that prazosin binds to the single drug binding site of human α1-AGP, that this site is slightly stereospecific for propranolol, and that anionic as well as cationic drugs bind with high affinity to this drug binding site of α1-AGP.
A possible pH-controlled drug delivery system based on a derivative of the polysaccharide scleroglucan
Authors: Alhaique F , Riccieri F M , Santucci E , Crescenzi V , Gamini A
Published: April 2011

Four carboxylated derivatives of scleroglucan have been obtained by oxidation, to different extents, of the glucopyranose side chains of the natural polysaccharide. The diffusion of model molecules through aqueous solutions of these new products was measured at various pH values. The reversible pH induced sol-gel transition of some of the polyelectrolyte solutions tested effects a remarkable variation in the diffusion rate of the permeating species; in this sense the most interesting polysaccharide appears to be the product with 70% oxidized glucopyranose moieties. The behaviour of scleroglucan and its derivatives has been compared with that of carboxymethylcellulose and the mechanism involved in drug permeation and release discussed. The possible application of one of the new products in controlled release formulations for oral use is also reported.
In-vitro and in-vivo metabolism of the presynaptic dopamine agonist 3-PPP to a catecholic analogue in rats
Authors: Rollema Hans , Mastebroek Dora , Wikströum Håkan , Horn Alan S
Published: April 2011

The dopamine agonist 3-PPP and its enantiomers are hydroxylated in-vitro by rat liver microsomes to the catecholamine 3-(3,4-dihydroxyphenyl)- N-n-propylpiperidine (4-OH-3-PPP) with Km and Vmax values of about 1 μM and 2 nmol (mg protein)−1 min−1 respectively. As the catecholamine formed appears to be a good substrate for catechol- O-methyltransferase, in-vivo catecholamine formation in rats from 3-PPP was only detectable after inhibition of COMT by tropolone. The resulting brain levels of 4-OH-3-PPP, as measured by HPLC with electrochemical detection 45 min after administration, were about 350 pmol g−1 after i.p., and about 100 pmol g−1 after s.c. injection of 45 μmol kg−1 3-PPP, with no significant difference between racemic, (+) or (-) 3-PPP. It was estimated that these catecholamine levels represent about 1–5% or the 3-PPP levels after i.p., and about 0.2-0.5% after s.c. administration of 3-PPP. The relevance of this metabolic conversion of 3-PPP for its pharmacological profile is discussed.
Cholic acids/salts as barriers to diffusing species: effect of pH
Authors: Alhaique F , Memoli A , Santucci E
Published: April 2011

Bile acids have been absorbed on a microporous polypropylene membrane and the diffusion of ionic and non-ionic compounds through the barriers obtained has been studied at different pH values. Results indicate that permeation rates are affected by environmental pH conditions and an explanation of this behaviour is proposed. This study represents an approach for a pH-controlled drug delivery system.
Distribution of azapropazone and its principal 8-hydroxy-metabolite in plasma, urine and gastrointestinal mucosa determined by HPLC
Authors: Rainsford K D
Published: April 2011

Methods are described for the HPLC determination of azapropazone and its 8-hydroxyl metabolite in plasma, urine and gastrointestinal mucosae after purification of samples on reverse-phase mini columns. Plasma levels of the drug in gouty patients receiving 900–2400 mg daily were relatively constant after 5 days, though overall the values were higher than after a single dose. Gastric absorption of azapropazone in rats is relatively rapid suggesting that the low gastric irritancy is probably due to its weak inhibitory effects on prostaglandin and mucus synthesis rather than slow gastric absorption.
GABA inhibits excitatory neurotransmission in rat pelvic ganglia
Authors: Maggi Carlo Alberto , Santicioli Paolo , Meli Alberto
Published: April 2011

Intravenous GABA inhibited, in a bicuculline-sensitive manner, contractions of the urinary bladder induced by preganglionic nerve stimulation in urethane anaesthetized rats, while it had no significant effect on contractions produced by postganglionic nerve stimulation. In addition, intravenous GABA strongly inhibited DMPP-induced bladder contractions; this effect was also prevented by bicuculline. These experiments suggest that GABA inhibits excitatory neurotransmission in rat pelvic ganglia through a mechanism involving, at least in part, the activation of postsynaptic GABA A receptors.
Repeated treatment with imipramine or amitriptyline increases the locomotor response of rats to (+)-amphetamine given into the nucleus accumbens
Authors: Maj J , Wedzony K
Published: April 2011

Effects of bilateral injections of (+)-amphetamine (5 μg/0.5 μl) into the nucleus accumbens were investigated in rats treated repeatedly with imipramine or amitriptyline. Repeated but not acute administration of either drug enhanced the locomotor hyperactivity induced by (+)-amphetamine given 2 or 72 h after the last dose of antidepressant. The results indicate that the increased responsiveness of the mesolimbic dopaminergic system may be involved in the action of antidepressant drugs.
Highly potent inhibition of prostaglandin 15-hydroxydehydrogenase in-vitro and of prostaglandin inactivation in perfused lung by the new azobenzene analogue, Ph CL 28A
Authors: Berry C N , Hoult J R S , Phillips J A , Mccarthy T M , Agback H
Published: April 2011

The new azobenzene analogue Ph CL 28A (2-hydroxy-5-(3,5-dimethoxycarbonyl-benzoyl)-benzene acetic acid) potently inhibited prostaglandin 15-hydroxydehydrogenase (PGDH) in the nanomolar range in-vitro and inhibited prostaglandin inactivation in rat perfused lung at similar concentrations, and is the most potent PGDH inhibitor yet available. It was synthesized because electronegative substituents in the B ring of homosalazine enhance PGDH inhibitory potency. Ph CL 28A inhibited human placental PGDH non-competitively with regard both to substrate PGF2α (Ki = 18.7 ± 0.9 nM) and the NAD+ cofactor (Ki= 57.6 ± 2.9 nM); inhibition was greatly reduced at pH > 8.0. PhCL 28A hydrolyses spontaneously in alkali (t 1/2 at pH 9.0 = 45 h) to the less active dicarboxylic acid (IC50 human placental PGDH 1.6 μM versus 0.028 μm for Ph CL 28A). The new analogue is 1000 x more active than the parent compound sulphasalazine from which it derives. The IC50 values for five azobenzene analogues in rat perfused lung (Ph CL 28A = 72 nM) correlated strongly with those obtained using purified PGDH (r = 0.99), suggesting that they inhibit pulmonary prostaglandin degradation at the enzyme step rather than at the hypothetical carrier. The new compound will be a useful probe for PGDH structure and function.
The binding of flurbiprofen to plasma proteins
Authors: Aarons Leon , Khan Azhar Z , Grennan David M , Alam-Siddiqi Masooma
Published: April 2011

The binding of flurbiprofen to human serum albumin and normal plasma was measured using ultracentrifugation. Flurbiprofen was bound in excess of 99% in all cases. Over the concentration range normally associated with therapy the data could be adequately described by a one-site binding model. The association constant decreased with increasing protein concentration, being 3.04 times 106 M−  1 at an albumin concentration of 2 g/100 ml and 1.19 times 106 M−  1 at a concentration of 4 g/100 ml. Flurbiprofen binding showed no dependence on pH over the range 7.0 to 8.0.
The effect of xanthine derivatives on red blood cells: microelectrophoretic studies
Authors: Luk Y O , Law S L , Chu F L
Published: April 2011

The effect of xanthine derivatives on the variation of surface charges of red blood cells has been investigated. Results of mobility curves showed that the derivatives increase the surface charges on the cells, whereas there is little effect on the surface charges of liposomes.
β-Kainic acid is not an amino acid antagonist
Authors: Stone Trevor W , Collins J F
Published: April 2011

β-Kainic acid has been reported to have anticonvulsant properties. In view of its structural relationship to α-kainic acid it has therefore been tested for antagonist activity at excitatory receptors for N-methylaspartate, quisqualate and α-kainate using anaesthetized rats and brain slice preparations. No antagonism was found against these three agonists though β-kainate itself caused excitation. If β-kainate interferes with excitatory amino acid neurotransmission it probably acts presynaptically.
Investigation of the film formation of magnesium stearate by applying a flow-through dissolution technique
Authors: Johansson Mats E , Nicklasson Martin
Published: April 2011

The film formation of magnesium stearate on the surface of acetylsalicylic acid was investigated by applying a flow-through dissolution technique. The effect of mixing time, lubricant surface area, and the addition of colloidal silica was studied. The film formation increased by increasing mixing time. The final level reached was independent of the specific surface area of the lubricants, but granular magnesium stearate gave a lower surface coverage than the powdered lubricants. The lubricating effect was independent of the mixing time and specific surface area of the lubricants. Colloidal silica was found to interact primarily with the free fraction of magnesium stearate.
9β-Methylcarbacyclin, a stable prostacyclin analogue, in prevention of platelet losses during charcoal haemoperfusion
Authors: Hughes R D , Lanoley P G , Guarner F , Williams Roger
Published: April 2011

The effect of 9β-methylcarbacyclin, a stable analogue of prostacyclin, as a platelet protective agent, has been investigated during in-vitro charcoal haemoperfusion with fresh heparinized human blood, a model of progressive platelet damage. There were no platelet losses over 3 h perfusion after an initial bolus (1 μg ml−1) of 9β-methylcarbacyclin (101.6 ± s.e. 1.9% of initial value) whereas in the paired control circuit there was a significant reduction in the platelet level (73.5 ± 4.1%, P < 1.05). Prevention of rises in plasma thromboxane B2 by 9β-methylcarbacyclin confirmed the lack of platelet damage and a significant, but less marked, effect on white cell losses was observed. In a second series of experiments a bolus of 9β-methylcarbacyclin in one circuit was compared with prostacyclin infusion in the other which demonstrated that this prostaglandin analogue was as effective as prostacyclin and on the basis of these initial results it would merit clinical evaluation.
α-Tocopherol as agonist in hypoxia
Authors: Kelly M J
Published: April 2011

In hypoxia, but not normoxia, α-tocopherol (vitamin E) acts as an agonist in guinea-pig isolated colon, producing dose-dependent increases in contractile activity. This effect is mimicked by agents, vitamin K1 and phytol, which contain a structural similarity to the phytyl side chain of α-tocopherol, but is antagonized by vitamin K3 which has a structure similar to the chromane ring of vitamin E. All of the agonist responses were blocked by atropine and potentiated by physostigmine but were unaffected by nexamethonium. However, responses to acetylcholine were not antagonized by vitamin K3 and these data suggest that α-tocopherol, phytol, vitamins K1 and K3 may be acting on a ‘hypoxia receptor’ which mediates release of acetylcholine onto muscarinic receptors.
Intestinal absorption of sodium cefoxitin in rats: effect of formulation
Authors: Nishihata Toshiaki , Yoshitomi Hironori , Higuchi Takeru
Published: April 2011

The absorption of cefoxitin from rat intestine, rectum and small intestine was greater when the powdered form was administered than when an aqueous solution was given. Cefoxitin absorption from the small intestine was significantly increased after its administration in suppository form prepared with a triglyceride base, although rectal absorption from the suppository did not differ from that of the drug in powdered form. The increase in absorption by the small intestine from the suppository form may be due to fatty acids produced from triglyceride by lipase.
[3H]Taurine binding on a cardiac sarcoplasmic fraction from rats, rabbits and pigs
Authors: Quennedey M C , Velly J , Schwartz J
Published: April 2011

A subcellular fraction was isolated from heart ventricles by differential centrifugation. Enzyme markers and electron microscopy showed that this fraction was rich in sarcoplasmic reticulum. It bound [3H]taurine specifically. Taurine might contribute to the regulation of Ca2+ transfer in the sarcoplasmic reticulum.