bluuebunny/crossref_metadata_2025 huggingface dataset:
An approach to reduce the number of skin samples in testing the transdermal permeation of drugs
Authors: Langguth P , Spahn H , Mutschler E , Hübner K
Published: April 2011

Although glyceryl trinitrate (GT) is a drug that easily permeates through skin, the variations in its transepidermal fluxes were high. The arithmetic mean of the GT flux (n = 31 skin samples from different individuals) was 16.5 μg cm−2 h−1 with a standard deviation of 42%. The extreme values were 4.1 and 36.9 μg cm−2 h−1, i.e. they differed by a factor of 9. Wide variations were also found for ephedrine, frusemide, caffeine, ethacrynic and benzoic acids and especially trospium chloride. All these fluxes were determined in an in-vitro permeation model at 32 °C using human epidermis. With the aim of standardizing epidermal preparations on their permeability, the extent to which the in-vitro GT fluxes through a human epidermal preparation correlate with those of other compounds was evaluated. The resulting standardization procedure consisted of two interactive parts: (i) the correlation of the flux of a test-substance with that of GT using epidermal samples from three donors and estimating the minimum, mean and maximum flux of the test compound and (ii) quantitation of the transepidermal permeation of the test compound with those standardized epidermal preparations by calculating the GT standard coefficient defined by the slope of the line derived from the relation between GT flux units and the corresponding flux from the test compound.
Pharmacological actions of ICI 180080, a novel thromboxane receptor antagonist
Authors: Jessup C L , Jessup R , Wayne M
Published: April 2011

ICI 180080 (5(Z)-7-[2,2-dimethyl-4-(2-hydroxyphenyl)-1,3-dioxan-cis-5-yl] heptenoic acid) potently inhibited contractions of rat and rabbit aortae and guinea-pig trachea elicited by 11,9-epoxymethano PGH2 (U-46619). This antagonism was selective because contractions of aortae to noradrenaline and 5-hydroxytryptamine and trachea to histamine were not antagonized by ICI 180080. Schild analysis of data obtained from experiments on rabbit aortae indicated that this thromboxane receptor antagonism was competitive (pA2 = 7.50, slope = 1.07). Addition of ICI 180080 to human platelet-rich plasma caused dose-related inhibition of U-46619-induced platelet aggregation. This modification of platelet aggregation was not associated with inhibition of thromboxane synthetase, cyclo-oxygenase or lipoxygenase. ICI 180080 did not modify the primary phase of ADP-induced aggregation of human platelets neither did it affect the platelet inhibitory activity of prostacyclin. When dosed orally to anaesthetized guinea-pigs, ICI 180080 (5–50 mg kg−1) caused dose-related inhibition of U-46619-evoked bronchoconstriction. We conclude that ICI 180080 is a potent, selective, competitive, orally active thromboxane antagonist.
Adrenal catecholamine concentration after chronic treatment with bromocriptine and haloperidol
Authors: Baksi Samarendra N , Hughes Maysie J , Strahlendorf Howard K
Published: April 2011

Adrenal catecholamine concentration was measured by HPLC with electrochemical detection in male rats after ten days of bromocriptine and haloperidol (0.05,0.5 and 5.0 mg kg−1) and vehicle (1.0 ml kg−1) treatments subcutaneously. There were four rats in each group. The results indicate that bromocriptine treatment significantly increased dopamine (DA), noradrenaline (NA) and adrenaline (A) content in a dose-dependent manner. The NA/DA ratio was unchanged, but the A/NA ratio was significantly increased after treatments with two higher doses of the drug. Haloperidol treatment, on the other hand, had no significant effect on dopamine and a biphasic effect on adrenaline content. Noradrenaline concentration increased only after the lowest dose of the drug. There was no significant change in NA/DA or A/NA ratios in any group. The dopamine metabolite, dihydroxyphenylacetic acid (DOPAC), was not detected in any adrenal gland.
Effect of fluoxetine pretreatment on the neurochemical changes induced by amfonelic acid combined with spiperone in rats
Authors: Fuller Ray W , Snoddy Harold D
Published: April 2011

Combined treatment with amfonelic acid plus spiperone caused large increases in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and a decrease in dopamine in rat striatum. 5-Hydroxytryptamine (5-HT) was decreased in striatum (but not in hypothalamus), and 5-hydroxyindoleacetic acid (5-HIAA) was increased in the striatum. Pretreatment with fluoxetine, an inhibitor of uptake into 5-HT neurons, antagonized the decrease in 5-HT and the increase in 5-HIAA and in the ratio 5-HIAA/5-HT but did not antagonize the changes in dopamine or its metabolites. The amfonelic acid-spiperone combination apparently causes increased release of dopamine in striatum, and the released dopamine is accumulated by 5-HT nerve terminals via the membrane uptake carrier. Inhibition of that carrier by fluoxetine prevents the release of 5-HT caused by the dopamine influx.
Evaluation of official instrumental methods for the determination of particulate matter contamination in large volume parenteral solutions
Authors: Montanari L , Pavanetto F , Conti B , Ponci R , Grassi M
Published: April 2011

The distribution pattern of particle contamination in nine different types of LV parenteral solutions and the possibility of correlating the counts made with two official instruments (Coulter Counter and HIAC) were studied. Two hundred containers of LV parenteral solutions (corresponding to 40 batches) produced in Italy, were sampled. Each bottle was submitted to HIAC and Coulter Counter countings, for particle sizes ranging between 2 and 25 μm. For about 50% of the products, the two straight lines that represent the distribution of particle contamination obtained with the two methods did not cross-over within the studied size range, the Coulter Counter counts always proving higher than the HIAC ones. In the other cases, the cross-over point of the two lines occurred at varying size levels. Statistical analysis of the results pointed to a relationship between the contamination values obtained with the two counting methods for sizes ranging between 2 and 5 μm, but there was no correlation for sizes equal to, or higher than, 10 μm. From the maximum contamination levels established by the BP and the FU IX for the HIAC method, the corresponding values were calculated for the Coulter Counter method. Similarly the values were calculated the HIAC method based on the maximum values set for the Coulter Counter.
Non-isotopic spectrophotometric determination of the unbound fraction of drugs in serum
Authors: Lim C-F , Wynne K N , Barned J M , Topliss D J , Stockigt J R
Published: April 2011

A spectrophotometric method to measure the free fraction of highly-bound drugs in serum has been established for a range of non-steroidal anti-inflammatory drugs (NSAIDs) and for frusemide. Spectrophotometry is used to measure fractional transit of drug from a large volume of dialysate to a small volume of serum during dialysis to equilibrium. The method, which depends on the principle that drug transit from dialysate to serum is proportional to serum binding, requires neither isotopic drug preparations nor specific drug assays, is independent of extraction efficiency from the dialysate and requires no measurements from the serum compartment. Estimates of percent unbound fraction (%UF) for aspirin (6.0 ± 0.9%), phenylbutazone (0.9 ± 0.2%), and frusemide (1.8 ± 0.2%) were comparable with those obtained with 14C drug preparations. Values for %UF were determined for eleven additional NSAIDs. The method was valid for a four-fold change in serum: dialysate ratio. Kinetics of frusemide binding to serum were comparable using [14C]frusemide and the test method. This technique may have general application in establishing the %UF for substances that are extensively bound to serum proteins and for identifying sera that show abnormal binding.
Effects of various cephem antibiotics on ethanol metabolism and their structure-activity relations
Authors: Kamei Chiaki , Sugimoto Yukio , Muroi Nobuaki , Tasaka Kenji
Published: April 2011

The effects of various cephem antibiotics and related compounds on ethanol metabolism were studied in association with their chemical structures. In rats, cefoperazone, cefbuperazone, cefamandole, latamoxef, cefmetazole, cefotetan, cefmenoxime and cefminox which have the [(1-methyl-1H-tetrazol-5-yl) thio] methyl group at position 3 of the cephem ring caused a significant increase in the blood acetaldehyde concentration. In the last three compounds, disulfiram-like activity was less potent than that evaluated in the preceding compounds. Cefazolin and ceftezole having a 1H-tetrazol group at position 7 also showed a disulfiram-like activity. A single administration of 1H-tetrazol also increased the blood acetaldehyde concentration. Both blood ethanol and acetaldehyde values were increased significantly on administration of these drugs. In beagle dogs, cefoperazone induced a less remarkable but much more sustained increase in the blood acetaldehyde. These results indicate that the 1H-tetrazol group, as well as the [(1-methyl-1H-tetrazol-5-yl) thio] methyl group, is responsible for inducing a disulfiram-like action and that there is a difference in the potency of the disulfiram-like activity among the drugs having a [(1-methyl-1H-tetrazol-5-yl)thio] methyl group at position 3 of the cephem ring in relation to those in which the side chain is substituted at position 7.
The affinity of some selective muscarinic receptor antagonists for the muscarinic receptor mediating endothelial-dependent relaxation of the rabbit and rat thoracic aorta
Authors: Choo L K , Malta E , Mitchelson F
Published: April 2011

The pKB values determined for pirenzepine, 4-DAMP, secoverine and gallamine against acetylcholine-mediated relaxant effects in rabbit aorta indicate that this muscarinic receptor closely resembles that which mediates contraction of non-vascular smooth muscle. The results of the present study argue against the presence of a novel type of muscarinic receptor mediating endothelium-dependent relaxation.
Inhibition of dimaprit- and pentagastrin-induced gastric acid secretion in cats by the new histamine H2 antagonist, CM 57755
Authors: Lavezzo A , Manzoni L , Bianchetti A , Manara L
Published: April 2011

The antisecretory effects of CM 57755, a new histamine-H2 receptor antagonist, have been compared with those of cimetidine on gastric acid secretion induced by intravenous infusions of dimaprit or pentagastrin into conscious cats with chronically implanted gastric fistulae. Intravenous infusion of CM 57755 induced a parallel shift to the right of the dimaprit dose-response curve. The potency of CM 57755 was comparable with that of cimetidine as shown by similar doses causing a 5-fold displacement to the right of the dimaprit dose-response curve (4.9 μmol kg−1 h−1 for CM 57755 and 4.7 μmol kg−1 h−1 for cimetidine). Unlike that with dimaprit, the acid secretion stimulated by increasing doses of pentagastrin was inhibited by CM 57755 with depression of the maximal effect, indicating noncompetitive antagonism. In a second series of experiments the time course of the anti-secretory action of intragastrically administered CM 57755 was studied from the gastric acid secretion induced by constant infusion of dimaprit. At equieffective doses, CM 57755 caused more sustained inhibition than cimetidine.
Acceleration of large intestine transit time in rats by sennosides and related compounds
Authors: Leng-Peschlow Elke
Published: April 2011

Sennosides A + B and their natural metabolites, sennidins A + B, rheinanthrone and rhein, as well as the synthetic laxative danthron, were investigated for their influence on small and large intestine transit time in rats. Carmine red, as a marker, was administered through a gastric tube for small intestine transit or intracaecally by a chronically implanted catheter for colon transit. High doses of sennosides (250–500 mg kg−1) given orally from 20 min or up to 6h before marker administration had no effect on small intestine transit time. The metabolites and danthron (10–100 mg kg−1 p.o.) also did not accelerate upper gastrointestinal passage. Intracaecal administration at the same time as carmine red, however, reduced the time for the appearance of the first coloured faeces from more than 8 h in the controls to 46 ± 9 min after sennosides, 34 ± 11 min after sennidins, 53 ± 83 min after rhein and 16 ± 4 min after rheinanthrone (50 mg kg−1 of each). Danthron was ineffective. Thus, sennosides and their natural metabolites specifically influence large intestinal motility. Acceleration of colonic transport seems to be a major component of the laxative action whereas for danthron motility changes are not responsible for its laxative action. Indomethacin partly inhibited the acceleration of large intestine transit induced by sennosides. An involvement of endogenous prostaglandins may therefore be possible, although a local bolus administration of PGF2α or PGE2 into the caecal lumen neither influenced transit time nor induced diarrhoea.
Coulter Counter measurements of solubility and dissolution rate of sparingly soluble compounds using micellar solutions
Authors: Nyström C , Bisrat M
Published: April 2011

A Coulter Counter, Model TAII, was used to determine both solubility and surface specific dissolution rate of two sparingly soluble materials suspended in micellar solutions. The equilibrium solubility increased linearly with surfactant concentration, thereby making it possible by extrapolation to characterize materials with an aqueous solubility down to 1 ppm or less. At high concentrations (>0.1% w/v) the effect of surfactant concentration on the surface specific dissolution rate was less than that predicted from the increased bulk solubility.
Phosphorolysis of 5′-deoxy-5-fluorouridine in human plasma, serum and blood platelets
Authors: Meynial D , Malet-Martino M C , Lopez A , Martino R
Published: April 2011

During the course of the study of 5′-deoxy-5-fluorouridine (5′dFUrd) plasma protein binding using 19F NMR spectroscopy, phosphorolytic cleavage of 5′dFUrd into 5-fluorouracil (5FU) was observed. This transformation was due to the enzymatic content of residual blood cells present in plasma, since the percentage conversion of 5′dFUrd into 5FU was lower as the number of residual blood cells fell, and an ‘acellular’ plasma or a serum effected a negligible phosphorolyis of 5′dFUrd. As platelets were the contaminants of the plasma samples studied, and a concentrate of human platelets demonstrated a high phosphorolytic activity towards 5′dFUrd, it was concluded that these blood cells were responsible for the 5′dFUrd cleavage. Thymidine phosphorylase, being the only pyrimidine nucleoside phosphorylase in human platelets, is suggested by the present results to catalyse 5′dFUrd phosphorolysis and is therefore not as specific for 2′-deoxyribonucleosides as has been reported.
The binding of amsacrine to human plasma proteins
Authors: Paxton J W , Jurlina J L , Foote S E
Published: April 2011

Determination of amsacrine plasma protein binding by both equilibrium dialysis and ultracentrifugation gave similar results and indicated that amsacrine is highly bound (approximately 97%) in human plasma. This binding is independent of amsacrine concentration over the range 1–100 μmol litre−1, but is very sensitive to plasma pH and, to a lesser extent, to temperature. Approximately 20% of the drug appeared to be covalently bound to plasma proteins. Amsacrine was bound by all plasma proteins investigated including albumin, α1-acid glycoprotein and various γ-globulins. The binding to albumin appeared to occur by two processes, a saturable process at a single site with a KD of 13.9 μmol litre−1 and a non-saturable process. Despite differences in individual protein concentrations, no significant difference was observed in the unbound amsacrine fraction in plasma from patients receiving this drug for treatment of acute myelogenous leukaemia and plasma from healthy individuals.
Prophylactic and therapeutic efficacy of the soman-simulator, pinacolyl dimethylphosphinate
Authors: Van Helden H P M , Van Der Wiel H J , Wolthuis O L
Published: April 2011

Atropinized rats, intoxicated with 6 or 8 × LD50 soman and subsequently treated with the oxime HI-6 died several hours after intoxication. Oral or intravenous administration of the soman-simulator, pinacolyl dimethylphosphinate (PDP), given at progressively increasing time intervals before soman, appeared to be very active in preventing death and secondary failure of neuromuscular transmission that followed HI-6-induced recovery. Therapeutically, PDP was only effective when given immediately after soman intoxication and oxime treatment. In animals that received no treatment otherwise, intravenous administration of PDP 10 min before intoxication with 1 × LD50 soman did not enhance lethality.
Pharmacological studies with SK&F 94120, a novel positive inotropic agent with vasodilator activity
Authors: Gristwood R W , Eden R J , Owen D A A , Taylor E M
Published: April 2011

The pharmacological properties of SK&F 94120 on the cardiovascular system have been studied in laboratory animal species. The compound was shown to have positive inotropic activity on hearts from guinea-pig, cat, dog and marmoset in-vitro and in cat and dog in-vivo. These responses in-vivo occurred in association with minimal changes in heart rate. Positive inotropic activity was not caused by SK&F 94120 in rat or hamster hearts in-vitro, thereby indicating a species dependence in myocardial response. SK&F 94120 was shown to have vasodilator activity in cats in-vivo. Detailed studies carried out on anaesthetized cats indicated that the compound caused a balanced dilatation of both resistance and capacitance blood vessels. Haemodynamic studies in anaesthetized cats indicated that, as a consequence of the positive inotropic and vasodilator actions, SK&F 94120 causes significant increases in cardiac output and stroke volume. Studies in conscious dogs showed the compound to be active as a positive inotrope after oral administration. The above properties suggest that this compound possesses useful haemodynamic properties for the treatment of congestive heart failure.
The effect of auranofin on the colonic transport of Na+ and fluid in the rat
Authors: Hardcastle J , Hardcastle P T , Kelleher D K , Fondacaro J D
Published: April 2011

Auranofin in the mucosal fluid caused a dose-dependent inhibition of fluid and Na+ absorption by everted sacs of rat colon. Serosal auranofin was without effect. (Na+ + K+)ATPase activity of homogenates of mucosal scrapes of rat colon was inhibited by auranofin in a dose-related manner, while Mg2+-ATPase activity was little affected. These actions of the drug on colonic transport mechanisms could contribute to the diarrhoea associated with auranofin therapy.
Sodium deprivation increases the antinociceptive activity of morphine
Authors: Poggioli Rosanna , Vergoni Anna Valeria , Bertolini A
Published: April 2011

In rats maintained for 50 days on a low-sodium diet and with a compensatory hyperactivity of the renin-angiotensin system, the antinociceptive activity of morphine was significantly longer-lasting than in controls. It is suggested that the renin-angiotensin system modulates opioid system responsivity.
A comparison of the effects of hyperosmotic salicylate solutions in closed and perfused rectal in-situ loops of rats
Authors: Derrick Gillian M , Thomas Norman W , Wilson Clive G
Published: April 2011

The effects of presentation of hyperosmotic solutions of sodium salicylate to the closed and perfused rectal loop preparations commonly used in assessing drug absorption nave been compared. Epithelial cell loss was quantified in control and treated loops. Tissue damage was significantly greater (P < 0.01) in treated perfused loops. Fluid efflux, which was associated with a small but significant change in the haematocrit value, was noted in both systems.
A study of powder adhesion to metal surfaces during compression of effervescent pharmaceutical tablets
Authors: Sendall F E J , Staniforth J N
Published: April 2011

Effervescent tablets were produced using four different formulations containing citric and/or tartaric acid and sodium bicarbonate with povidone and macrogol 6000. The same formulations were prepared with the addition of 1% sucrose ester powder. The adhesion of each formulation to the metal faces of tableting machine punch tips was determined using electron microscopy, surface roughness measurements and quantification of punch weight variations during tablet production. The basic formulations were inherently adhesive and produced tablets with a weak, porous structure which were qualitatively and quantitatively rougher than conventional, non-effervescent compressed tablets. Both formulations containing tartaric acid produced tablets with a lower surface roughness and with less tendency to stick to tablet punch faces than the two formulations containing citric acid alone. The addition of a water-soluble sucrose ester had a beneficial effect especially on the formulations with inherently high adhesive tendencies.
Self-association of local anaesthetic drugs in aqueous solution
Authors: Attwood D , Fletcher P
Published: April 2011

The aggregation characteristics of a series of local anaesthetic drugs in water and electrolyte solution have been examined using total intensity light scattering, photon correlation spectroscopy and vapour pressure osmometry. The association of cinchocaine hydrochloride was micellar. An appreciable increase in the effective diffusion coefficient as solutions of cinchocaine were diluted close to the critical micelle concentration was observed and has been discussed. The association of amethocaine hydrochloride could be described using a co-operative stepwise association model. No association could be detected in water or 0.1 mol dm−3 electrolyte for butacaine hemisulphate and the hydrochlorides of procaine, proparacaine, mepivacaine, lignocaine, bupivacaine and prilocaine at drug concentrations of less than 0.2 mol dm−3.
Electrokinetic properties of endotoxins and their significance for the limulus amoebocyte lysate test
Authors: Baggerman C , Bonekamp B C , Kannegieter E M , Loos J A , Junginger H E
Published: April 2011

The electrokinetic properties of the endotoxins of Escherichia coli and Serratia marcescens have been examined. Both endotoxins are negatively charged, with the zetapotential being increased by the presence of cations whose relative influence resembles the Schulze-Hardy rule for colloid stability. Fe3+ and Th4+ ions are capable of reversing the negative charge of the endotoxin particles to positive. These cations were found to have a strong inhibitory effect on the activity of endotoxins in the limulus amoebocyte lysate test but the inhibitory effect did not parallel changes in the zetapotential because the effect occurred at concentrations too low to affect this parameter.
Evaluation of the percutaneous absorption and metabolism of some aminopropiophenones
Authors: Markantonis S L , Kyroudis A , Beckett A H
Published: April 2011

The absorption of diethylpropion (DEP I), dimethylpropion (DMP I) and some of their basic metabolites into and passage through the skin was investigated and a comparison of their metabolism following oral and percutaneous administration made. High percentages (60–80%) of DEP I and its metabolites and a small percentage of DMP I and its metabolites were taken up into the skin in less than 2 min—the remaining percentages of the compounds were absorbed into the skin by a first order process. The rate of appearance of the compounds in the blood, which reflects their rate of passage through the skin, did not correlate with their rate of absorption into the skin. More metabolism occurred with all the compounds after their oral administration than after their percutaneous application.
Locomotion and stereotyped behaviours induced by 1-amino-3,5-dimethyladamantane (D 145) and apomorphine in the rat: a comparison
Authors: Ljungberg Thomas
Published: April 2011

The locomotion and stereotyped behaviours induced by the two dopamine agonists, 1-amino-3,5-dimethyladamantane (D 145) and apomorphine in rats have been investigated using a holeboard apparatus. Unlike apomorphine, D 145 did not induce compulsive gnawing, but it did induce locomotion dose-dependently. However, the pattern of locomotion was different from that induced by apomorphine and the locomotion itself was potently antagonized by haloperidol but not by sulpiride; this is the opposite to apomorphine-induced locomotion. This indicates that locomotion induced by dopamine agonists is not a unitary phenomenon but that different ‘types’ of locomotion, with different pharmacological properties, can be induced. Low doses of D 145, given before apomorphine, reduced apomorphine-induced gnawing and enhanced apomorphine-induced locomotion. The long lasting ‘priming’ effect known to occur after repetitive injections of apomorphine was not mimicked by D 145. Apomorphine and D 145 are considered to be two specific DA agonists; their behavioural-pharmacological profiles, however, are quite different.
Localized cracking around pigment particles in tablet film coatings: a theoretical approach
Authors: Rowe R C
Published: April 2011

The problem of localized cracking around pigment particles in tablet film coatings has been treated as being analogous to stress cracking in two phase ceramics. For this purpose a simple model of a spherical cavity in an infinite isotropic medium has been used. As well as allowing the estimation of the stresses generated by the differences in thermal expansion of the dispersed pigment and the polymer matrix, the model predicts the effect of some formulation variables. The predictions are in agreement with the observed cracking on film-coated tablets.
The influence of chronic or acute nicotine pretreatment on ethanol-induced gastric ulceration in the rat
Authors: Wong S H , Ogle C W , Cho C H
Published: April 2011

The effects in rats of chronic or acute nicotine pretreatment were studied on three gastric parameters: ethanol-induced ulceration, gastric wall mucus content and gastric acid secretion, under basal or histamine-stimulated conditions. Oral administration of ethanol (40%, 10 ml kg−1) depleted gastric wall mucus and produced ulceration in the gastric glandular mucosa. Ten-day nicotine pretreatment (15 or 25 μg ml−1 drinking water) worsened the adverse effects of ethanol on mucosal ulceration and mucus content, potentiated the gastric secretory action of histamine, but did not affect basal acid secretion. Single oral doses of nicotine (2 or 4 mg kg−1, given 1 h beforehand) prevented ulceration and mucus depletion in ethanol-treated animals; however, they did not influence either basal or histamine-stimulated gastric acid output. It is concluded that chronic nicotine administration aggravates ethanol ulceration, possibly by decreasing gastric wall mucus content and sensitizing the stomach to the acid secretory action of histamine. On the other hand, an acute oral dose of nicotine preserves the mucus content and prevents ethanol-induced ulcer formation.
Effects of chloroquine and didesethylchloroquine on rabbit myocardium and mitochondria
Authors: Essien E E , Ette E I
Published: April 2011

The effects of chloroquine and didesethylchloroquine on the rabbit isolated perfused heart and on calcium binding and accumulating ability of the heart mitochondria were investigated. The drugs produced negative chronotropy, negative inotropy and a decrease in coronary flow rate in the isolated perfused myocardium. Both chloroquine and didesethylchloroquine significantly decreased mitochondrial calcium binding and accumulation. These results suggest that the cardiodepressant actions of chloroquine could be due in part to alterations in the calcium accumulating abilities of the mitochondrial membranes, and that didesethylchloroquine, among other metabolites, does contribute significantly to the total observed effect of chloroquine on the cardiovascular system.
The ability of amine N-methyltransferases from rabbit liver to N-methylate azaheterocycles
Authors: Damani L A , Shaker M S , Godin C S , Crooks P A , Ansher S S , Jakoby W B
Published: April 2011

The substrate specificity of two homogeneous amine N-methyltransferases from rabbit liver has been demonstrated to extend to the azaheterocycles pyridine, R-(+)-nicotine and S-(−)-nicotine. Both enzymes methylate R-(+)-nicotine at the pyridyl nitrogen to afford the N-methylnicotinium salt, whereas S-(−)-nicotine does not act as a substrate for either enzyme. Surprisingly, R-(+)-nicotine is methylated at either the pyridyl nitrogen, or the pyrrolidine nitrogen, to afford the two isomeric monomethylate nicotinium ions when an enzymic preparation containing both methyl transferase activities was used. Under similar conditions S-(−)-nicotine was methylated only at the pyridyl nitrogen. The production of charged metabolites in-vivo, from the large number of pyridine-compounds that are used as drugs, or are present in the environment, may be of toxicological significance, in view of the reported toxicities of several such quaternary ammonium compounds.
A thermodynamic analysis of the Collander equation and establishment of a reference solvent for use in drug partitioning studies
Authors: Beezer Anthony E , Gooch Carolyn A , Hunter William H , Volpe Pedro L O
Published: April 2011

A thermodynamic analysis of the Collander equation, In PI = a + b In PII (I and II refer to two different partitioning systems with partition coefficients PI and PII, respectively), is given and applied to three forms of correlation. The intercept, a, is shown to have no general fundamental significance whereas the slope, b is shown to reflect differences in non-aqueous solvent properties; b is also shown to be of use in scaling solvent behaviour to select solvents which closely represent biological membrane properties for use in partitioning studies. Laboratory and literature data are subjected to the analysis.
Crystallographic, theoretical and molecular modelling studies on the conformations of the salicylamide, raclopride, a selective dopamine-D2 antagonist
Authors: Högberg Thomas , Norinder Ulf , Rämsby Sten , Stensland Birgitta
Published: April 2011

The structure of the potent dopamine-D2 antagonist, raclopride, (S)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamide (+)-tartrate, has been determined by X-ray crystallography. The benzamide moiety of raclopride is planar in accordance with other salicylamides (FLA 797 and eticlopride). The planar conformation is stabilized by two intramolecular hydrogen bonds, i.e. one between the amide hydrogen and the methoxy group and one between the phenol hydrogen and the carbonyl group. The side-chain of raclopride has an extended conformation in contrast to the solid state conformations of FLA 797 and eticlopride. The side-chain conformations were studied by rigid rotations followed by MM2PI relaxations of the eight local minima found. Small energy differences (<4ṁ0 kcal mol−1) exist between the various extended and folded conformations. Based on modelling studies with piquindone as template, it is suggested that the salicylamides with N-ethyl-2-pyrrolidinylmethyl side-chains interact with the dopamine-D2 receptor in a folded or a half-folded conformation.
Transmitter releasing action of selegiline ((—)-deprenyl) from peripheral sympathetic nerves under different experimental conditions
Authors: Török Tamás L , Pauló Tünde , Tóth Péter T , Nguyen Tinh Thi , Azzidani Awad M , Magyar Kálmán
Published: April 2011

A high concentration of selegiline ((—)-deprenyl; 10−4M) potentiated low frequency (2 Hz) nerve stimulation-evoked release of [3H]noradrenaline from the isolated main pulmonary artery of the rabbit in the presence of neuronal (cocaine, 3 times 10−5M) and extraneuronal (corticosterone, 5 times 10−5M) uptake blockers, and inhibited the postsynaptic response. The transmitter-releasing action of 10−4M selegiline was inhibited by a moderate increase of external K+ (23ṁ6mM). Excess K+ by itself abolished the nerve-evoked release of [3H]noradrenaline but did not increase the resting outflow of radioactivity. Excess Ca2+ (7ṁ mM) increased the stimulation-evoked transmitter release. In the presence of excess Ca2+, selegiline (10−4M) was effective in increasing the [3H]noradrenaline release in response to nerve-stimulation. Excess Ca2+ partly antagonized the postsynaptic inhibitory action of selegiline. In Ca2+-free, 1 mM EGTA-containing Krebs solution both the nerve-evoked 3H release and the transmitter releasing action of selegiline were abolished, in agreement with the ‘Ca-hypothesis’. The voltage-dependent K+-channel blocker, 4-ami-nopyridine (10−5M), increased the nerve-stimulation-evoked release of tritium from arteries. If selegiline was also present in the perfusion medium the nerve-evoked transmitter release further increased. 4-Aminopyridine completely antagonized the inhibitory action of selegiline on the postsynaptic contraction.
Effect of 8-phenyltheophylline, enprofylline and hydrochlorothiazide on glycerol-induced acute renal failure in the rat
Authors: Yates M S , Bowmer C J , Kellett R , Collis M G
Published: April 2011

The adenosine antagonist 8-phenyltheophylline (8-PT) is a diuretic in normal rats and can ameliorate glycerol-induced acute renal failure (ARF) in this species. To define which action of 8-PT is important in its salutary effect in ARF, we have compared its effects with those of enprofylline (a xanthine with little affinity for adenosine receptors) and with those of the tubular diuretic hydrochlorothiazide. In one series of experiments, groups of rats with ARF of 24 h duration were given a single dose of drug or vehicle. Only 8-PT enhanced urine volume when compared with the vehicle-treated group. In a second set of experiments, groups of glycerol-injected rats received drug or vehicle treatment (i.p.) twice daily for 2 days. Rats which received a course of 8-PT treatment had significantly lower plasma urea and creatinine concentrations, a higher glomerular filtration rate, a lower kidney weight and improved kidney morphology when compared with vehicle-treated rats. The only beneficial effect noted after enprofylline treatment was an improved kidney morphology. Hydrochlorothiazide treatment compared with vehicle treatment did not ameliorate any index of renal function but resulted in significant elevations in plasma urea and creatinine levels. The inability of enprofylline or hydrochlorothiazide to mimic the effects of 8-PT in ARF indicate that the effects of 8-PT are probably associated with adenosine receptor blockade and not with a tubular diuretic action.
Relationship between antipyrine elimination rate constant, clearance and volume of distribution in the rat
Authors: Svensson Craig K
Published: April 2011

While the relationship between the inverse of antipyrine half-life and clearance has been shown to be approximately linear in man, a recent report indicated that there was no significant relationship between antipyrine elimination rate constant (λ) and clearance (CL) in the rat. Since this relationship is critical to the use of non-invasive methods to estimate drug metabolizing capacity, we have re-examined the relationship between λ and CL in the rat. A significant correlation (r = 0·887) was found between antipyrine λ and CL, while only a weak relationship (r = 0·442) was found between λ and volume of distribution. These data support the use of non-invasive methods to estimate antipyrine elimination in the rat when invasive methods need to be avoided.
Effect of ibuprofen and indomethacin on human plasma melatonin
Authors: Surrall K , Smith J A , Bird H , Okala B , Othman H , Padwick D J
Published: April 2011

Ibuprofen reduced human plasma melatonin (MT) after 2 h when administered orally (400 mg) at 2400h. Increasing plasma concentrations correlated well with increasing inhibition of serum MT levels during this time. Maximum plasma ibuprofen coincided with minimum plasma MT in 3 out of 4 volunteers. Although two volunteers exhibited a partial recovery in MT levels, concentrations after 6 h were significantly less than 0600h values in drug-free volunteers. Administration of ibuprofen (400 mg) at 1800h delayed the nocturnal surge of plasma MT. When a slow release preparation of indomethacin (75 mg) was administered at 1800h, the dark phase rise of plasma MT was completely prevented. Thus the longer acting cyclooxygenase inhibitor exhibited a longer lasting inhibition of plasma MT concentration.
Choice and concentration of contractile agent influence responses of rat aorta to vascular relaxant drugs
Authors: O'Donnell Stella R , Wanstall Janet C
Published: April 2011

Concentration-response (relaxation) curves to diltiazem, forskolin, isobutylmethylxanthine (IBMX), procaterol, isoprenaline and sodium nitrite were obtained on isolated ring preparations of rat aorta contracted either submaximally or maximally with noradrenaline or KCl. Diltiazem was more potent on KCl-contracted than on noradrenaline-contracted preparations whether the preparations were submaximally or maximally contracted. The other relaxant drugs were at least 20-fold less potent against KCl than against noradrenaline, but only on maximally contracted preparations. On submaximally-contracted preparations there was no potency difference between preparations contracted with these two contractile agents. Increasing the KCl concentration had a marked influence on the location of the concentration-response (relaxation) curves to all the drugs except diltiazem. This influence was different for drugs that act via cyclic AMP and those that act via cyclic GMP. It is concluded that both the choice of contractile agent (noradrenaline or KCl) and the concentration (especially of KCl) influence relaxant responses of rat aorta to vasodilator drugs.
Stability of insulin mixtures in disposable plastic insulin syringes
Authors: Adams P S , Haines-Nutt R F , Town R
Published: April 2011

The miscibility of short and long acting porcine, human and bovine insulins has been investigated using HPLC. Soluble insulin is rapidly lost from solution when mixed with both isophane and zinc insulin, although the mechanism may be different in these two cases. The time for up to 50% or more to be lost is often less than 2 min. The percentage lost is dependent upon the ratio of the mixture and the type and origin of the insulin. In the case of soluble: zinc mixtures it is greatest for porcine and least for bovine, in the case of soluble: isophane mixtures it was least for human and greatest for bovine. The greater the original amount of soluble insulin present the less the loss. The results help explain recent clinical reports that mixtures of soluble and zinc insulins fail to achieve satisfactory control of post-prandial blood sugar levels.
Effects of glucagon on cAMP accumulation and ketogenesis in hepatocytes from euthyroid and hypothyroid rats
Authors: Shaheen Omar , Otham Sadeq , Al-Turk Walid A , Sliman Naif
Published: April 2011

The resistance to the effects of glucagon was studied in isolated hepatocytes prepared from male rats treated with 6N-propyl-2-thiouracil (PTU). Incorporation of [14C]oleate into ketone bodies in response to various concentrations of glucagon (10−5 to 10−10 M) was reduced in hepatocytes from hypothyroid rats compared with the euthyroid group. The reduced sensitivity to the effects of glucagon on ketogenesis after treatment with PTU was associated with a reduced ability of those hepatocytes to maintain cyclic adenosine-3’,5’- monophosphate (cAMP) at levels required to stimulate ketogenesis. The concentration of cAMP in response to glucagon (10−5 to 10−10 M) was diminished in hepatocytes from hypothyroid rats, compared with those from euthyroid animals.
Comparison of the mode of action of succinylcholine and succinylmonocholine on rat skeletal muscle after denervation
Authors: Andrews Margaret M , Doro Catherine , Nolan Jennifer , Whittaker R
Published: April 2011

The effects of equimolar concentrations (3.0 × 10−5 M) of succinylcholine (SCh) and succinylmonocholine (SMC) were studied in-vitro at 20°C in rat extensor digitorum longus muscle (EDL) 0–147 days after common peroneal nerve section. Analysis of simultaneous measurements of K+ efflux (mmolL−1 g−1) and contracture tension (mN) to SCh showed that there was a rapid increase in the mean values of both parameters up to 22–28 days after denervation (7.7 mmolL−1 g−1, 36 mN). At the end of the period studied, the contracture response declined to 4.0 mN whilst the capacity for K+ efflux remained relatively high (4.8 mmolL−1 g−1) in comparison with normal contralateral EDL muscle (n = 82) K+ efflux measurements (0.62 mmolL−1 g−1). A significant correlation (r = 0.86, P ≤ 0.001) was found between SCh-induced K+ efflux and contracture tension 1–56 days following nerve section which indicated that the development of the contracture response and K+ efflux were concomitant during the period specified. The ratios of maximum contracture tension/K+ efflux in response to SCh and SMC, 18–22 days after denervation were similar, 4.9 and 5.0, respectively. Results indicated that the mode of action of each agent was similar in denervated rat skeletal muscle, and that they were equally potent in their hyperkalaemic potential. Results of comparative measurements of membrane depolarization and contracture tension in response to SCh and SMC showed that both agents produced quantitatively similar responses at 7 and 14 days after denervation; 23 mN c.f. 20 mN/17 mV c.f. 15 mV, and 32 mN c.f. 33 mN/20 mV c.f. 19 mV, respectively. It is proposed that SMC would not be a suitable substitute for SCh for use with either normal or denervated skeletal muscle.
The synergistic effects of concurrent administration to rats of EDTA and sodium salicylate on the rectal absorption of sodium cefoxitin and the effects of inhibitors
Authors: Nishihata Toshiaki , Lee Chia-Shun , Rytting J Howard , Higuchi Takeru
Published: April 2011

Plasma levels of cefoxitin, as enhanced by rectal coadministration of sodium salicylate, were reduced by concurrent administration of <0.5 mg mL−1  N-ethylmaleimide (NEM) or p-chloromercuriphenylsulphonic acid, sodium salt (p-CMP). Concentrations of these inhibitors above 1 mg mL−1 resulted in enhanced peak plasma values of cefoxitin. This did not occur after coadministration with either ethylenediaminetetraacetic acid (EDTA) or polyoxyethylene-23 lauryl ether (POE). Ouabain and 2,4-dinitrophenol (DNP) suppressed plasma cefoxitin levels in the presence of salicylate and the enhancing effects of EDTA and POE when EDTA and POE were administered at low doses. At higher concentrations of EDTA and POE, DNP had little effect, while ouabain had little effect on POE and only partially suppressed the effects of EDTA. Plasma concentrations of cefoxitin after coadministration with salicylate and POE together, or with EDTA and POE together, were about the same as expected from summing the plasma levels resulting from coadministration of each adjuvant individually at the same concentrations. However, combined administration of salicylate and EDTA with cefoxitin yielded plasma cefoxitin concentrations which were much higher than expected from the sum of their individual actions.
Effects of the pyrones, maltol and ethyl maltol, on iron absorption from the rat small intestine
Authors: Barrand Margery A , Callingham Brian A , Hider Robert C
Published: April 2011

The pyrones, 3-hydroxy-2-methyl-4-pyrone (maltol) and 3-hydroxy-2-ethyl-4-pyrone (ethyl maltol) chelate iron with a high affinity and selectivity. The resulting 1:3 (metal-igand) complexes, being neutral, are able to partition readily across cell membranes and thus may facilitate iron transport across the intestinal wall. Absorption of radioactive iron (59Fe) in the presence of these pyrones was investigated in male rats 1, 2, 4 and 6 h after intraduodenal administration of a 7 μg dose and compared with that of 59Fe given as the sulphate, gluconate, fumarate or complexed to EDTA. Total body absorption and distribution were calculated from the 59Fe content of various tissue samples. With all the iron preparations used, blood levels of 59Fe were highest 1 h after injection whilst the 59Fe content at the major site of deposition, i.e. the bone marrow, increased up to 6 h. No 59Fe was found in the urine. Total body absorption of 59Fe was significantly higher from the pyrones than from the other four preparations. Over the dose range 0.7–700 μg, the proportion of 59Fe absorbed from both iron maltol and iron sulphate decreased with increasing dose. Enhanced 59Fe uptake from maltol was evident at 0.7–70 μg but not at 700 μg suggesting that use of these pyrones will not result in iron overload. Absorption of 59Fe given into the stomach was slower in onset but was sustained longer presumably via a steady delivery of iron to the duodenum from the gastric reservoir. The presence of excess maltol to maintain the integrity of the neutral 1:3 iron-maltol complex under a variety of physiological conditions did not appear critical in-vivo for effective iron absorption. There was no difference in 59Fe uptake between maltol, ethyl maltol or a mixture of ethyl maltol and maltol. 59Fe uptake was significantly enhanced in iron-deficient animals. Within 1 min of i.v. injection of iron complexed to maltol or ethyl maltol, 59Fe became associated with a plasma protein of molecular ratio similar to that of transferrin. With EDTA this process was much slower, i.e. up to 60 min. The half-life of 59Fe in the blood was similar whether administered as the maltol, ethyl maltol, sulphate or EDTA; at the 110 μg iron dose it was 133 ± 8 min and at 1 μg it was 74 ± 10 min in iron-replete animals and 44 ± 5 min in iron-deficient animals. The rate of absorption from the duodenum of 59Fe given as maltol, ethyl maltol or as iron sulphate increased with increasing dose but the shape of the absorption curve depended on the rate of movement of iron along the intestine. It is concluded that the pyrones, maltol and ethyl maltol, are able to enhance the initial stages of iron uptake from the intestinal lumen, possibly by holding the iron in a readily absorbable form, but do not influence subsequent iron distribution and so may provide safe and palatable alternatives to those iron preparations presently available for the treatment of iron deficiency.
The binding of the benzimidazole dye H8208 to DNA and to polyinosinic-polycytidylic acid
Authors: Bardsley Hazel J , Sharples Derek , Grèzes Jean-René
Published: April 2011

The benzimidazole dye H8208 (2-(4-aminophenyl)-5-(4-methylpiperazin-1-yl)benzimidazole) has been shown to intercalate into calf thymus DNA and into polyinosinic-polycytidylic acid (a model for A conformation DNA) by a variety of spectroscopic techniques. The binding affinity of the dye was found to be similar to both nucleic acids.
Kinetics of hydrolysis of meclofenoxate hydrochloride in human plasma
Authors: Yoshioka Sumie , Aso Yukio , Uchiyama Mitsuru
Published: April 2011

The kinetics of hydrolysis of meclofenoxate hydrochloride in human plasma have been compared with those of clofibrate. The hydrolysis rate in fractionated plasma was determined in the presence and absence of a plasma esterase inhibitor, tetraethyl pyrophosphate. The kinetic data indicated that clofibrate decomposed only by esterase-induced hydrolysis, which was inhibited by binding of clofibrate to plasma proteins. In contrast to clofibrate, meclofenoxate decomposed rapidly in human plasma via spontaneous hydrolysis as well as esterase-induced hydrolysis. The spontaneous hydrolysis appeared to be inhibited by some components present in the esterase fraction isolated from plasma, while no significant inhibition of the hydrolysis by protein binding was observed.