bluuebunny/crossref_metadata_2025 huggingface dataset:
The anticoagulant activity of heparins in dextrose solutions
Authors: ANDERSON W , HARTHILL J E
Published: April 2011

Changes with time in the anti-factor Xa activity of several heparins were determined in freshly autoclaved and unautoclaved dextrose solutions. In the former, activity was raised, in the latter a reversible fall occurred at certain heparin concentrations, and the term ‘dextrose effect’ is applied to the difference in activity in the two types of dextrose solutions. A simple dependence on heparin concentration for the rise in activity in autoclaved dextrose solutions contrasted with a threshold heparin concentration in the unautoclaved dextrose solutions. Above this a fall and below it a rise in activity were demonstrated with one factor Xa method. The pH of the two dextrose solutions differed by one unit but pH was not the principal factor in the effect; salt tended to eliminate the dextrose effect which was found mostly with the high and to some extent also with the low molecular weight fractions of pharmacopoeial heparin. There was no evidence for heparin degradation but activity changes, which differed for different heparins, are thought to be associated with the effects of heparin-dextrose interaction modified in the case of autoclaved dextrose by by-products of autoclaving. Generally, proprietary dextrose solutions gave variable results.
Inhibition of human lymphocyte transformation by two aryloxyalkylamidines
Authors: TRIST D G , WEATHERALL M
Published: April 2011

The incorporation of [3H]thymidine into human lymphocytes stimulated by phytohaemag-glutinin (PHA) was inhibited by anilino-N-2-m-chlorophenoxypropylacetamidine (501C) and xylamidine. These amidines antagonize 5-HT, but 5-HT did not alter [3H]thymidine incorporation. 501C inhibited PHA-induced lymphocyte transformation as observed by [3H]thymidine incorporation, [3H]uridine incorporation, [3H]leucine incorporation, DNA content, potassium content, and histological examination. 501C also inhibited increased [3H]thymidine incorporation in human mixed lymphocyte cultures. The IC50 of 501C for inhibition of these processes lay between 4 and 8 μM. When added late in culture (after 6-8 h) 501C was less effective. Possible mechanisms by which 501C inhibits transformation are discussed.
Plasma protein binding of fentanyl: the effect of hyperlipoproteinaemia and chronic renal failure
Authors: BOWER SUSANNE
Published: April 2011

Hyperlipoproteinaemic patients with raised pre β-, or pre β- and β-lipoprotein fractions snowed a significant (P < 0.001) increase in binding of fentanyl to whole plasma, compared with normal subjects. The presence of chylomicra had no significant effect on binding. In patients with chronic renal failure, a correlation of probability P < 0.07 was found between percent binding and concentrations of pre β-lipoprotein (P = 0.001), serum albumin (P = 0.0101), total protein minus albumin (P = 0.0576) and β-lipoprotein (P = 0.0625). There was no significant correlation of binding with elevation of α- or γ-globulins, with urea or creatinine concentrations, or with age or sex (P ≥ 0.223). The magnitude of changes in the free fraction found in these patients should not produce a clinical effect as the total distribution volume of fentanyl exceeds 200 litres.
Effects of N-aralkyl substitution of β-agonists on α- and β-adrenoceptor subtypes: pharmacological studies and binding assays
Authors: DECKER N , QUENNEDEY M C , ROUOT B , SCHWARTZ J , VELLY J
Published: April 2011

The pharmacological and binding properties of four β-adrenomimetic drugs with N-alkyl substitutions (isoprenaline, terbutaline, salbutamol and soterenol) were compared with those of four corresponding drugs with N-aralkyl substitutions (protokylol, ME 506, salmefamol and zinterol). BD-40 A, a very powerful β2-agonist with a related chemical structure, was also included in this study. The β1- and β2-activities of these drugs were determined on guinea-pig atria and trachea, their α-adrenolytic activity was measured on rat aorta and their affinities (Ki) for α1- and α2-adrenoceptors on rat cortical membranes were assessed using [3H]prazosin and [3H]yohimbine. In this group of β-agonists, substitution of the N-alkyl by an N-aralkyl group had a variable effect on the β2-selectivity whereas α-adrenolytic properties were always enhanced. An increase of the affinities (Ki) for both α1- and α2-adrenoceptors was found but the effect was much more pronounced for α1-adrenoceptors. These results indicated that the α-adrenolytic activity observed with the N-aralkyl β-agonists was selective for α1-adrenoceptors.
Interparticle forces in binary and ternary ordered powder mixes
Authors: STANIFORTH J N , REES J E , LAI F K , HERSEY THE LATE J A
Published: April 2011

An ultracentrifuge technique, previously described by Staniforth et al (1981), has been used to study the adhesion profiles of several binary and ternary ordered powder mixes of pharmaceutical interest. The adhesion profile of an ordered mix provides information about the proportion of drug powder adhering with different forces of attraction to the carrier excipient particle surface. The excipient particle size is shown to affect adhesion between the components of a binary ordered mix-recrystallized lactose formed more stable ordered mixes with drug powder when the carrier particle size was increased. Changes in the adhesion profile of each binary system on adding three different fine-powder excipients to form a ternary ordered mix are also examined. The physical properties of carrier particles and the charge interactions of a third powder component with previously formed binary ordered mixes, are found to influence the physical stability of ternary ordered mixes.
A comparison of log P and molecular connectivity in the structure-activity analysis of some antimicrobial agents
Authors: BOYD J C , MILLERSHIP J S , WOOLFSON A D
Published: April 2011

Several congeneric series of antimicrobial agents previously studied by Hansch analysis have been investigated using molecular connectivity as the descriptor of molecular structure. In all cases connectivity gave comparable or improved correlations compared with log P, particularly where the pattern of molecular substitution was more complex. It was concluded that the use of computer-generated connectivity terms had advantages over calculated log P values in its ease of application and should be considered at least for initial screening of structure-activity data.
Quantitation and urinary pattern of 4,4′-dihydroxyantipyrine, 4-hydroxy-antipyrine and 3-hydroxymethyl-antipyrine, as main metabolites of antipyrine in man and rat
Authors: BÖTTCHER J , BÄSSMANN H , SCHÜPPEL R
Published: April 2011

A t.l.c.-assay has been developed for the simultaneous determination from the urine of man and animals of three major hydroxylated metabolites of antipyrine (4,4′-dihydroxy-antipyrine, 4-hydroxy-antipyrine, 3-hydroxymethyl-antipyrine). The methodology is also applicable to bile fluid, liver perfusate and liver homogenate. Genuine conjugates are cleaved by acid hydrolysis and free, acid stable metabolites are extracted. Extracts are subjected to t.l.c. and the chromatograms analysed quantitatively by u.v.-reflectance measurements using authentic materials as standards. Calibration curves are linear with a correlation coefficient r > 0.990. Recovery for each metabolite is <95%. Reproducibility of the method is good, with variation coefficients in the range of 3–7%, depending on concentration. The sensitivity of the method is sufficient for practical needs. The specificity of the procedure was confirmed using radio-labelled antipyrine. In man, 4-hydroxy-antipyrine is the principal hydroxylation product in this series, accounting for about 35–40% of the dose. 3-Hydroxymethyl-antipyrine makes up for about 13–17% and 4,4′-dihydroxy-antipyrine represents 3–6% of the dose of antipyrine. In the rat, 4-hydroxy-antipyrine accounts for about 15–31%, 3-hydroxymethyl-antipyrine for 22–28% and 4,4′-dihydroxy-antipyrine for up to 11–18% of the dose. Variation of this pattern in different strains is moderate. In both species, the major portion of phase-I-metabolites is excreted as conjugates. Part of them appears in a free form.
Gastrointestinal and hepatic first-pass metabolism of aspirin in rats
Authors: IWAMOTO KIKUO , TAKEI MIYUKI , WATANABE JUN
Published: April 2011

The first-pass effect of aspirin was measured in male Wistar rats by comparing the plasma concentration after intravenous, oral or intraportal administration (10 mg kg−1) of the drug. Approximately 88 and 86% of the dose was excreted mostly as salicylic acid and its conjugated forms, glucuronide and sulphate, in urine within 48 h of i.v. or oral administration, respectively. This suggests that the gastrointestinal absorption of aspirin was essentially complete in rats. On the average, the area under the plasma concentration-time curve for unchanged aspirin following oral dosing (AUCo) was 0.35 of that obtained following i.v. administration (AUCi.v) and 0.53 of that following intraportal administration (AUCp). Therefore, orally administered aspirin is subject to first-pass metabolism both in the gut and in the liver of rats. The gastrointestinal first-pass effect is estimated to be relatively more important than the hepatic effect.
The uptake of fentanyl by erythrocytes
Authors: BOWER SUSANNE
Published: April 2011

Fentanyl passed rapidly into and out of erythrocytes to equilibrate with plasma concentration, and a red cell/plasma partition coefficient of 1.01 ± 0.0083 s.e.m. was found in 15 normal subjects. Most of the binding of fentanyl by red cells was by haemoglobin. 10% was bound by the cell membrane. Partition was unaffected by haematocrit, pH, or the concentration of fentanyl up to 0.5 mg ml−1 of blood. Dilution of plasma proteins, and replacement of plasma by buffer showed that uptake of fentanyl by red cells is a linear function of the concentration of free drug in plasma. A partition coefficient for red cells/buffer of 4.91 ± 0.032 s.e.m. was found. This relation was confirmed where binding to plasma proteins was altered in uraemia or hyperlipoproteinaemia, or by competitive displacement of fentanyl by aspirin and phenylbutazone thereby changing the size of the free fraction of fentanyl in plasma. Quinidine, however, inhibited the binding of fentanyl to plasma proteins and red cells equally, to maintain a partition coefficient of unity.
Characterization of 5-hydroxytryptaminergic autoreceptors in the rat hypothalamus
Authors: COX BARRY , ENNIS CHRISTINE
Published: April 2011

5-hydroxytryptamine (5-HT) (3 × 10−9 to 10−6 M) produced a concentration-related inhibition of potassium-evoked tritium release from slices of rat hypothalamus preloaded with [3H]-5-HT. The response to 5-HT was unaffected by the presence of yohimbine (10−6 M), pimozide (10−7 M), domperidone (10−7 M) or tetrodotoxin (10−7 M), indicating that the response was not mediated via α1- or α2-adrenoceptors or dopamine receptors and that the receptors that were involved were located directly on the 5-HT nerve terminal. The 5-HT antagonist metergoline (10−8 to 3 × 10−7 M) produced a parallel rightward shift in the concentration-effect curve to 5-HT with no reduction in the size of the maximum response. The pA10 value for metergoline was 6.82 and the slope of the Arunlakshana-Schild plot was not significantly different from 1.0 indicating that it was a competitive antagonist. Methiothepin produced a similar effect to metergoline whilst cyproheptadine and methysergide were less potent as antagonists of 5-HT and were not competitive. Cinanserin was inactive. Thus we have characterized the 5-HT autoreceptor in the rat hypothalamus using a classical pharmacological approach and found that it has more in common with the autoreceptor which we have previously identified in the raphe nuclei of the rat than it has with the 5-HT receptor located on dopamine neuroterminals in the striatum.
Effects of solvent medium on solubility. A linear free energy relationship treatment
Authors: MANZO RUBEN H
Published: April 2011

Linear relationships exist between the logarithms of the solubility equilibria of structurally closely related compounds, as they vary with changes in solvent or solvent composition in water and water-like solvents, trie slope Py of these linear free energy relationships quantitatively accounts for the direction and intensity of the relative solubility variations due to medium effects. Results obtained by applying the concept to series of both p-hydroxy- and p-aminobenzoic esters, and α-aminoacids, are presented. These results are explained by a simple model in terms of solute-solvent interactions.
Particulate contamination of sterile syringes and needles
Authors: TAYLOR S A
Published: April 2011

Commercially available sterile needles and syringes have been examined for particulate contamination using the Hiac light blockage technique. The number of particles delivered was small compared with the total number permitted for large volume parenterals. Where syringes are used in particle counting techniques, the contribution of particles should be taken into account.
Analgesia and increases in limbic and cortical MOPEG-SO4 produced by periaqueductal gray injections of morphine
Authors: REIGLE THOMAS G , WILHOIT CANDIDA S , MOORE MELISSA J
Published: April 2011

Analgesia and changes in limbic and cortical concentrations of the major brain noradrenaline metabolite, 3-methoxy-4-hydroxy-phenylethylene glycol sulphate (MOPEG-SO4), were investigated in rats following the bilateral injection of morphine into the periaqueductal gray (PAG). Morphine, at a dose of 5 μg per bilateral site, produced a significant antinociceptive effect within 15 min of injection. This effect, as measured by the tail flick analgesic test, remained constant at a level of approximately 75% of the maximum for 60 min. Significant increases in limbic and cortical MOPEG-SO4 were also observed 15, 30 and 60 min after the 5 μg bilateral PAG injection of morphine. However, MOPEG-SO4 concentrations exhibited a sharp peak in both brain areas at 30 min. Analgesia and the regional increases in MOPEG-SO4 were antagonized by the prior systemic injection of naloxone (1 mg kg−1, i.p.). Thus, analgesia and increases in noradrenaline metabolism in two brain regions appear to be mediated by the specific activation of opiate receptors in the PAG. Although these findings indicate that brain noradrenergic systems may be involved in the mediation of morphine analgesia, the lack of a strict temporal relationship between antinociceptive action and increases in MOPEG-SO4, suggests that analgesia cannot be totally attributed to changes in brain noradrenergic transmission.
Pharmacological isolation of a single β-adrenoceptor subtype makes Schild plots which have slopes of 1 possible for selective β-adrenoceptor antagonists in carbachol-contracted guinea-pig trachea
Authors: TAYLOR SAMUEL E
Published: April 2011

The effects of selective β-adrenoceptor agonists and antagonists on isometric relaxation of carbachol-contracted, guinea-pig isolated trachea were studied. An attempt was made to pharmacologically isolate the β1- and β2-adrenoceptors by use of appropriate selective agonists and antagonists. The slopes of the Schild plots for butoxamine vs noradrenaline and terbutaline as well as for practolol vs terbutaline did not differ significantly from 1, the predicted value for a competitive antagonist acting at a single receptor type. These data differ from a previous report suggesting that slopes of less than 1 are characteristic for selective β-adrenoceptor antagonists in carbachol-contracted guinea-pig trachea. They support the hypothesis that the low slopes in this preparation are due to interaction of the agonist with both β1 and β2-adrenoceptors rather than the state of contraction of the trachea.
Contractile actions of lysophosphatidic acids with a chemically-defined fatty acyl group on longitudinal muscle from guinea-pig ileum
Authors: TOKUMURA A , FUKUZAWA K , TSUKATANI H
Published: April 2011

Various lysophosphatidic acids caused phasic contractions of longitudinal muscle from guinea-pig ileum, followed by rhythmical contractions of lower magnitude. Polyunsaturated lysophosphatidic acids were more potent than saturated lysophosphatidic acids. Among the lysophosphatidic acids tested, linolenoyl-lysophosphatidic acid was the most active, but its activity was about 3–5 times less than that of prostaglandin F2α. Contractile responses to various lysophosphatidic acids, were partially suppressed by tetrodotoxin, atropine and chlorpheniramine. In addition, lysophosphatidic acid-induced contractions were considerably reduced by pretreatment of the muscle with indomethacin.
Effect of nabumetone (BRL 14777), a new anti-inflammatory drug, on human platelet reactivity ex vivo: comparison with naproxen
Authors: NUNN BARBARA , CHAMBERLAIN P D
Published: April 2011

The effect of nabumetone (BRL 14777) on human platelet reactivity ex vivo was compared with that of naproxen at equitherapeutic doses in the same six subjects. Nabumetone had only a weak and equivocal effect on collagen-induced and second phase aggregation in response to adenosine diphosphate and adrenaline. After nabumetone, platelets fully aggregated in response to sodium arachidonate, though approximately twice as much was needed as on control occasions. Sodium arachidonate was unable to elicit a full aggregation response after naproxen. These results suggest that nabumetone may cause less interference with haemostasis than other non-steroidal anti-inflammatory drugs.
Physicochemical and in-vitro biological studies on the possible association between theophylline and ethylenediamine in solution
Authors: Cotgreave Ian A , Caldwell John
Published: April 2011

The possible association in solution between the components of aminophylline, theophylline and ethylenediamine, has been studied using physicochemical and biochemical techniques. Addition of ethylenediamine to solutions of theophylline caused characteristic changes in its u.v. and 13C-n.m.r. spectra, which were due solely to the pH change, and not to any molecular association between the molecules in solution. Both compounds crossed the erythrocyte membrane extensively from plasma or 0˙9% NaCl and had no influence on each other’s behaviour. Theophylline partitioned approximately equally between octanol and pH 7˙4 phosphate buffer, while ethylenediamine remained in the aqueous phase. Again, neither compound affected the properties of the other. Theophylline was reversibly bound to plasma protein, the extent of which was dependent upon the temperature used for equilibrium dialysis. However, ethylenediamine was not bound to plasma protein, and did not alter the binding of theophylline. These data show that the components of aminophylline behave independently in solution, and suggest that there is no association between theophylline and ethylenediamine in biological systems.
The purported dopamine agonist DPI inhibits [3H]noradrenaline release from rat cortical slices but not [3H]dopamine and [14C]acetylcholine release from rat striatal slices in-vitro
Authors: van Oene J C , Sminia P , Mulder A H , Horn A S
Published: April 2011

The effects of the purported dopamine (DA) receptor agonist (3,4-dihydroxyphenylimino)-2-imidazolidine (DPI) upon the in-vitro K+-induced release of [3H]DA and [14C]acetylcholine from rat neostriatal slices, and of [3H]noradrenaline from rat neocortical slices have been investigated and compared with those of the DA receptor agonist TL-99 and the α-adrenoceptor agonist clonidine, respectively. The rapid decomposition of the catechol compounds DPI and TL-99 in the Krebs-Ringer bicarbonate superfusion medium was shown to be inhibited by both the chelating agent EDTA and the reducing agent ascorbic acid. The results suggest that in-vitro DPI is unable to stimulate striatal DA receptors, whereas it is effective in stimulating cortical α2-adrenoceptors (EC50 = 61 nm). It is concluded that DPI should be considered as a mixed α1/α2-adrenoceptor agonist and that the designation of DPI as a DA receptor agonist should be abandoned.
Rheological and sedimentation studies on Instant Clearjel and Primojel suspensions
Authors: Sabra K , Deasy P B
Published: April 2011

The suitability of Instant Clearjel and Primojel for use as extemporaneous suspending agents has been investigated by continuous shear and creep analysis using a specially constructed air turbine viscometer. Aqueous dispersions of both of the modified starches exhibited non-Newtonian, pseudoplastic flow with little thixotropy and some irreversible shear breakdown. Apparent viscosities, determined from the apices of flow curves obtained at constant maximum shear rate, decreased progressively with increase in temperature over the range 10–50 °C. An Arrhenius plot gave a low apparent activation energy of flow for Primojel. The two modified starches showed a marked rise in apparent viscosity with rise in pH from 3 to 11 of the dispersion medium. Only Instant Clearjel dispersions exhibited a linear viscoelastic region in creep testing, studies which confirmed that this system behaved as a viscoelastic liquid. Sedimentation studies on 10% w/v sulphadimidine suspensions containing varying concentrations of either suspending agent indicated that 3% w/v Primojel could form permanent suspensions even after 6 months storage at room temperature. The significance of these results in relation to the usefulness of these starch derivatives as suspending agents is discussed.
Effects of the vasodilator endralazine given with the antihypertensive agent guanfacine on heart rate and blood pressure of spontaneously hypertensive rats and normotensive dogs
Authors: Salzmann R , Pally W Gerber Ch , Scholtysik G
Published: April 2011

Endralazine (BQ 22–708, Miretilan) and guanfacine (BS 100–141, Estulic) were tested alone and in combination for their effects on blood pressure and heart rate in conscious spontaneously hypertensive rats and conscious normotensive dogs. During combined administration of endralazine and guanfacine to spontaneously hypertensive rats, guanfacine 1 mg kg−1 i.v. blocked the tachycardia caused by endralazine, 1 mg kg−1 i.v. After oral administration, the tachycardia induced by 0·5 and 1 mg kg−1 of endralazine was inhibited dose-dependently by 0·05, 0·1 and 0·5 mg kg−1 of guanfacine. The antihypertensive efficacy of endralazine was either unchanged or increased by guanfacine at 0·05-1 mg kg−1. In normotensive conscious dogs, 0·2 mg kg−1 i.v. of guanfacine antagonised the tachycardia elicited by 0·3 mg kg−1 i.v. of endralazine. The elimination of the endralazine-induced reflex tachycardia by guanfacine suggests that the combination of both drugs could be useful in antihypertensive therapy.
Temperature dependence of ethanol lethality in mice
Authors: Malcolm Richard D , Alkana Ronald L
Published: April 2011

The present study provides systematic evidence indicating a direct relationship between environmental temperature, rectal temperature and ethanol lethality. Male, C57 BL/6J mice, previously housed at room temperature (23 ± 1 °C), were injected intraperitoneally with 4·8 to 9·2 g kg−1 ethanol and then exposed for 24 h to ambient temperatures that did not appreciably exceed the thermally neutral range for sober mice (20 to 35 °C). There was a direct relationship between temperature and ethanol lethality at 8 and 24 h after injection. The 8 h LD50 increased by 64%, from 5·3 to 8·7 g kg−1, as environmental temperature decreased from 35 to 20 °C. The 24 h LD50 increased by 51%, from 5·3 to 8·0 g kg−1, across this temperature range. Each 5 °C reduction in ambient temperature induced a significant decrease in the rectal temperature of ethanol-injected mice. Mean rectal temperature ranged from 2·2 °C above baseline at an ambient temperature of 35 to 15 °C below baseline in the 20 °C environment. Ethanol induced a significant dose-related hypothermia in mice exposed to the 20, 25 and 30 °C environments but did not produce hypothermia in animals kept in the 35 °C environment. These findings indicate that the potency of potentially lethal ethanol doses varies with body temperature in accordance with partition and membrane expansion-fluidization theories of anaesthesia.
Absorption and excretion of isosorbide dinitrate and isosorbide-2-mononitrate in dogs
Authors: Cayen Mitchell N , Hicks David , Karounis Joanne , Dvornik Dushan
Published: April 2011

In a crossover design, four male dogs were given orally or i.v. [14C]isosorbide dinitrate (ISDN) or [14C]isosorbide-2-mononitrate (2-ISMN) at a dose of 1 mg kg−1 (70–80 μCi). Virtually all of the oral dose was absorbed and all of the radioactivity was excreted in the urine. The profile of serum radioactivity was similar after all drug administrations. ISDN was rapidly denitrated, giving rise to isosorbide-5-mononitrate (5-ISMN) as a major metabolite, and 2-ISMN as a minor metabolite. The apparent elimination half-life from serum of 2-ISMN and 5-ISMN was 2–3 h. More than 50% of the serum radioactivity after [14C]2-ISMN was due to unchanged drug. The apparent volume of distribution of 2-ISMN averaged 8·3 litres. The results show that, in contrast to ISDN, administration of 2-ISMN resulted in relatively high unchanged drug levels in the serum; the disposition of radioactivity after [14C]ISMN was however similar to that after [14C]ISDN. The findings support the concept that the concentrations of ISDN, 2-ISMN and 5-ISMN in the blood are inversely related to the rates of denitration, and that the vascular activity of the nitrates of isosorbide relates to the rates of their dinitration.
An evaluation of the properties of enteric coating polymers: measurement of glass transition temperature
Authors: Porter S C , Ridgway K
Published: April 2011

When submitted to X-ray crystallography, two enteric coating polymers, cellulose acetate phthalate and polyvinyl acetate phthalate, were found to be essentially amorphous in structure. Values for the glass transition temperature, Tg, of each polymer have been obtained using both a surface microindentation technique and differential scanning calorimetry. The effect on this parameter of an increasing concentration of a plasticizer, diethyl phthalate, has also been determined. Measured values for Tg have been compared with predicted values obtained using a suitable mixture-rule model: the surface microindentation technique values were closer to the predicted.
The influence of pH of dissolution fluid and particle size of drug on the in-vitro release of drug from hard gelatin capsules
Authors: Muhammad N A H , Newton J M
Published: April 2011

The influence of pH of the dissolution fluid on the in-vitro release of acetylsalicylic acid from hard gelatin capsules has been studied for a series of particle size fractions of the drug. Generally, the time required for 50% of the drug content of the capsule to appear in solution during a dissolution test, T50, increased as the pH increased from 1·2 to 2·0; thereafter the value of T50 decreased as the pH increased from 3 to 7. These changes were found to be related to the apparent solubility of the drug. The extent of the changes was found to be further dependent on the particle size of the drug. For capsules filled with particle size fractions of 2·5 and 5·5 μm median diameter, the changes were small. Larger changes were observed with particles of median diameters of 45,100, 220 and 330 μm while the largest changes (greater than two-fold) were obtained with particles of median diameter 130 and 430 μm. The type of kinetics that could be used to express the release rates was found to be particle size-dependent. For particles of 45 μm and larger, the release rate followed an apparent zero order process while an apparent first order process represented the release for the two smallest particle size fractions.
Enthalpies of solution of a series of m-alkoxy phenols in water, n-octanol and water-n-octanol mutually saturated: derivation of the thermodynamic parameters for solute transfer between these solvents
Authors: Beezer Anthony E , Hunter William H , Storey David E
Published: April 2011

Enthalpies of solution in both water and n-octanol have been determined for a series of phenols, in a microcalorimeter modified for titration. The thermodynamic data for solution in n-octanol and in water, as well as for transfer between the two, have been calculated from the free energies of transfer, based upon partition coefficients, and the free energies of solution, based upon solubility data. The results are discussed in terms of solute-solvent interactions in both phases and are used to assess, critically, the use of n-octanol as lipid-like solvent in QSAR studies.
Comparative plasma pharmacokinetics of theophylline and ethylenediamine after the administration of aminophylline to man
Authors: Cotgreave Ian A , Caldwell John
Published: April 2011

Plasma concentrations of theophylline and ethylenediamine have been examined after the oral and intravenous administration of aminophylline to three healthy male volunteers who received on separate occasions 250 mg aminophylline i.v. or 300 mg aminophylline by mouth. Blood samples were taken at regular intervals and the plasma levels of theophylline and ethylenediamine were assayed by h.p.l.c. After i.v. injection, plasma concentrations of theophylline were described by a two-compartment open model, with t1/2α 6 min, Vc 191 ml kg−1, t1/2β 6·0 h and Vp 217 ml kg−1. The plasma concentrations of ethylenediamine also exhibited a biphasic decline, the parameters of the two-compartment open model being t1/2α 7 min, Vc 214 ml kg−1, t1/2β 32 min and Vp 133 ml kg−1 (all values given are means of three subjects). The ratio of theophylline/ethylenediamine in plasma rose rapidly from the initial value of 6·2 (the ratio of the two compounds in aminophylline) over the first 10 min post injection to 47 at 120 min. After this time, ethylenediamine was not measurable in plasma, although theophylline was present for at least 6 h after dosing. Upon oral administration of aminophylline, plasma concentrations of theophylline rose to a peak value of 7·4 μg ml−1 at 1 h, falling thereafter with a t1/2 of 8·0 h. Ethylenediamine, by contrast, could only be detected over the first 2 h after dosing, in amounts below 0·4 μg ml−1. Comparison of oral and i.v. data showed the bioavailability of ethylenediamine was approximately 34% in comparison with a value of 88% for theophylline. These data indicate that the two components of aminophylline are handled independently by the body and that there is no molecular association between theophylline and ethylenediamine in biological media.
The effects of salicylate on enzymes of vitamin K metabolism
Authors: Hildebrandt E F , Suttie J W
Published: April 2011

The mechanism of salicylate-induced hypoprothrombinaemia has been investigated in the rat. Salicylate administration produced an increase in the percentage of the total liver vitamin that was present as vitamin K 2,3-epoxide, but the addition of salicylate did not influence vitamin K epoxide reductase activity in-vitro. Neither did it influence vitamin K-dependent carboxylase or vitamin K epoxidase activity. Both cytosolic and microsomal DT-diaphorase activities were, however, inhibited about 50% by 75 μM sodium salicylate. Salicylate inhibition was also observed when vitamin K quinone and NADH or dithiothreitol were used to support carboxylation. To achieve 50% inhibition required 0·5 mM salicylate with NADH as a reductant and 4 mM salicylate when dithiothreitol was the reductant. These results suggest that the main effect of salicylate on vitamin K metabolism is to inhibit quinone reductases and may be useful in explaining the inhibition of the biosynthesis of vitamin K-dependent clotting factors that occurs in salicylate-induced hypothrombinaemia. These data also demonstrate that the percentage of total liver vitamin present as vitamin K epoxide can be increased by agents that do not have a direct effect on the vitamin K epoxide reductase in-vitro.
The efficacy of bispyridinium derivatives in the treatment of organophosphonate poisoning in the guinea-pig
Authors: Inns Robert H , Leadbeater Levence
Published: April 2011

The efficacy of a number of bispyridinium compounds, including both oxime and non-oxime derivatives, has been determined against poisoning by sarin, soman, tabun and VX in guinea-pigs receiving various supporting treatments. In conjunction with atropine therapy only, the oximes were effective against sarin and VX poisoning and of them only the 4-substituted oximes were beneficial against tabun poisoning. None of the compounds was effective against poisoning by soman. When the supporting drug treatment consisted of pyridostigmine pretreatment and therapy with atropine and diazepam (this treatment itself gave considerable protection against organophosphate poisoning) both the non-oxime and oxime derivatives increased the protection against all four agents although obidoxime and TMB-4 were not beneficial against soman poisoning. The results are discussed in relation to published studies in which these compounds have been found to be beneficial against soman poisoning in atropine-treated rats and mice. It is suggested that the guinea-pig is a better model for predicting the efficacy of treatments for organophosphate poisoning in primate species.
Neurotropic effects of the optical isomers of the selective adenosine cyclic 3′,5′-monophosphate phosphodiesterase inhibitor rolipram in rats in-vivo
Authors: Wachtel Helmut
Published: April 2011

The efficacy of the selective adenosine cyclic 3′,5′-monophosphate (cAMP) phosphodiesterase (PDE) inhibitor (±)-rolipram and its optical isomers (0·006 to 25 mg kg−1) in inducing characteristic behavioural changes like hypothermia, hypoactivity, forepaw shaking, grooming and head twitches in rats has been examined. (+)-Rolipram was found some 15 times less potent than the racemate suggesting a stereoselective interaction with a rat brain cAMP phosphodiesterase isoenzyme. Following their intracerebral administration, the stereoisomers also demonstrated their unusual potency ratio. These findings suggested that (+)-rolipram is a less potent neurotropic PDE inhibitor in-vivo than its (-)-enantiomer.
Disposition of topically applied sodium cromoglycate in the albino rabbit eye
Authors: Lee Vincent H-L , Swarbrick James , Stratford Robert E , Morimoto Kim W
Published: April 2011

The influence of pH, tonicity, preservatives, polymers and instilled drop size on the disposition of sodium cromoglycate, an agent used in the prophylaxis of vernal keratoconjunctivitis, in the tear chamber of the albino rabbit eye has been examined. Radiotracer techniques were used throughout. The initial decline in concentration in the tear chamber was found to be unaffected by the presence of preservatives, pH, and tonicity over the ranges studied. However, significant increases in the residence time of sodium cromoglycate in the precorneal area were noted when a smaller instilled drop size was used and when 5% polyvinyl alcohol (PVA) was added to the aqueous vehicle. Tissue uptake was found to be greatest in the conjunctiva, followed by the cornea, the iris-ciliary body and the aqueous humor. In both the conjunctiva and the cornea, the addition of 5% PVA produced an elevation in the peak concentration of sodium cromoglycate and an increase in the time at which the peak concentration was achieved, indicating improved drug delivery to these sites.
Precorneal drainage of polyvinyl alcohol solutions in the rabbit assessed by gamma scintigraphy
Authors: Wilson C G , Olejnik O , Hardy J G
Published: April 2011

A method for monitoring the ocular distribution of solutions for ophthalmic use was developed using the technique of gamma scintigraphy. This method was used to monitor the effects of polyvinyl alcohol on the precorneal drainage of [99mTc]pertechnetate in the rabbit. The rate of drainage of solutions decreased on addition of PVA and precorneal residence of the marker was significantly prolonged, compared with saline controls, at a PVA concentration of 5% w/v. Increases in the activity in the inner canthal region mirrored the decrease in corneal counts. The method has a more general application for the study of ophthalmic formulations and devices in larger mammals and in man.
Particle size analysis of microcapsules
Authors: Morris Natalie J , Warburton B
Published: April 2011

To standardize the preparation of three-walled w/o/w microcapsules it was necessary to assess their particle size distribution, since they occur as both unicored and multicored types. The log-normal law, reported to be obeyed by many particulate systems, including microcapsules, was not applicable to the size data. A curve-fitting computer program using least squares minimization was used to assess the size distribution data. The models tested were the unimodal and bimodal log-normal distributions, the bimodal form being the most appropriate. Using the equations to the curves of best fit, the modal size and standard deviation of each population were estimated, and the relative percentages of unicored and multicored microcapsules could be deduced from an analysis of the bimodal curves in which they were represented as the sum of two constituent unimodal distributions.
Inhibition of bacterial DNA cytosine-5-methyltransferase by S-adenosyl-l-homocysteine and some related compounds
Authors: Crooks Peter A , Tribé Malcolm J , Pinney R J
Published: April 2011

S-Adenosyl-l-homocysteine and five related compounds have been evaluated as inhibitors of a DNA cytosine-5-methyltransferase. DNA methylation was assayed in cell extracts from E. coli strain J6-2 dcm+, proficient in DNA cytosine-5-methyltransferase activity, containing substrate DNA isolated from E. coli strain J6–2 dcm−, a strain deficient in DNA cytosine-5-methyltransferase. S-Adenosyl-l-homocysteine and its 7-deaza analogue, S-tubercidinylhomocysteine, were competitive inhibitors of DNA cytosine-5-methyltransferase with Ki’s of 14·2 and 17·6 μm, respectively, in the above enzyme assay.
An in-vitro model of intracellular bacterial infection using the murine macrophage cell line J774·2
Authors: Stevenson M , Baillie A J , Richards R M E
Published: April 2011

A simple model of intracellular bacterial infection based on the ability of the macrophage cell line J774·2 to phagocytose Escherichia coli in a reproducible manner is described. Viable counting of intracellular bacteria and microscopic examination of infected macrophage cultures after treatment with fluorescent E. coli antibody showed that the bacteria multiplied within the J774·2 cells. Viable intracellular bacteria may be used to study the activity of bactericidal and bacteriostatic drugs within the macrophage. The low apparent intracellular bactericidal activity of streptomycin, which was time- and concentration-dependent, accords with a low permeability of the J774·2 macrophages to this antibiotic. An exclusively intracellular infection could be achieved by inactivation of non-phagocytosed extracellular bacteria by streptomycin treatment of infected macrophage cultures. Under appropriate conditions intracellular bacterial viability was unaffected.
Modifications in prolactin binding capacity in the rat liver induced by non-steroidal anti-inflammatory drugs
Authors: Muccioli Giampiero , Bellussi Giuseppina , Lando Donata , Di Carlo Raffaele
Published: April 2011

Modifications in prolactin specific binding in the rat liver induced by different non-steroidal anti-inflammatory drugs (indomethacin, piroxicam, ketoprofen, phenylbutazone, mefenamic acid and acetylsalicylic acid) have been studied. All caused a dose-dependent inhibition of prolactin binding capacity whereas no change was found in dissociation constant values. The inhibitory effect is reversible and highly specific, since insulin binding to the same membrane preparation is not affected. The degree of inhibitory activity on prolactin binding is related to the anti-inflammatory activity of each drug, which supports the hypothesis of an involvement of prostaglandin synthesis.
Effect of secoverine and atropine on intestinal secretion and motor activity in the rat small intestine in-vivo
Authors: Greenwood B , Read N W , Hardcastle P T , Hardcastle J
Published: April 2011

The actions of secoverine and atropine on bethanechol-induced intestinal secretion, hypermotility and transintestinal potential difference were investigated in the rat jejunum in-vivo. Both secoverine (10−7 mol kg−1) and atropine (1·2 times 10−9 mol kg−1) inhibited motility at doses that did not affect secretion or transintestinal potential difference. However, secoverine was a less potent antagonist of all the bethanechol-induced changes than atropine. Increases in transintestinal potential difference were more closely related to production of fluid secretion than to increases in motility.
Distribution coefficients of atenolol and sotalol
Authors: Taylor P J , Cruickshank J M
Published: April 2011

The distribution coefficient (D) of atenolol is lower than that of sotalol, despite the latter’s lower partition coefficient (P). Since D is the relevant quantity under physiological conditions, it is re-established that atenolol is in practice the more hydrophilic. Because of the common confusion between P and D which this case exemplifies, the relation between them is set out.
The prolonged retention of sodium cromoglycate in the rabbit eye
Authors: Swarbrick James , Shrewsbury Robert P
Published: April 2011

The retention of sodium cromoglycate in the rabbit eye over a 6 h period following its administration in two different vehicles is reported. When formulated as a dispersion in a hypo-allergenic acetylated lanolin/paraffins base, prolonged retention was observed. Thus, the concentration of sodium cromoglycate in the tears, conjunctiva and cornea 6 h after administration equalled or exceeded the concentration obtained with an aqueous solution 1 h post-instillation.
Haemodynamic effects of bromocriptine in the conscious spontaneously hypertensive rat
Authors: Struyker-Boudier H A J , van Essen H , Smits J F M
Published: April 2011

The systemic haemodynamic effects of 0·3 mg kg−1 bromocriptine s.c. in conscious, chronically instrumented spontaneously hypertensive rats (SHR) has been investigated. Bromocriptine caused a gradual, long-lasting significant fall in mean arterial pressure with a maximum of 26 ± 3 mmHg (-17%). The fall was related to a significant decrease in stroke volume index (-9 ± 2 μl 100 g−1; -10%) and cardiac index (-3·9 ± 0·8 ml min−1 100 g−1; -12%). No significant changes in heart rate or total peripheral resistance index were observed. These data do not support previous suggestions that the antihypertensive effect of bromocriptine is caused by inhibition of the release of vasopressor substances. It is suggested that bromocriptine causes a reduction of venous return of the blood to the heart, possibly related to intrarenal effects.
Effects of 6-methoxytetrahydro-β-carboline on 5-hydroxytryptamine binding in rat brain
Authors: Taylor Dorothy L , Silverman Peter B , Ho Beng T
Published: April 2011

6-MeOTHBC competes for 5-HT binding sites in rat brain in-vitro and in-vivo. The β-carboline is significantly more active at the type 1 [3H]-5-HT, than the type 2 [3H]spiperone receptors, in-vitro. Following injection, 6-MeOTHBC significantly decreases [3H]-5-HT binding in the cortex. The ineffectiveness on [3H]spiperone binding in-vivo corresponds with the low affinity in-vitro. The effect of 6-MeOTHBC on central 5-HT binding may be a significant aspect of its 5-HT-ergic activity.
Time-related effects of benzodiazepines on intestinal motility in conscious dogs
Authors: Fargeas M J , Fioramonti J , Bueno L
Published: April 2011

The effects of diazepam and GABA on intestinal motility were investigated in fasted dogs fitted with strain-gauge transducers. Injected intravenously at 9.00 and 16.00 h, diazepam (0·5 mg kg−1) affected intestinal motility only during darkness i.e. from 19.00 to 7.00 h. These jejunal motor effects which were mimicked by GABA, (0·3 mg kg−1 i.v.) corresponded to a disruption of the migrating myoelectric complex (MMC) with an increased contractile activity. These results demonstrate that benzodiazepines affect the intestinal motility in dog and suggest that the effects are related to sleep-stages.
Suppression of laxative action of phenolphthalein by orally-administered indomethacin or aspirin
Authors: Capasso F , Mascolo N , Autore G , Duraccio M R
Published: April 2011

Oral administration of phenolphthalein produced a dose-dependent increase of wet faeces excreted by mice. The response to phenolphthalein was reduced by pretreatment with indomethacin, aspirin or polyphloretin phosphate (PPP), but not with benoxaprofen. These findings support the view that the effect of phenolphthalein may be suppressed by PG synthetase inhibitors (indomethacin, aspirin) and by PPP.
Potentiation of cyclo(N-methyl-Tyr-Arg)-induced antinociceptive activity by thyrotropin-releasing hormone in mice
Authors: Kawamura Shunsuke , Sakurada Shinobu , Sakurada Tsukasa , Kisara Kensuke , Akutsu Yasuyuki , Sasaki Yusuke , Suzuki Kenji
Published: April 2011

The effect of thyrotropin-releasing hormone (TRH) and its metabolite, cyclo(His-Pro) (C.HP), on cyclo(N-methyl-Tyr-Arg) (C.NMTA)-induced antinociception as measured by the tail-pressure test in mice has been examined. C.NMTA-induced antinociception was significantly potentiated by simultaneously intracerebroventricular or intraperitoneal injection of TRH (approximately 20–50%) in a dose-dependent manner, whereas the effect of morphine was not influenced significantly by TRH. C.HP had no significant effect on the antinociceptive response induced by C.NMTA or morphine. It is concluded that the mechanism of C.NMTA-induced antinociception may be involved in TRH neuronal system in the brain.
Vehicle effects in ophthalmic bioavailability: An evaluation of polymeric inserts containing pilocarpine
Authors: Saettone M F , Giannaccini B , Chetoni P , GALLI G , Chiellini E
Published: April 2011

A series of polymeric ophthalmic inserts containing pilocarpine were formulated with four different types of polyvinyl alcohol, PVA, and two types of hydroxypropylcellulose. Pilocarpine was present as the nitrate, or as the salt with polyacrylic acid, PAA. In-vivo miosis vs time experiments on albino rabbits, showed that all inserts increased significantly the bioavailability of pilocarpine, with respect to a standard solution of pilocarpine nitrate. Two PVA inserts, containing the PAA-salt of pilocarpine, were particularly effective. The preparations were also submitted to in-vitro release tests and to differential scanning calorimetry, to ascertain the release mechanism, and to verify, via the thermal behaviour, possible interactions between drug and polymers. The chemical and physicochemical factors, most likely to influence the ophthalmic bioavailability of pilocarpine from the present preparations, are briefly reviewed.
Lignocaine kinetics in the rat
Authors: Supradist S , Notarianni L J , Bennett P N
Published: April 2011

After intravenous injection of lignocaine 2·5, 5·0 or 10·0 mg kg−1 in the rat blood concentration declined in a bi-exponential manner. The data were analysed according to a two-compartment open model with elimination from the central compartment. Analysis of variance revealed no significant differences in k12, k21, k13, t1/2α, t1/2β, AUC or in the volume constants for the different doses used. After lignocaine 50·0, 70·0 or 90·0 mg kg−1 by mouth there was no significant change in t1/2β for the different doses or in peak plasma concentration normalized for dose. For both routes of administration blood concentration-time curves were superimposible and AUC was linearly related to dose. Renal excretion was negligible. Systemic availability of lignocaine was the lowest of species so far studied (mean 0·019 ± 0·001) did not alter with dose, and was very similar to the values in the literature quoted for the isolated perfused liver. Clearance of lignocaine related to anticipated liver mass was almost identical to the values for liver blood flow quoted using other techniques. The data indicated high hepatic extraction of lignocaine by the intact rat and the absence of dose dependency within the range studied.