bluuebunny/crossref_metadata_2025 huggingface dataset:
Assignment of configuration to 2î-hydroxy-2-methyl-9-hydroxy-5,9-dialkyl-6, 7-benzomorphans using mass spectrometry
Authors: Vaughan D P , Hill M , Mitchard M
Published: April 2011

The configuration and structure of α- and β-2î-hydroxy-2-methyl-9-hydroxy-5,9-dialkyl-6,7-benzomorphans have been determined by mass spectrometry.
A useful transformation for comparing dose-response curves
Authors: MacKay D , Wheeler J
Published: April 2011

Several mathematical equations have been tested for their ability to fit pharmacological dose-response curves over the range 5 to 95% of the maximal response. It has been shown that one such equation, which will be called the L-transformation, adequately fits sets of dose-response data obtained from a number of different tissues. The graphical application of this equation has been suggested previously by other workers but has been used only to a very limited extent.

Techniques have now been developed which enable the L-transformation to be fitted to single sets of dose-response data, and to pairs of sets of data simultaneously. By itself the L-transformation cannot adequately fit all dose-response curves. However if another preliminary transformation is carried out on the measured responses then the L-transformation can usefully be applied to dose-response curves of widely different shapes and slopes. Various applications of these techniques are discussed. When the L-transformation is applied to pairs of dose-response curves obtained, for example, from a single piece of isolated tissue, it can be used to calculate potency ratios, with standard errors and fiducial limits. When combined with the occupation theory of drug action and use of the null method, the L-transformation can be applied to suitable pairs of dose-response curves to provide estimates of the affinity constants (with their standard errors) of drugs for their receptors. The techniques can be extended to other models of drug-receptor interaction. Computer programs are available which greatly facilitate the application of these curve fitting methods to the types of problem outlined above.
Effect of neuroleptics on the disappearance rate of [14C] labelled catecholamines formed from [14C]tyrosine in mouse brain
Authors: Hyttel John
Published: April 2011

The accumulation and disappearance of [14C] labelled dopamine and noradrenaline formed from [14C]tyrosine in mouse brain has been investigated. After reaching peak concentrations the [14C]dopamine and noradrenaline concentration declined exponentially with half-lives of 2·5 and 6·7 h respectively. The effect of some known neuroleptics belonging to different chemical groups as well as of a new neuroleptic compound, Lu 10–022 [2-trifluormethyl-6-fluoro-9-(3-(4-(2-hydroxyethyl) piperazin-l-yl)propyl) thioxanthen], on the disappearance rate of [14C]catecholamines between 1·5 and 3 h after administration of [14C]tyrosine was compared. All neuroleptics tested, except clozapine, increased the disappearance rate of [14C]dopamine in a dose-dependent manner at the lower dose intervals. However, above a certain dose the disappearance rate was not elevated further. Halo-peridol, fluphenazine and Lu 10–022 increased the disappearance of [14C]dopamine more strongly than the rest of the neuroleptics. The disappearance rate of [14C]noradrenaline was also increased by all the neuroleptics, except clopenthixol, although the change was less than for [14C] dopamine disappearance, resulting in a rather poor dose-response relation. Pimozide and Lu 10–022 influenced the [14C] noradrenaline disappearance less than the other neuroleptics. The hypothermic effect caused by the neuroleptics was not related to the change in the disappearance rate of the catecholamines.
Hypothermic and toxic actions of 2–butyne-1, 4-diol and other related diols in the rat
Authors: Taberner P V , Pearce M J
Published: April 2011

The effects of 2-butyne-1,4-diol (BYDL) and related congeners on the body temperature of the rat have been determined. BYDL, at doses above 0·4 mmol kg−1 intraperitoneally, produced a significant fall in body temperature which was dose dependent. 2-butene-1,4-diol (BEDL) had no hypothermic action, and butane-1,4-diol (BDL) produced only a moderate fall in temperature (1·9°) which correlated with the time course of the hypnotic effect of the drug. γ-Butyrolac-tone (GBL), γ-hydroxybutyric acid (GHB) and pentobarbitone at hypnotic doses had similar hypothermic actions which correlated with the period of hypnosis. The hypothermia produced by BYDL could not be prevented by pretreatment with scopolamine or by maintaining the rats at high environmental temperature (32°). BYDL was far more toxic than the other diols examined (LD50 = 0·609-0·635 mmol kg−1 compared to BEDL: 3·71-3·74 mmol kg−1 and BDL: 11·87-11·90 mmol kg−1). Pretreatment of rats with pyrazole, an inhibitor of liver alcohol dehydrogenase, prevented the toxic and hypothermic actions of BYDL. From earlier studies with pyrazole and BDL it was concluded that BYDL itself was not active but that it was possibly converted in vivo by liver alcohol dehydrogenase to a toxic metabolite.
Inhibition of α-chymotrypsin by dibenamine
Authors: Shabibi H al , Smith H J
Published: April 2011

α-Chymotrypsin is rapidly inhibited by an acid solution of dibenamine in an irreversible manner when the reactants are mixed in a buffer at near neutral pH. The degree of inhibition depends on the molar ratio of the reactants. The alkylating species is probably the ethyl-eniminium ion from dibenamine, this ion being present at a higher level in the acid media than in the near neutral media used here.
The difference in activity between (+)- and (-)-methadone is intrinsic and not due to a difference in metabolism
Authors: Sullivan Hugh R , Due Susan L , McMahon Robert E
Published: April 2011

The disposition and metabolism of (+)- and (-)-methadone has been compared in rats. At equal molecular doses, somewhat higher plasma levels of (-)-isomer were observed. At equal analgesic doses, brain and plasma concentrations of (+)-methadone were at least 25 times greater than those of (-)-methadone. No qualitative differences were observed between isomers with respect to in vivo metabolic pattern or in vitro N-demethylation rates. The results strongly support the conclusion that the large differences in analgesic potency between the isomers is due to an intrinsic difference in pharmacologic properties and is not related to a difference in disposition or metabolism.
The surface activity of some antihistamines at the air-solution interface
Authors: Attwood D , Udeala O K
Published: April 2011

The surface activity of some antihistamines at the air-solution interface has been examined. Change of the counterion associated with the drug from chloride to maleate or chloro-theophyllinate considerably decreased the critical micelle concentration and increased the surface activity. The effect on surface activity of changes in the nature of the hydrophobic and hydrophilic groups have also been evaluated.
Narcotic agonist and antagonist potencies of a homologous series of N-alkyl-norketobemidones measured by the guinea-pig ileum and mouse vas deferens methods
Authors: Kosterlitz H W , Leslie Frances M , Waterfield Angela A
Published: April 2011

The narcotic agonist and antagonist potencies of the series of N-alkyl-norketobemidones from norketobemidone to decylnorketo-bemidone have been determined. The values obtained in the electrically stimulated preparations of the guinea-pig ileum and the mouse vas deferens are closely correlated. The agonist potencies observed in the guinea-pig ileum agree well with those found in the mouse hot-plate test (Oh-ishi & May) and those obtained by determining the inhibition of naloxone binding in brain homogenates (Wilson, Rogers, Pert & Snyder). The antagonist potencies in the guinea-pig ileum and, to a lesser extent, those in the mouse vas deferens agree with the values obtained in the morphine-dependent monkey.
Generation of prostaglandin E-like material by the guinea-pig trachea contracted by histamine
Authors: Grodzinska L , Panczenko B , Gryglewski R J
Published: April 2011

Challenges of the superfused (1 ml min−1) trachea with histamine (100–200 μg) result in the release of prostaglandin E-like material (3–25 ng in terms of prostaglandin E2) but no prostaglandin F-like activity has been detected in the superfusate. This release is blocked by indomethacin (1 μg ml−1) and then the contractile action of histamine is enhanced. It is concluded that the release of a prostaglandin E-like material by histamine from tracheal smooth muscles is a self-defensive mechanism protecting against the strong constriction of airways. The maximal relaxation of trachea by isoprenaline (50–500 μg) is not accompanied by the release of a prostaglandin-like material.
Non-ionic surfactants and membrane transport of thioridazine in goldfish
Authors: Florence A T , Gillan J M N
Published: April 2011

Polysorbate 80, which has been widely used in studies of the effects of surfactants on drug absorption, increases the rate of absorption of some drugs at concentrations near its critical micelle concentration (cmc). To determine whether all non-ionic surfactants were capable of inducing this effect, the effects of six commercial non-ionic surfactants on thioridazine absorption in goldfish have been compared with the effect of polysorbate 80. The reciprocal death time (T−1) determined when the fish were immersed in the solution under study was the index of absorption rate used. Not all surfactants tested increased T−1. Cremophor EL (polyoxyethylated castor oil), Atlas G1295 (a polyoxyethylene fatty glyceride), Atlas G1300 (a polyoxyethylene glyceride ester) had no effect below their cmc’s. Those surfactants that did increase T−1 [polysorbate 80 (a polyoxyethylene sorbitan monooleate), Atlas G1790 (a polyoxyethylene lanolin derivative), G2162 (a polyoxyethylene oxypropylene monostearate) and Renex 650 (a polyoxyethylene alkyl aryl ether)] display the concentration-dependent behaviour reported previously–a decrease in absorption rate when the surfactant concentration is increased above its cmc. The factor determining whether or not the surfactant will increase absorption rate appears to be the configuration of the surfactant molecule rather than its hydrophile-lipophile balance or its surface activity.
Quantitative determination of morphine in biological samples by gas-liquid chromatography and electron-capture detection
Authors: Dahlström Bengt , Paalzow Lennart
Published: April 2011

A highly sensitive method for the determination of morphine in plasma and brain samples down to 500 pg ml−1 in plasma and 100 pg in 30 mg of brain tissue is described. This sensitivity is in the range of that described for radioactive and radioimmunological techniques. The samples (50–500 μl) are extracted with toluene–butanol (9:1) at pH 8.9 and then re-extracted into 0.1N sulphuric acid and back extracted to a toluene–butanol phase at pH 8.9. The pentafluoro-propionic anhydride derivatives of morphine and the internal standard nalorphine were quantitatively determined by gas–liquid chromatography with a 3H electron capture detector.
Dextromethorphan inhibits 5-hydroxytryptamine uptake by human blood platelets and decreases 5-hydroxyindoleacetic acid content in rat brain
Authors: Ahtee Liisa
Published: April 2011

The effect of dextromethorphan on the uptake and metabolism of 5-hydroxytryptamine (5-HT) was studied in human blood platelets and in rat brain. In the concentration of 120 nM dextromethorphan inhibited the uptake of 5-HT (1 μM) into platelets by 50%. The corresponding concentrations of imipramine and methadone under similar conditions were 22 and 590 nM, respectively. Dextromethorphan (20 to 40 mg kg−1) decreased the concentration of brain 5-hydroxyindoleacetic acid (5-HIAA) and the probenecid-induced accumulation of 5-HIAA time- and dose-dependently. However, dextromethorphan did not alter the pargyline-induced changes in brain 5-HT metabolism. Dextromethorphan-induced changes in brain 5-HT metabolism could arise from the inhibition of the reuptake of 5-HT into neurons.
Evidence for a central α-sympathomimetic action of Clonidine in the rat
Authors: Finch L , Buckingham R E , Moore R A , Bucher T J
Published: April 2011

The antihypertensive effects of Clonidine (0.15 mg kg−1, i.p.) were studied in conscious DOCA/saline hypertensive rats having chronically implanted arterial cannulae. The response to Clonidine was markedly reduced by simultaneously administered desipramine (3 mg kg−1, i.p.), antagonized dose-dependently by piperoxan (2–10 mg kg−1, i.v.) and prevented by pretreatment with phentolamine (0.2 mg, i.c.v.). Pretreatment with 6-hydroxydopamine (3 × 250 μg, i.c.v.), halo-peridol (1 mg kg−1, i.p.), p-chloro-N-methylamphetamine (3.5 mg kg−1, i.p.) or 5, 6-dihydroxytryptamine (50 μg and 25 μg, i.c.v.) did not significantly modify the antihypertensive response. It is concluded that the antihypertensive response to Clonidine is mediated via stimulation of central α-adrenoceptors and is independent of central dopaminergic receptors and intact central serotoninergic neurons. The necessity for intact central noradrenergic neurons remains uncertain.
Tyrosine hydroxylase activity in rat brain regions after chronic treatment with ±-propranolol
Authors: Peters D A V , Mazurkiewicz-Kwilecki I M
Published: April 2011

Rats were injected twice daily with ±-propranolol (6 mg kg−1 day−1) for 14 days and killed 16 h after the final injection. Tyrosine hydroxylase activity was measured in both soluble and particle-bound forms in various brain regions. The activity of the soluble enzyme was not significantly altered by propranolol treatment in any of the brain regions studied. The tyrosine hydroxylase activity in the particulate fraction was significantly increased in corpus striatum and unchanged in other brain regions. The propranolol concentrations in the various brain regions in this chronic study were far lower than necessary to produce a significant change in tyrosine hydroxylase activity in acute experiments. It was concluded that chronic propranolol treatment produces a persistent increase in bound tyrosine hydroxylase activity in rat corpus striatum.
Oxotremorine- and atropine-induced changes of dopamine metabolism in the rat striatum
Authors: Javoy France , Agid Yves , Glowinski Jacques
Published: April 2011

The effects of various doses of oxotremorine and of atropine (30 min, i.p.) on the metabolism of dopamine were examined in the striatum of the rat. Changes in striatal dopamine metabolism were estimated by following either the accumulation of [3H] dopamine 15 min after intravenous injection of [3H] tyrosine or the accumulation of dopa (taken as an index of dopamine synthesis) in animals pretreated with a dopa decarboxylase inhibitor Ro4–4602. Oxotremorine, 0·1 mg kg−1, and atropine, 1 mg kg−1, did not affect dopamine metabolism. Oxotremorine, 0·5 and 1·5 mg kg−1, did not modify dopamine concentrations but increased the accumulation of [3H]dopamine. The drug enhanced dopa formation in animals pretreated with Ro4–4602. Atropine, 5 and 20 mg kg−1, increased the accumulation of [3H]dopamine but did not affect dopamine concentrations. The accumulation of dopa was not modified there being no difference from the saline value in animals pretreated with the dopa decarboxylase inhibitor. Thus at high doses oxotremorine stimulated dopamine metabolism and atropine reduced dopamine utilization.
Evidence for a clorgyline-resistant monoamine metabolizing activity in the rat heart
Authors: Lyles G A , Callingham B A
Published: April 2011

When benzylamine was used as substrate, a component of the total monoamine oxidase (MAO) activity in the rat heart was found to be resistant to inhibition by clorgyline. The proportion of the total activity represented by this component, decreased as the rat grew. It was also inhibited by both semicarbazide and isoniazid but not by potassium cyanide. Inhibitor studies with MAO in subcellular fractions showed that this component was more concentrated in the microsomal and soluble fractions. However, it could not be concluded that the activity was entirely a soluble enzyme. Determination of quasi-Michaelis constants (“Km”) for total benzylamine oxidizing activity revealed a high (“Km” of approximately 10−5M) and low (“Km” of approximately 5 times 10−4M) affinity component. The high affinity component was inhibited by semicarbazide and the low affinity component by clorgyline. In the presence of 10−3M clorgyline, the high affinity component showed substrate inhibition at higher substrate concentrations. The possibility is discussed that the clorgyline-resistant activity is due to an amine-oxidizing activity distinct from mitochondrial MAO.
Effect of surfactant monomers on chloramphenicol association to an albuminlecithin complex: a model for modified drug absorption
Authors: Alhaique F , Giacchetti D , Marchetti M , Riccieri F M
Published: April 2011

The binding of chloramphenicol to an albumin-lecithin complex in the presence or absence of premicellar concentrations of both ionic and non-ionic surfactants has been examined. Long chain, strong ionic detergents, such as sodium dodecyl sulphate or cetyltrimethylammonium bromide, severely perturb protein structure and eventually allow full separation of the complex into lecithin and albumin-detergent complexes. The dissociation process is reversible upon the removal of the detergent by exhaustive dialysis. After the splitting of the complex, the amount of antibiotic associated with the lipid-protein mixture increases. Structural alteration of the albumin-lecithin complex and the increase in the binding of chloramphenicol have an effect on the transfer rate of this antibiotic across an artificial barrier consisting of an aqueous dispersion of the same complex, as observed in a model system. It is suggested that a reversible alteration in membrane structure, and consequently in membrane permeability, might be easily effected, at the molecular level, through a reversible dissociation of structural lipoproteins into their components, operated by premicellar concentrations of ionic surfactants. This represents a tentative picture of the possible events taking place within the membrane and modifying the absorption rate of a drug, when it is associated with surfactants in a pharmaceutical preparation.
The effect of blending on the rheological properties of gelatin solutions and gels
Authors: Robinson John A J , Kellaway Ian W , Marriott Christopher
Published: April 2011

The effect of blending on rheological properties for an acid and alkaline processed gelatin has been investigated. Blending of weak gels (1·0–3·5% w/v at 25°), resulted in a decrease in gel rigidity whereas in the stronger gels (5–50% w/v at 25°) and solutions (18% and 30% w/v at 35°), an increase occurred. The decrease in structure in the weak gels is considered to be due to coulombic effects, minimum strength occurring for a mixture which possessed zero charge in solution. A tentative explanation for effects in rigid gels and concentrated solutions is offered.
Metabolism of Δ1-tetrahydrocannabinol by the isolated perfused dog lung. Comparison with in vitro liver metabolism
Authors: Widman Marianne , Nordqvist Marianne , Dollery Colin T , Briant Robin H
Published: April 2011

The metabolism of (—)-Δ1-tetrahydrocannabinol (Δ1-THC) has been studied in the isolated perfused dog lung. After intravascular administration of [3H]-Δ1-THC there was an overall biotransformation of 12%. Two major metabolites were isolated and identified as 3“-hydroxy-Δ1-THC and 4”-hydroxy-Δ1-THC. 7-Hydroxy-Δ1-THC was also present together with small amounts of 6α-hydroxy-Δ1-THC and 6β-hydroxy-Δ1-THC. An in vitro experiment using a dog liver microsomal preparation was also carried out and showed that the major metabolites were 6β-hydroxy-Δ1-THC and 6α-hydroxy-Δ1-THC. 7-Hydroxy-Δ1-THC and 1,2-epoxy-hexahydrocannabinol were also isolated together with small amounts of 3“-hydroxy-Δ1-THC and 4”-hydroxy-Δ1-THC. The side-chain hydroxylated compounds are hitherto undescribed metabolites of Δ1-THC.
Determination of low concentrations of the quaternary ammonium compound thiazinamium methylsulphate in plasma and urine
Authors: Jonkman Jan H G , Wijsbeek Jaap , Boer Suse Hollenbeek Brouwer-de , de Zeeuw Rokus A , van Bork L E , Orie N G M
Published: April 2011

A sensitive and selective method for the quantitative determination of the quaternary ammonium antiacetylcholine-compound thiazinamium methylsulphate (Multergan) in plasma and urine is described. The procedure is based on ion pair extraction of the compound with iodide as the counter ion. This is followed by gas chromatography using an alkali flame ionization detector. The detection limit is 2 ng ml−1 with a recovery of 88·0 ± 6·2% from plasma, 91·4 ± 4·6% from urine. The described method can also be applied to other quaternary ammonium compounds.
Cerebral monoamine metabolism in guinea-pigs with ascorbic acid deficiency
Authors: Saner A , Weiser H , Hornig D , da Prada M , Pletscher A
Published: April 2011

Guinea-pigs kept on a diet deficient in vitamin C showed, after 3 weeks, a marked decrease of ascorbic acid in brain and blood leucocytes as well as of the activity of alkaline phosphatase in blood plasma. Pair-fed animals did not exhibit these changes. The α-methyl-p-tyrosine (αMpT)-induced diminution of noradrenaline in the hypothalamus and the rest of the brain was attenuated in pair-fed animals, but restored in guinea-pigs deficient in ascorbic acid. The cerebral noradrenaline content (without administration of αMpT) showed a decrease in both pair-fed and ascorbic acid deficient animals. The noradrenaline of the heart exhibited a similar tendency. The αMpT-induced dopamine decrease in the striatum of ascorbic acid deficient animals was attenuated and the dopamine content (without αMpT administration) decreased. Pair-fed animals showed a similar tendency. The striatal concentration of homo-vanillic acid (HVA) was diminished in both pair-fed and ascorbic acid deficient guinea-pigs. The cerebral content of 5-hydroxy-indoleacetic acid showed a decrease in pair-fed as well as in ascorbic acid deficient animals. It is concluded that ascorbic acid deficiency enhances the turnover of brain noradrenaline, whereas under-nutrition without ascorbic acid deficiency (pair-feeding) diminishes the turnover of cerebral noradrenaline, 5-hydroxytryptamine and striatal dopamine.
A study of the human metabolism of secbutobarbitone
Authors: Gilbert J N T , Powell J W , Templeton J
Published: April 2011

The urinary excretion of secbutobarbitone (I) and its metabolites has been studied quantitatively using combined gas chromatographymass spectrometry. After a single oral dose was given to healthy male volunteers, unchanged drug (5–9%), 2′-hydroxysecbutobarbitone (II, 1·7–3·2%), 2′-oxosecbutobarbitone (III, less than 1%), and the carboxylic acid (IV, 24–34%) were found. The kinetics of the excretion process were studied.
The identification and analysis of the metabolic products of mephentermine
Authors: Beckett A H , Bélanger P M
Published: April 2011

Phentermine (Ib), N-hydroxymephentermine (Ic) and N-hydroxyphentermine (Id) were identified as metabolic products after in vitro incubation of mephentermine (Ia) with rabbit liver microsomal fractions. Compounds Ia, Ib and Ic were also identified as excretion products in the urine of a human subject given a single dose of mephentermine (Ia) sulphate. Derivatization with acetic anhydride, trifluoroacetic anhydride and the trimethylsilyl donor reagent N,O-bis-(trimethylsilyl)-trifluoroacetamide (BSTFA) or hexamethyldisilazane (HMDS) were used for qualitative identification of the metabolic products Ib–Id by g.l.c.-mass spectrometry and for quantitative determination of Ia–Id after extraction from rabbit hepatic homogenates. The synthesis of N-hydroxymephentermine (Ic) and the properties of the metabolic products are reported.
Factors influencing the excretion and relative physiological availability of pethidine in man
Authors: Chan K , Kendall M J , Wells W D E , Mitchard M
Published: April 2011

Factors influencing the urinary excretion of pethidine, norpethidine and pethidine N-oxide have been examined. The proportion of a dose of pethidine excreted unchanged or as norpethidine depends on the urinary pH and the route of administration. Older people appear to metabolize more of the drug and therefore excrete less unchanged pethidine. The rate of excretion of pethidine in acid urine is directly proportional to the plasma pethidine concentration and under these conditions the relative physiological availability of pethidine has been determined. It has not been possible to explain variations in the amounts of pethidine excreted as the N-oxide.
α-Methyl derivatives of biogenic amines as inhibitors of monoamine oxidase
Authors: Inoue F , Robinson J B , Stansfield Susan A
Published: April 2011

The values of Km app and Vmax for three natural substrates of monoamine oxidase have been determined at various stages in the isolation of the enzyme from rat liver tissue. The results are consistent with the presence in the enzyme preparation of at least two distinct molecular forms of the enzyme.

Using the α-methyl derivatives of the natural substrates as inhibitors of the enzyme, the substrate dependence of Ki further substantiates this view. In addition, the kinetics of the inhibition suggest that the value of Km app may not for all substrates, necessarily be a measure of the affinity of the substrate for the enzyme.
Comparative study of the effects of mianserin, a tetracyclic antidepressant, and of imipramine on uptake and release of neurotransmitters in synaptosomes
Authors: Raiteri Maurizio , Angelini Francesco , Bertollini Alberto
Published: April 2011

The effects of mianserin, a tetracyclic antidepressant, on uptake and release of [3H]noradrena-line (3H-NA), [3H]dopamine (3H-DA), [3H]-5-hydroxytryptamine(3H-5-HT) and [3H]γ-aminobutyric acid (3H-GABA) in synaptosomes from different areas of the rat brain were investigated in a comparative study with the tricyclic antidepressant imipramine. Mianserin and imipramine were inhibitors of 3H-NA uptake in the hypothalamus, but could not increase 3H-NA release from noradrenergic nerve endings. This behaviour was similar to that of (+)-amphetamine. Both mianserin and imipramine had essentially no effect on 3H-DA transport mechanisms in striatal synaptosomes. (+)-Amphetamine, in contrast, strongly affected both 3H-DA uptake and release. Imipramine was stronger than mianserin in inhibiting 3H-5-HT accumulation by striatal synaptosomes. In contrast, mianserin stimulated 3H-5-HT release whereas imipramine was ineffective. Mianserin had virtually no inhibitory activity on 3H-5-HT uptake by rat blood platelets. Imipramine was a modest inhibitor of 3H-GABA accumulation by whole brain synaptosomes; mianserin had no effect. Both drugs did not alter 3H-GABA release. These results indicate that mianserin interferes in a way different from that of tricyclic antidepressants with the neurotransmitter transport mechanisms at the presynaptic level.
The absorption of warfarin from the rat small intestine in situ
Authors: Iulkunen R J K
Published: April 2011

The in situ absorption from the rat small intestine of the weakly acidic drug, warfarin (pKa 5·05), at 200 μg ml−1 in the instilled fluid with initial pH levels of 3, 5, 7 or 8 has been examined. These initial pH's in the buffer changed rapidly towards neutrality. The buffers at pH's 3 and 5 probably caused different amounts of warfarin precipitation, which resulted in different rates of warfarin disappearance from the instilled fluid which paralleled the initial rates of accumulation of warfarin in (or on) the intestinal wall. Where greater drug precipitation had probably occurred the initial rates of absorption into the plasma were slower. At the initial pH of 3 and by solubilization of warfarin with propylene glycol, the rate of absorption was similar to that from a fluid of pH 7. Propylene glycol in 15% solution did not affect the system significantly. The relatively high transfer of warfarin into octanol from buffer solution at pH 7 might indicate that the small fraction of unionized drug (1:100) at pH 7 is enough for remarkable transfer of this highly lipid-soluble drug.
A dual action of 5-hydroxytryptamine on the ovarian suspensory ligament of the rat
Authors: Davis W G
Published: April 2011

5-Hydroxytryptamine has a dual effect on the spontaneously contracting rat ovarian ligament, in vitro, a contraction which is antagonized by the prior administration of methysergide and a relaxation of the ligament observed in the methysergide-treated preparation. The relaxatory effect was not antagonized by propranolol or tetrodotoxin but treatment of the ligament with indomethacin abolished this response. Prostaglandins of the E series produced an inhibition, and PGF2α; a contraction of the ligament. Thin layer chromatographic separation indicates that 5-HT causes the release of a PGE2-like substance which relaxes the ovarian suspensory ligament.
Colorimetric analysis of immunogenic impurities in acetylsalicylic acid
Authors: Bundgaard Hans
Published: April 2011

A rapid and convenient colorimetric method is described for the quantitative determination of the immunogenic impurities in acetylsalicylic acid, acetylsalicylsalicylic acid and acetylsalicylic anhydride. The method involves initial aminolysis of the compounds by ammonia to give salicylamide and subsequent coupling of this with 4-amino-phenazone in the presence of an oxidizing agent. In conjunction with a previously described method for analysis of the anhydride the method allows a specific determination of acetylsalicylsalicylic acid in concentrations down to 0–005%. Applying the methods to 15 different commercial acetylsalicylic acid samples and formulations, acetylsalicylic anhydride and acetylsalicylsalicylic acid were found to be present in amounts ranging from 0001 to 0·024% and from 0·006 to 0·58 % (w/w), respectively.
A method for screening diuretic agents in the mouse: an investigation of sexual differences
Authors: Hill T W K , Randall P J
Published: April 2011

Acetazolamide, aminophylline, frusemide, ethacrynic acid and triamterene were tested for diuretic action at dosages of 3, 10 and 30 mg kg−1 (s.c.) in male and female mice. Each drug significantly raised sodium excretion and all but acetazolamide elevated urine volume and chloride excretion. Potassium excretion was significantly raised by acetazolamide and frusemide. Acetazolamide and triamterene evoked urinary alkalinization whereas frusemide and ethacrynic acid reduced urinary pH. Female mice were markedly more sensitive than males to the diuretic, natriuretic, chloruretic and urinary acidifying actions of ethacrynic acid.
Brain tyrosine hydroxylase activity and systolic blood pressure in rats treated with either deoxycorticosterone and salt or angiotensin
Authors: Rylett P , Dean H G , Lee M R
Published: April 2011

The hypertension induced in adult male rats by doca/salt was found to be accompanied by a significant rise in whole brain tyrosine hydroxylase (TH) activity. A smaller hypertensive effect, produced by angiotensin (750 ng kg−1 daily) was also accompanied by a proportional rise in whole brain TH activity. The specific antagonists spironolactone and saralasin completely blocked both responses in the doca/salt- and angiotensin-treated animals respectively and spironolactone showed a partial inhibition of the effects of angiotensin. In all the animals treated there was a clear correlation between systolic blood pressure and whole brain TH activity. The significance of these changes is discussed in the light of the central mechanism of hypertension.
A four parameter model for oral drug absorption
Authors: Saunders L , Natunen T
Published: April 2011

A method has been developed for assessing absorption parameters from plasma concentration-time results taken over a relatively short time period. In this method, the disposition function is simplified so as to reduce the number of parameters to be evaluated from the five of the two compartment disposition equation to four, and to avoid the requirement for the evaluation of a slow disposition rate constant. The measurements need not therefore be continued over a period long after absorption is complete. A suitable design for kinetic experiments using this method for interpreting the results, is described. A random noise statistical method is proposed for assessing the stability of the calculated parameters.
Effects of animal maturity on smooth muscle and blood pressure responses to prostaglandins E2 and F2α
Authors: Okpako D T
Published: April 2011

The effects of prostaglandins E2 (PGE2) and F2α (PGF2α) on muscle strips from mature and immature rats and guinea-pigs and on rat blood pressure were investigated in the presence of atropine. The colon and stomach strips from immature rats were equally responsive to PGE2 and PGF2α whereas mature colons were significantly more sensitive to PGF2α and mature stomach strips significantly more sensitive to PGE2. On the ileum from immature guinea-pigs the maximum responses to PGE2 and PGF2α were 16 and 8% of the histamine maximum respectively. The corresponding figures on the mature ileum were 86 and 75%. Whereas PGE2 was only twice as active as PGF2α on immature ilea, it was ten times more active than PGF2α on mature muscles. On blood pressure PGF2α and PGE2 were both hypotensive in immature rats whereas PGE2 was hypotensive and PGF2α hypertensive in mature rats. The results suggest that as the animal gets older, receptors for prostaglandins became increasingly differentiated.
Actions of the muscle relaxant chandonium iodide on guinea-pig ileum and vas deferens preparations
Authors: Harvey A L , Paul Dharam , Rodger I W , Singh Harkishan
Published: April 2011

The effects of the newly synthesized neuromuscular blocking agent, chandonium iodide (17a-methyl-3β-pyrrolidino-17a-aza-D-homo-5-androstene dimethiodide) have been investigated on guinea-pig isolated ileum and vas deferens preparations. On the ileum, chandonium (0·1–10·0 μg ml−1; 1·6 × 10−7m–1·;6 × 10−5m) had weak muscarinic receptor blocking action (pA2 is 5·7), but no antihistamine properties at the concentration tested. No evidence for anticholinesterase actions was found. On the vas deferens, chandonium (10·50 μg ml−1; 1·6–8·1 × 10−6 m) potentiated responses to exogenous noradrenaline; responses to electrical stimulation were potentiated only in the presence of 50 μg ml−1 chandonium. No adrenoceptor or adrenergic neuron blockade was found. The results provide evidence that chandonium acts selectively at acetylcholine receptors and that it is more active as a nicotinic receptor antagonist than as a muscarinic receptor antagonist.
A comparative study of the effect of bile salts on the absorption of quinalbarbitone sodium in goldfish
Authors: Marriott Christopher , Kellaway Ian W
Published: April 2011

The goldfish has been used as a model membrane to estimate the absorption of quinalbarbitone sodium by measurement of overturn time. The effect of sodium cholate, sodium deoxycholate, sodium chenodeoxycholate and sodium taurodeoxycholate on the quinalbarbitone-induced overturn time has been investigated and differences in capacity to promote absorption have been demonstrated. These differences could not be attributed to variations in solubility or partitioning of the drug within the membrane by the bile salts or to the relative hydrophobicity of each molecule. It is suggested that the bile salts must in someway affect the integrity of the goldfish membrane rendering it more permeable to quinalbarbitone sodium.
Changes in crystallinity and solubility on comminution of digoxin and observations on spironolactone and oestradiol
Authors: Florence A T , Salole E G
Published: April 2011

Using infrared spectroscopy, X-ray diffractometry, differential thermal analysis, scanning electron microscopy, solubility and dissolution rate measurements, it was demonstrated that the comminution of digoxin results in the appearance of an amorphous phase. The examination of spironolactone and 17β-oestradiol by infrared spectroscopy and differential thermal analysis showed that these compounds also undergo changes in their crystallinity on grinding. Since the dissolution characteristics of poorly soluble drugs may be complex functions of surface area and crystallinity, it is concluded that the most pertinent method for standardizing a sample of a polymorphic drug of low solubility is by means of a powder dissolution test, as the results embrace the influences of particle size, aggregation and polymorphism.
The effects of administering N-(2-benzoyloxyethyl) norfenfluramine to rats on the hepatic synthesis of glycerolipids
Authors: Brindley David N , Bowley Mariana , Burditt Susan , Pritchard P Haydn , Lloyd-Davies Katherine A , Boucrot Philippe
Published: April 2011

N-(2-Benzoyloxyethyl) norfenfluramine (S-780) was administered to rats by stomach tube at a dose of 50 mg kg−1 of body weight. Livers of the rats which were given an acute dose of the drug synthesized more triacylglycerol, phosphatidylcholine and phosphatidylethanolamine from [1,3-3H]glycerol and [14C]palmitate than did those of control rats. The measurements were made by injecting a mixture of the radioactive precursors into the portal veins of anaesthetized rats and freeze clamping a portion of the liver 1 min later. Different results were obtained after treating rats daily with S-780 for 5 days. Liver slices from these rats synthesized less triacylglycerol and relatively more phosphatidylinositol plus phosphatidyl-serine from [3H]glycerol than did those of control rats. S-780 treatment depressed the hepatic synthesis of phosphatidylcholine and phosphatidylethanolamine as measured in vivo after intraportal injection of [14C]palmitate and [3H]glycerol. Chronic treatment with S-780 also depressed food intake and lowered liver weight and body weight of rats fed the 41B diet. The results are discussed in relation to the effects of S-780 on the synthesis of glycerolipids.
The stability of cannabis and its preparations on storage
Authors: Fairbairn J W , Liebmann J A , Rowan M G
Published: April 2011

Solutions of pure cannabinoids, nine samples of herbal and two of resin cannabis (one freshly prepared) were stored in varying conditions for up to 2 years. Exposure to light (not direct sunlight) was shown to be the greatest single factor in loss of cannabinoids especially in solutions, which should therefore be protected from light during analytical and phytochemical operations. Previous claims that solutions in ethanol were stable have not been substantiated. The effect of temperature, up to 20°, was insignificant but air oxidation did lead to significant losses. These could be reduced if care was taken to minimize damage to the glands which act as “well filled, well closed containers”. Loss of tetrahydrocannabinol after exposure to light does not lead to an increase in cannabinol, but air oxidation in the dark does. It is concluded that carefully prepared herbal or resin cannabis or extracts are reasonably stable for 1 to 2 years if stored in the dark at room temperature.
Some formulation factors affecting the tensile strength, disintegration and dissolution of uncoated oxytetracycline tablets
Authors: Esezobo S , Pilpel N
Published: April 2011

A study has been made of the effects of gelatin binding agent and moisture content on the tensile strength, disintegration and dissolution times of oxytetracycline tablets. These properties all increase with the gelatin content, and maximum tensile strengths occur when the tablets contain between 2·5 and 4·5% w/w of moisture. The properties of the tablets depend on their packing fraction and in general, the disintegration and dissolution times are minimal when the packing fraction is between 0·77 and 0·82.

A connection has been established between the disintegration times of the tablets and the time required for 50 % of the drug content to dissolve.
Changes in the particle size distribution during tableting of sulphathiazole powder
Authors: Carless J E , Shear A
Published: April 2011

Five size fractions of sulphathiazole powder (volume surface mean diameter 155, 133, 86, 50 and 41 μm) were compressed into 12 mm diameter tablets on an instrumented single punch tablet machine. The size analysis of the tablet material after compression showed an attrition of the coarser fraction and an agglomeration of the finer fraction. It is postulated that there is a critical particle size where the effects of crushing and bonding cancel each other. The changes in particle size are discussed in relation to some of the compressive characteristics of the powder.
The persistence of dextran 70 in blood plasma following its infusion, during surgery, for prophylaxis against thromboembolism
Authors: Walkley J W , Tillman J , Bonnar J
Published: April 2011

An infusion of dextran (mean molecular weight 70 000) in normal saline (either 1 litre or 500 ml) was given to patients undergoing hysterectomy. The infusion was started at induction of anaesthesia and continued throughout the operation and for up to 6 h thereafter. The rate of elimination of dextran was independent of the dose given. The time to eliminate half the dose was nearly two days and up to 10% was still present in the circulation after one week. The persistence of dextran in the plasma in these amounts and for this length of time may have considerable implications in the prophylaxis of postoperative deep venous thrombosis.
Release of prostaglandin E-like material from perfused mesenteric blood vessels of rabbits
Authors: Grodzińska L , Panczenko B , Gryglewski R J
Published: April 2011

Infusions of noradrenaline (1–3 μg ml−1 min−1) into the mesenteric vascular preparation of the rabbit caused a 2 to 5 fold rise in perfusion pressure and a release of prostaglandin E-like material (3·23 ± 0·65 (s.e.) ng PGE2 equivalents ml−1). Indomethacin (3 μg ml−1) prevented whereas arachidonic acid (0·2 μg ml−1) augmented, the nor-adrenaline-evoked release of a prostaglandin E-like material. The walls of arterioles or precapillary vessels are the proposed site of prostaglandin generation.
Prostaglandins and leucotaxis
Authors: Walker J R , Smith M J H , Ford-Hutchinson A W
Published: April 2011

Freshly prepared solutions of prostaglandin E1 exhibit chemotactic activity against rabbit polymorphonuclear leucocytes harvested from the peritoneal cavity but are devoid of such activity either against similar cells obtained from the rat or against polymorphonuclear leucocytes obtained from the blood of the rabbit, rat and man. Some implications of these findings with respect to the development of inflammatory responses and the mode of action of non-steroidal acidic anti-inflammatory drugs are discussed.
Aggregation of antiacetylcholine drugs in aqueous solution: monomer concentrations in non-micellar drug systems
Authors: Attwood D
Published: April 2011

The self-association of the antiacetylcholine drugs, propantheline bromide, methantheline bromide and methixene hydrochloride in aqueous solution, has been examined by surface tension, light scattering and conductimetric methods. Surface tension graphs were similar to those of conventional surfactants, showing apparent critical micelle concentrations (cmc) at distinct inflection points. Surface tension measurements in the presence of increasing amounts of electrolyte indicated a decrease in the apparent cmc with increase in electrolyte concentration for propantheline bromide. Light scattering curves for propantheline bromide in electrolyte solution showed no significant discontinuity attributable to a cmc. A mode of self association involving aggregate growth by the stepwise addition of monomers was assumed and equilibrium constants for the initial stages of the association were evaluated. An increase in the magnitude of the stepwise association constants with increase in electrolyte concentration was noted. Integration of the light scattering data according to 1n x = ∫co [(M/M app) — 1] dln c (where M and M app are the monomer and apparent aggregate weights respectively and x is the weight fraction of monomers) showed an asymptotic increase in monomer concentration towards a limiting concentration, as the solution concentration, c, was increased. Limiting monomer concentrations determined by this method were in reasonable agreement with the apparent cmcs from surface tension studies. It was not possible to detect a cmc for methantheline or propantheline bromide from conductivity measurements.
Stability of salicylamide-caffeine complex at different temperatures and its thermodynamic parameters
Authors: Donbrow M , Touitou E , Shalom H Ben
Published: April 2011

The stability constants for formation of complexes of salicylamide with caffeine have been measured between 15 and 45°, by means of the solubility method. There was a linear solubility increase at all temperatures but phase diagrams indicated that at 15 and 25° an additional phase was formed which was found to be an insoluble 1: 1 complex. The enthalpies and entropies of interactions were evaluated. They indicate that the interaction is exothermic and enthalpy controlled.
Dihydroxylated metabolites of cannabinol formed by rat liver in vitro
Authors: Fonseka Kanthi , Widman Marianne
Published: April 2011

Cannabinol (CBN) was metabolized in vitro by a 10 000 g supernatant from rat liver. After removal of unchanged CBN and its monohydroxylated metabolites four dihydroxylated metabolites were isolated. By nuclear magnetic resonance and mass spectrometry the compounds were identified as 1“,7-dihydroxy-CBN, 2”,7-dihydroxy-CBN, 3“,7-dihydroxy-CBN and 4”,7-dihydroxy-CBN. Side chain hydroxylation occurred predominantly at C-4″ and C-3″.
Oxidation of aliphatic hydroxylamines in aqueous solutions
Authors: Beckett A H , Purkaystha A Rashid , Morgan P H
Published: April 2011

The effects of pH, buffer constituents, duration of storage, presence of air, heavy metal ions, extracting solvents and various additives and cofactors on the aerial oxidation of some aliphatic primary and secondary hydroxylamines were investigated. Copper ions were particularly effective catalysts of the oxidation reaction. Conditions to minimize this transformation are described.
Black lipid membranes as a model for intestinal absorption of drugs
Authors: Inui Ken-Ichi , Tabara Katsue , Hori Ryohei , Kaneda Akemi , Muranishi Shozo , Sezaki Hitoshi
Published: April 2011

Black lipid membranes were generated in isotonic buffer (pH 4·5 and pH 6·5) from egg phosphatidylcholine and intestinal lipid, and the permeability to salicylamide, salicylic acid, p-aminobenzoic acid and tryptophan of these membranes was studied. Electrical resistance of intestinal lipid membranes was higher than that of phosphatidylcholine membranes. The presence of cholesterol produced an increase in the electrical resistance of black lipid membranes and a small decrease in the permeability of membranes to drugs. The permeability coefficient of salicylamide, an uncharged drug, was much larger than the coefficients of the charged drugs examined. The values for salicylic acid and p-aminobenzoic acid were much larger than comparable values predicted from their partition coefficients. Intestinal lipid membranes were more permeable to acidic drugs than phosphatidylcholine membranes. It is suggested that phospholipids and other lipid components of the small intestine may play an important role in the membrane permeability to acidic drugs. This method may be of interest in studying the complex processes of drug absorption from intestine.