bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of thymoxamine on peripheral blood vessels as monitored by the 133Xe clearance technique
Authors: DICK W CARSON , PROVAN C , RITCHIE D , BUCHANAN W WATSON
Published: April 2011

The rate of clearance of intra-articularly administred 133Xe provides an indirect method for the measurement of synovial tissue perfusion. The effect of an intra-articular injection of thymoxamine, and of isoprenaline was to increase the clearance rate whereas the converse was seen with noradrenaline. The prior administration of thymoxamine did not affect the isoprenaline response. In suitable doses, thymoxamine both prevented, and reversed the noradrenaline effect.
The metabolism and urinary excretion in man of phentermine, and the influence of N-methyl and p-chloro-substitution
Authors: BECKETT A H , BROOKES L G
Published: April 2011

The urinary excretion of phentermine, mephentermine and chlorphentermine was examined after oral administration of phentermine and chlorphentermine hydrochlorides and mephentermine sulphate to man under normal and acidic conditions of urinary pH. The rate of excretion of both phentermine and mephentermine fluctuated with changes in urine pH, a more acidic pH causing a faster rate of excretion; changes in urine flow rate had only a slight effect. The rate of excretion of chlorphentermine was affected by changes in pH and urinary flow rates. Phentermine and mephentermine were recovered almost quantitatively within 24 h from subjects under acidic urine control; only about 35% chlorphentermine was recovered under similar conditions.
Amphetamine tachyphylaxis in the pithed guinea-pig
Authors: Gerald Michael C
Published: April 2011

A single dose of (+)-amphetamine (8 mg kg−1, i.p.) administered 4 h before experimentation, reduced the pressor and positive chronotropic effects elicited by this drug (0·6 mg kg−1, i.v.) and augmented the rate of the development of tachyphylaxis to these responses in the pithed guinea-pig preparation. Amphetamine pretreatment reduced the pressor and positive chronotropic effects of phenylephrine (0·1 mg kg−1, i.v.) and the positive chronotropic effects of angiotensin (30 μg kg−1, i.v.). The rate of the development of tachyphylaxis to the cardiovascular responses elicited by phenylephrine and angiotensin was augmented by amphetamine pretreatment. These results suggest that an indirect mechanism (noradrenaline) may in part mediate the cardiovascular effects of these 3 drugs and/or that amphetamine may act as a competitive antagonist at adrenoceptor sites.
The quantification of kanamycin ototoxicity in the rat using conditioned tone discrimination
Authors: Harpur E S , D’arcy P F
Published: April 2011

Twelve male Lister hooded rats were conditioned to discriminate an 8 kHz tone (56·5 ± 0·5 dB re 0·0002 dyne cm−2) and were subsequently injected subcutaneously with kanamycin (400 mg kg−1 day−1) for 28 days; during this time and for five weeks after dosage was stopped, the nature and extent of the resultant hearing deficits were studied. The animals’ Preyer reflex thresholds were determined at intervals during the study. Only one rat was unaffected by the kanamycin dosage. The onset of hearing impairment (reduced discrimination performance), which was gradual in some rats and sudden in others, generally occurred during the fourth week of kanamycin dosage although the earliest onset was towards the end of the second week. In most animals the hearing impairment progressed after kanamycin was stopped and in one rat there was a latency between the end of drug dosage and onset of hearing impairment. Hearing impairment was irreversible in five rats. One rat, whose impairment was slight, recovered normal hearing. Some rats showed a reduced discrimination performance at a time when their Preyer reflex threshold showed no elevation suggesting that kanamycin, at least initially, caused a threshold elevation rather than reduced sensitivity to intense sounds.
The action of colloidal silicon dioxide as a glidant for lactose, paracetamol, oxytetracycline and their mixtures
Authors: Varthalis S , Pilpel N
Published: April 2011

Anomalies are observed in some of the physical and mechanical properties of mixtures of lactose, paracetamol and oxytetracycline when small amounts of colloidal silicon dioxide are added to them. Owing to its differing propensities to coat the particles of the host powders, the silicon dioxide acts as a glidant for the lactose and paracetamol, but as an antiglidant for the oxytetracycline.
The granulation of ternary mixtures: the effect of the solubility of the excipients
Authors: Jaiyeoba K T , Spring M S
Published: April 2011

The importance of excipient solubility in wet granulation has been shown using mixtures of lactose and boric acid containing third components of differing solubility characteristics. Sucrose dissolved in the binder solution and increased the amount of liquid available to form liquid bridges between other solid particles and therefore increased the number of solid bridges when the damp mass was dried. Thus, stronger, larger granules were formed. The results obtained with Sta-Rx 1500 and magnesium carbonate powders were also dependent upon the extent of solubility of these powders in the granulating solution.
Evaluation of glycine as an inactivator of glutaraldehyde
Authors: CHEUNG H Y , BROWN M R W
Published: April 2011

Glycine was evaluated as an inactivator of the sporicidal activity of glutaraldehyde. Spores from glucose depleted cultures of Bacillus stearothermophilus grown in a chemically defined medium were used. When glycine is used as an inactivator of glutaraldehyde, it lowers the pH value of the solution. Glycine 1% failed to inactivate 0.5% or higher concentrations of alkaline glutaraldehyde in sporicidal studies. If viable counts cannot be performed within the first hour after inactivation, the concentration of glycine should be at least 2% to inactivate effectively 2% alkaline glutaraldehyde.
The macroanionic activity of heparins in the presence of dextrose and calcium ion
Authors: ANDERSON W , HARTHILL J E
Published: April 2011

The effect of dextrose on heparin was investigated using the heparin-azur A interaction as a measure of macroanionic activity. Dextrose solutions did not diminish heparin – azur A metachromasia but prior autoclaving of the dextrose solution resulted in a slight decrease. When calcium chloride was added to the dextrose (autoclaved or unautoclaved) there was a reduction which was greater than that caused by calcium ion in the absence of dextrose. The effects of calcium ion and dextrose acting together were each concentration - dependent. A low molecular weight fraction (8400) was more susceptible to the effects of calcium in the presence of dextrose than a fraction of mol. wt. 19 000, hence unfractionated heparins with different amounts of various fractions may respond differently to calcium in the presence of dextrose. This has not been considered in earlier studies of the anticoagulant activity of unfractionated heparins in dextrose infusion and could have contributed to reported discrepancies, particularly in view of the variety of test methods used. At present, it is not possible to predict from in vitro tests whether dextrose will modify the in vivo anticoagulant activity of heparin.
Identification and measurement of desethylamiodarone in blood plasma specimens from amiodarone-treated patients
Authors: FLANAGAN R J , STOREY G C A , HOLT D W , FARMER P B
Published: April 2011

Desethylamiodarone has been identified as the principal lipophilic metabolite of amiodarone present in plasma specimens from amiodarone-treated patients. This structure has been confirmed by probe-injection mass spectrometry of column effluent fractions and comparison with the authentic compound using both chromatographic and mass spectrometric techniques. Although there is no information available as to the pharmacological activity of desethylamiodarone in man, the plasma concentrations of this metabolite attained during chronic amiodarone therapy are similar to those of the parent compound (0.1–4 mg litre−1).
Are dopamine receptors present on human lymphocytes?
Authors: FLEMINGER S , JENNER P , MARSDEN C D
Published: April 2011

The characteristics of [3H]spiperone binding to human lymphocytes have been examined. The haloperidol displaceable component of [3H]spiperone binding to human lymphocytes was not saturable, and stereoselective displacement by the isomers of butaclamol was not observed. There was no correlation between the ability of known dopamine active drugs to cause displacement of the ligand and their rank order of potency. Chloroquine, a drug with no dopaminergic action, was the most potent displacing agent examined. Fragmentation of the cells caused a marked decrease in the haloperidol displaceable component of [3H]spiperone binding, and saturable binding to the lymphocyte membrane fragments was not observed. Lysis of cells after equilibrium incubation with [3H]spiperone caused a marked reduction in the haloperidol displaceable component of ligand binding. Association of [3H]spiperone with lymphocytes was unaffected by the metabolic inhibitor iodoacetate, or by replacement of sodium ions by lithium ions in the incubation medium, suggesting that such association did not involve an active uptake process. We cannot confirm the existence of dopamine receptors on the surface of human lymphocytes. We suggest that the apparent association of [3H]spiperone with lymphocytes is due to some passive uptake process causing accumulation of the ligand within the cells.
The effect of membrane filters on cultured cells
Authors: ENGEL FREDERIK
Published: April 2011

The use of membrane filters for filtration of serum-containing culture media can change a medium in such a way that cells cultured therein attain a significantly higher lactate-glucose metabolism than the same type of cells cultured in unfiltered medium. Five different filtertypes were examined, but the response was only found after filtration with MF-filters of Millipore (mixed esters of cellulose). Furthermore, in two of the three cell lines examined minor growth inhibitions were also observed. The MF-filters were found to contain a compound bound to the filter material so that serum-containing medium, but not serum-free medium, or water, could extract it in amounts sufficient for metabolic – and growth effects. The compound in MF-filters is closely related to Triton-X-100 both with respect to u.v.-spectra and to biological effects.
Reaction of ampicillin with serum albumin to produce penicilloyl-protein conjugates and a piperazinedione
Authors: BUNDGAARD HANS , HANSEN JENS
Published: April 2011

Formation of penicilloyl-protein conjugates in the body by reaction of penicillins with nucleophilic groups of proteins is considered to be involved in penicillin allergy. In this study the kinetics and mechanism of reaction of ampicillin with human and bovine serum albumin in aqueous solution at 37 °C and pH 6.6–10.4 have been investigated and compared with the reaction of benzylpenicillin previously reported. In addition to forming penicilloyl-protein conjugates, ampicillin was found to react with the proteins to yield a free piperazine-2,5-dione derivative. This product is suggested to arise from intramolecular aminolysis of an N-(penicilloyl)imidazole intermediate at pH 6–8 and of a penicilloyl ester intermediate at higher pH values. The piperazinedione formation was found to compete effectively with formation of penicilloyl-protein conjugates at physiological pH and, along with studies of ampicillin with protein model compounds, the reaction allowed suggestions to be made about the penicillin-reacting sites in the proteins.
Interaction of local anaesthetics with model phospholipid membranes. The effect of pH and phospholipid composition studied by quenching of an intramembrane fluorescent probe
Authors: SUREWICZ W K , LEYKO W
Published: April 2011

The interaction of local anaesthetics, tetracaine and procaine, with model phospholipid membranes has been examined by measurement of drug-induced quenching of the fluorescence of a membrane incorporated probe, 12-(9-anthroyl)stearic acid. The pH dependence of quenching curves obtained for neutral phosphatidylcholine and acidic phosphatidylserine bilayers indicates that, contrary to previous suggestions, both charged and uncharged forms of amine local anaesthetics may be incorporated into lipid membranes.
Acute effects of ethanol and acetaldehyde on plasma phosphate level
Authors: MATSUBARA K , NAKAHARA M , TAKAHASHI S , FUKUI Y
Published: April 2011

Oral administration of ethanol in a dose of 65 mmol kg−1 produced marked change of plasma phosphate level in rabbits. Hypophosphataemia was observed for the first 2 h after administration followed by significant increase of plasma phosphate at 5 h. Hypophosphataemia did not appear when ethanol was given to the rabbits pretreated with pyrazole. When animals were injected with disulfiram in advance, the duration of hyperphosphataemia due to ethanol was prolonged. Administration of acetaldehyde at a dose of 1.5 mmol kg−1 produced hyperphosphataemia. In this study, plasma phosphate was not associated with change in calcium level. These results suggest that the hypophosphataemia observed was related to the metabolic process of ethanol utilizing alcohol dehydrogenase, and that acetaldehyde, a metabolite of ethanol, might induce the hyperphosphataemia in the animals.
The uptake of mepacrine by horse polymorphonuclear leucocytes in vitro
Authors: Read N G , Trist D G
Published: April 2011

The uptake of mepacrine by isolated horse polymorphonuclear leucocytes (PMN) was measured using spectrophotofluorimetry. Two phases of uptake were observed, the first, rapid fraction, essentially complete by 10 min, and a second, slow fraction, which was still proceeding after 60 min. The appearance of mepacrine within the PMN was also visualized by fluorescence microscopy. Discrete yellow points of fluorescence were observed in the cytoplasm of PMN within 30 s. These discrete points corresponded both in size and number to the PMN granules. After 5 min, the nuclei showed faint fluorescence which increased in intensity with time. It was concluded that the accumulation of mepacrine by horse PMN consists of at least two phases, an initial rapid component which represents uptake of the drug through the plasma membrane into the cytoplasmic granules, and a subsequent slower component, possibly representing nuclear binding.
Role of lipoproteins and erythrocytes in the in vitro binding and distribution of cyclosporin A in the blood
Authors: Lemaire M , Tillement J P
Published: April 2011

The distribution of cyclosporin A between plasma, leucocytes and erythrocytes was studied in vitro by means of sedimentation in Ficoll-Paque and dextran. The uptake by erythrocytes was found to be about 50% and the fraction of cyclosporin A bound to leucocytes amounted to 15%. Fractionation of plasma by ultracentrifugation also showed that two thirds of the drug were associated with lipoproteins whereas binding studies with isolated lipoproteins and plasma also indicated that lipoproteins were the major complexing constituents for cyclosporin A in plasma. The binding of cyclosporin A to erythrocytes and lipoproteins seems to be a linear process. The binding to the leucocytes may be a saturable process, however it is of minor importance in terms of the overall binding capacity in the blood.
Interaction of prostaglandins and clonidine in the rat vas deferens
Authors: Griffiths R J , Moore P K
Published: April 2011

Stimulation of presynaptic α2-adrenoceptors by clonidine may lead to local synthesis of prostaglandins which contribute to the inhibition of noradrenaline release observed with this drug. The present investigation was undertaken to determine the role of prostaglandins in the effect of clonidine and xylazine on the rat vas deferens. Both drugs inhibited the twitch response to field stimulation in this preparation. Inhibition was reversed by yohimbine. This effect of clonidine (but not xylazine) was reduced by preincubating vasa deferentia in Krebs containing indomethacin for 1h. Clonidine (but not xylazine) stimulated the synthesis of prostaglandin-like activity in pieces of intact vas deferens incubated in Krebs containing arachidonic acid. Such stimulation was prevented by inclusion of yohimbine (but not prazosin) in the incubation medium. Clonidine did not stimulate prostaglandin synthesis in a cell-free preparation of sheep seminal vesicle microsomes incubated with arachidonic acid or inhibit PGE2 catabolism by purified swine lung 15-PGDH. We conclude that clonidine (but not xylazine) stimulates prostaglandin synthesis possibly by activating phospholipase activity and releasing arachidonic acid from membrane phospholipids. This effect on prostaglandin production is secondary to activation of α2-adrenoceptors.
Solubility behaviour of griseofulvin in fatty acids
Authors: Grant D J W , Abougela I K A
Published: April 2011

The solubility of griseofulvin in the straight-chain alkanoic acids from C2 to C22 and in the C4 and C5 alkanoic acids branched at C-2 was measured at various temperatures. The enthalpy of fusion of griseofulvin, measured by differential scanning calorimetry, was 39.39 kJ mol−1 at the melting point (495.15 K) and 36.95 kJ mol−1 at 373.15 K. The standard Gibbs free energy (ΔG°), standard enthalpy (ΔH°) and standard entropy (ΔS°) of solution were calculated at 373.15 K, from the van't Hoff plot of the temperature dependence of the mole fraction solubility in terms of the pure supercooled liquid solute as the standard state. With increasing chain length of the alkanoic acid solvents, ΔG° increased in parallel with the increase in pKa of the acids in water, suggesting that the solubility behaviour involves specific solute-solvent proton interactions, while ΔH° and ΔS° fluctuated but tended to decrease in parallel with the corresponding decreases in their enthalpies and entropies of ionization, respectively. The fluctuations in ΔH° and ΔS° may be attributed to the different solid adducts containing griseofulvin and the solvent. An observed non-linear (logarithmic) decrease in solubility with decreasing molality of the carboxyl group in the liquid solvent on ascending the homologous series is attributed to the disturbing influence of the hydrocarbon chains on the specific solute-solvent hydrogen bonding. Chain-branching of the solvent at C-2 gave a reduced solubility of griseofulvin and higher ΔG°, ΔH° and ΔS° values compared with the corresponding straight chain acid.
Effects of cold stress and ether stress on aminopyrine demethylation kinetics in vivo
Authors: Lockwood G F , Houston J B
Published: April 2011

The effect of cold stress and ether stress on mixed function oxidase activity in vivo has been studied using the aminopyrine-−14CO2 exhalation rate (CER) method. Cold stress following both acute and chronic exposure resulted in enhanced rate of demethylation of both aminopyrine (CER α half-life) and its monomethyl metabolite (CER β half-life). However the time course of the response to cold stress differs for the two demethylations. The characteristics of the cold-induced enhancement of aminopyrine-CER would appear to differ in several aspects from that reported for phenobarbitone pretreatment. In contrast, ether exposure did not produce any consistent effect on drug metabolizing status of the rat.
Interactions of ionic and non-ionic surfactants with plasma low density lipoprotein
Authors: Tucker Ian G , Florence A T
Published: April 2011

Surfactants might be useful in facilitating the replacement of the interior of low density lipoprotein (LDL2) (ρ = 1˙02-1˙063 g ml−1) with drug molecules. We have used photon correlation spectroscopy, supported by sedimentation velocity measurements to study the effects of surfactants on LDL2. Sodium dodecyl sulphate, cetrimide, and all non-ionic surfactants studied caused rapid increases of ca 50% in the Stokes' radius up to surfactant/LDL2 molar ratios of ca 1000:1. This was interpreted as due to partial unfolding of the LDL2 protein and intercalation of surfactant with the LDL2 surface layer. At higher concentrations, ionic surfactants and non-ionics with HLB values <14˙6 decreased the Stokes' radius due to delipidation of LDL2. These interactions are similar to those between surfactants and biological membranes, thus LDL2 might be a useful model system to study surfactant structure-activity relationships.
The refractive indices of polymer film formers, pigments and additives used in tablet film coating: their significance and practical application
Authors: Rowe R C , Forse S F
Published: April 2011

The refractive indices of both the polymer film formers and additives are a fundamental factor in defining the appearance of the subsequent film coatings. The refractive indices of the polymer film formers are all in the region of 1·5 but those of pigments and additives vary between 1·5-3·2. Most pigments and additives are also anisotropic, i.e. they possess different refractive indices depending on their orientation. These observations have implications in the use of pigments and additives for the production of both opaque films with good hiding power and film-coated tablets with highlighted intagliations.
Enterohepatic circulation of radioactivity following an oral dose of [14C]temazepam in the rat
Authors: Tse F L S , Ballard F , Jaffe J M , Schwarz H J
Published: April 2011

The enterohepatic circulation of radioactive material after administering [14C]temazepam was evaluated in three sets of male Wistar strain rats connected in pairs by bile duct-duodenum cannulae. After a single oral dose (10 mg kg−1) to the donor rat, the excretion of radioactivity in the urine and faeces of both rats and in the bile of the recipient rat was determined. Mean total recovery of the administered radioactivity was 92·2%. Based on the amount remaining in the donor rat (gastrointestinal tract and faeces), 81·7% of the dose was absorbed by the donor. The total amount recovered from the recipient, 69·4% of original dose (85·1% of donor’s absorbed dose), represented the amount excreted in the donor’s bile. Similarly, 54·1% of the original dose (77·9% of the transferred biliary excretion from donor) was reabsorbed by the recipient, and the biliary excretion from this animal (45·9% original dose) accounted for 86·% of the amount reabsorbed.
The effect of clonidine on the response to stimulation of non-adrenergic non-cholinergic nerves in the guinea-pig urinary bladder in-vitro
Authors: Muir T C , Smart N G
Published: April 2011

The effects of clonidine on the response of the guinea-pig urinary bladder detrusor muscle to stimulation of non-adrenergic non-cholinergic (NANC) nerves were investigated in-vitro. In tissues from both treated and chemically sympathectomized animals, in the presence of atropine (10−5 M) to inhibit cholinergic responses, clonidine (10−10-10−6 M) invariably enhanced the contractile response to NANC nerve stimulation at 2, 5, 10 and 20 Hz. The enhancement was not inhibited by yohimbine (10−5 M), phentolamine (10−5 M), or the histamine H1 or H2-receptor antagonists mepyramine (10−6 M) or cimetidine (10−5 M) respectively. Phentolamine (10−5 M), like clonidine, enhanced the response to stimulation of NANC nerves at 2, 5, 10 and 20 Hz. Xylazine, another α2-agonist, which, unlike both clonidine and phentolamine, is not a substituted 2-imidazoline compound, failed to enhance the response in the bladder to NANC nerve stimulation. The results suggest that clonidine enhances the response to NANC nerve stimulation, independently of its effects on α-adrenoceptors, by increasing the amount of NANC transmitter available.
Release of non-electrolytes from liposomes
Authors: Guy Richard H , Hadgraft Jonathan , Taylor M Joan , Kellaway Ian W
Published: April 2011

Equations have been derived to describe the release of non-electrolytes from liposomal suspensions. The effects of simple physicochemical parameters are shown and the way in which slow interfacial kinetics may dominate release is predicted.
Radioimmunoassay of the new opiate analgesics alfentanil and sufentanil. Preliminary pharmacokinetic profile in man
Authors: Michiels M , Hendriks R , Heykants J
Published: April 2011

The development of two analogous radioimmunoassay (RIA) procedures based on dextran-charcoal separation is described for the quantification of two fentanyl-like analgesics, alfentanil and sufentanil. Immunization of rabbits with conjugates of bovine serum albumin and carboxy-derivatives of the respective drugs resulted in the production of antisera capable of detecting less than 0.05 ng ml−1 of the parent analgesics with high specificity and almost no cross-reactivity with major metabolites. Excellent agreement was obtained between RIA—without prior extraction—and gas chromatography for alfentanil concentrations in human plasma. Because of sufentanil’s low therapeutic plasma levels, no comparison could be made between its RIA and an alternative assay, however, there was strong evidence for the specificity of the assay when applied directly to plasma. With these RIA methods preliminary information was obtained on plasma concentrations and elimination of alfentanil or sufentanil in patients given an intravenous bolus injection of 50 μg kg−1 of alfentanil, or 5 μg kg−1 of sufentanil. For both analgesics, the pharmacokinetic profile in man could be described by a three-compartment model. The terminal elimination half-life was 88 min for alfentanil and 140 min for sufentanil. Six hours after a therapeutic dose, plasma levels were in the order of 3 and 0.3 ng ml−1 for alfentanil and sufentanil respectively.
Inhibition of acetylcholine-stimulated secretion in the isolated whole stomach of the rat
Authors: Parsons M E , Price Carolyn , Wintermeyer Donna
Published: April 2011

The rat isolated whole stomach preparation has been used to investigate acetylcholine-stimulated pepsin secretion. Acetylcholine stimulated pepsin output in a dose dependent manner over the range 3 times 10−4 to 3 times 10−3 M. Metiamide (10−3 M) had no significant effect on the pepsin response to acetylcholine suggesting that histamine H2-receptors are not involved in this response. Atropine (2 times 10−8, 2 times 10−7 and 2 times 10−6 M) produced a dose-related inhibition of the pepsin output to 7 times 10−4 M acetylcholine, indicating that this response is mediated by muscarinic receptors. Pirenzepine also produced a dose-related inhibition of acetylcholine (7 times 10−4 M) stimulated pepsin output at 2 times 10−6, 2 times 10−5 and 2 times 10−4 M. Increasing the concentration of acetylcholine to 3 times 10−3 M completely reversed the effect of atropine (2 times 10−6 M) but pirenzepine (2 times 10−4 M) still produced a significant inhibition of acetylcholine-stimulated pepsin secretion. In each series of experiments acid and pepsin secretion responded in a similar manner to the effects of inhibitors, providing no evidence for a separation of these responses.
The mammalian metabolism of R-(-)-m-synephrine
Authors: Ibrahim Kamal E , Midgley John M , Crowley Jan R , Williams Clyde M
Published: April 2011

The metabolism of R-(-)-m-synephrine (administered orally and by inhalation in man and intraperitoneally in rats) was studied quantitatively by a gas chromatography-mass spectrometry-selected ion monitoring (g.c.–m.s.–s.i.m.) method using deuterated internal standards. When m-synephrine hydrochloride was administered orally to humans in normal dosage regimens four main metabolites were excreted in urine: (i) unconjugated m-hydroxymandelic acid (MHMA, 30%), (ii) m-hydroxyphenylglycol (MHPG) sulphate (6%), (iii) m-synephrine sulphate (47%) and (iv) m-synephrine glucuronide (12%). The comparable figures after inhalation of the drug were 24, 6, 56 and 5%. Intraperitoneal injection of m-synephrine into rats gave: unconjugated MHMA (5%), MHPG sulphate (35%), unconjugated m-synephrine (7%) and conjugates of m-synephrine (9%:4% as the glucuronide and 5% as the sulphate).
Segregation of vibrated powder mixes containing different concentrations of fine potassium chloride and tablet excipients
Authors: Staniforth John N , Rees John E
Published: April 2011

The effect of different drug/excipient concentrations on the segregation tendency of three ordered powder mixes was studied. In addition, the influence of vibration frequency on the segregation intensity and mechanisms of segregation was also studied. Differences in content uniformity of the powders were measured by comparing samples from regions at different depths between the upper exposed powder surface and the base of the cylindrical container. Ordered mixes containing recrystallized lactose excipient and fine-particle potassium chloride as a model drug were found to be least susceptible to segregation at most vibration conditions for all potassium chloride concentrations. Dipac excipient/potassium chloride particles were most susceptible to segregation under all test conditions. In general, segregation intensity was most marked in conditions where high potassium chloride concentrations, above 2% w/w, were subjected to low-frequency vibration, below 100 Hz. Segregation mechanisms were considered to be mainly dependent on vibration conditions, although carrier excipient type markedly modified mechanisms and influenced segregation intensity.
Inhibition of sympathetic neurotransmission in the rat anococcygeus muscle by diazepam
Authors: Oriowo M A
Published: April 2011

In the rat anococcygeus muscle, diazepam (1·8 times 10−6 − 2·8 times 10−5 M), dipyridamole (2 times 10−6 − 3·2 times 10−5 M) and ATP (2 times 10−4 − 6·4 times 10−3 M) concentration-dependently inhibited the motor response to field stimulation. Glycine (up to 7·5 times 10−3 M) and GABA (up to 10−4 M) had no effect on field stimulation. Concentrations of diazepam and dipyridamole which reduced motor response to field stimulation did not relax the tonically contracted rat anococcygeus muscle. However, at these concentrations, diazepam and dipyridamole potentiated the inhibitory responses of the tonically contracted rat anococcygeus muscle to ATP and field stimulation. It is suggested that diazepam and dipyridamole reduced the motor response to field stimulation by potentiating the inhibitory transmitter released during nerve stimulation. Also, since the time-course of the effect of diazepam and dipyridamole on the inhibitory responses to ATP and field stimulation are closely similar, the results would tend to provide additional support for the concept of purinergic transmission in the rat anococcygeus muscle.
The ionization of β-adrenoceptor agonists: a method for unravelling ionization schemes
Authors: Ijzerman A P , Bultsma T , Timmerman H , Zaagsma J
Published: April 2011

To investigate the ionization schemes of β-adrenoceptor agonists, a combined electrochemical/uv-spectrophotometric method with computer-assisted data-analysis was developed, yielding the macroscopic and microscopic ionization constants. From the four species possible, cations and zwitterions were found the main species present at physiological pH, the formation of uncharged molecules and anions being less favourable or apparently negligible.
Counter-ion binding to mucus glycoproteins
Authors: Crowther Roger S , Marriott Christopher
Published: April 2011

The affinity of pig gastric mucus glycoprotein for counter ions of various valencies was examined. Ions of higher valency were bound with increasing avidity, but the degree of binding was apparently not influenced by the ionic radius. The affinity of the glycoprotein for the ions studied may be ranked: Fe3+ > Al3+ > Ca2+ > Cs+ ≃ Na+. The binding of calcium was inhibited by high ionic strength and was sensitive to the pH of the environment. Enzymatic removal of sialic acid slightly reduced the calcium binding capacity.
Effect of sulfhydryl group modification on the neurotoxic action of a sea snake toxin
Authors: Ishizaki Hiroyuki , Allen Matthew , Tu Anthony T
Published: April 2011

Pelamis toxin a is a major neurotoxin isolated from the venom of Pelamis platurus (yellow-bellied sea snake). The effect of sulfhydryl group modification by NN’-1,4-phenylenedimaleimide on the neurotoxic action of Pelamis toxin a has been investigated. The cross-linked toxin having a molecular weight of 11 000 was formed without significant structural changes in the toxin. Lethality tests on the modified toxin indicated that it retained considerable toxicity, although its potency was weaker than that of the native toxin. Binding studies with the acetylcholine receptor isolated from the electroplax of Torpedo californica indicated that the modified toxin binds to the receptor but less effectively than the native toxin. These results suggest that the decreases in toxicity and binding to the receptor are due to a decrease in accessibility of cross-linked neurotoxin to the receptor. This leads us to the conclusion that the region of the neurotoxin containing the sulfhydryl group is not essential for its biological activity. Analysis of the structure and function relationships of the modified toxin suggests that the neurotoxin-acetylcholine receptor interaction requires the proper orientation of the neurotoxin molecule.
Biochemical effects of minaprine on striatal dopaminergic neurons in rats
Authors: Ferretti P , Algeri S , Benfenati F , Cimino M , Ferretti C , Garattini S , Lipartiti M
Published: April 2011

The biochemical effects of minaprine, a new psychotropic drug, were investigated on striatal dopaminergic neurons in the rat. Minaprine did not displace [3H]spiperone in-vitro binding from striatal membranes but had clear effects on dopamine (DA) metabolites. Homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) were significantly decreased in a dose-dependent manner after intraperitoneal administration of minaprine 30 min before killing. In rats injected with minaprine 15 mg kg−1 i.p. at different intervals, the decrease in striatal HVA and DOPAC was time-dependent and a concomitant rise in 3-methoxytryramine (3-MT) concentrations was observed. The maximum of these effects was reached 30 min after minaprine. When administered 5 min after a monoamineoxidase (MAO) inhibitor (pargyline, 100 mg kg−1 i.p.) and 30 min before killing, minaprine did not affect pargyline-induced changes in HVA, DOPAC and 3-MT levels. This together with other data suggests that minaprine affects DA metabolism by acting, at least partially, at presynaptic level through in-vivo inhibition of MAO activity.
An in-vitro investigation of mucosa-adhesive materials for use in controlled drug delivery
Authors: Smart J D , Kellaway I W , Worthington H E C
Published: April 2011

An in-vitro test system was developed to investigate the adhesiveness of various materials to mucus. The results obtained showed good agreement with the findings of previous in-vivo evaluations of mucosa-adhesives. Further investigations found that these materials become adhesive on hydration. Chain length, and the presence of ionizable groups in the molecule, were found to be determinate factors. The physical nature of the gel, and the location at which the mucoadhesive materials hydrated, were of less importance.
New simulators in the prophylaxis against soman poisoning: structural specificity for the depot site(s)
Authors: Van Helden Herman P M , Benschop Henk P , Wolthuis Otto L
Published: April 2011

The oxime HI−6 is effective as an antidote in the soman poisoned (6–8LD50) rat, however, successfully treated animals subsequently show a gradual relapse of signs of poisoning and eventually die after several hours. The relapse is caused by the reappearance of soman at specific sites, after having been elsewhere in the body. Diaphragms isolated from poisoned rats successfully treated with HI−6 also showed a ‘secondary’ relapse of poisoning. Eight compounds chemically related to soman-soman-simulators–-have been tested as prophylactic agents, for their potency in preventing the reappearance of poisoning. The idea was that such compounds may block the non-synaptic binding sites for soman. Three of the 8 compounds proved very effective, which gave some insight into the chemical structure needed for this type of prophylactic action.
Evidence that a novel dopamine receptor agonist, RDS-127 [2−di-n-propylamino−4,7−dimethoxyindane] has some centrally mediated cardiovascular actions
Authors: Arnerić Stephen P , Long John P
Published: April 2011

The cardiovascular effects of RDS−127 [2−di-n-propylamino−4,7−dimethoxyindane] were examined in normotensive, anaesthetized rats. RDS−127 given i.v. (12·5–125 μ kg−1) produced dose-dependent bradycardia. The bradycardic effect was 20·5 times more potent when the drug was administered intracerebroventricularly (i.c.v.) than when given i.v. RDS−127 produced a slight, but significant hypotension. Haloperidol given i.c.v. or i.v. reversed these bradycardic and hypotensive actions, whereas phentolamine was ineffective. Methylatropine partially reduced the bradycardic effect. These results suggest that RDS−127 activates central DA receptors to produce hypotension and bradycardia in rats.
The peripheral narcotic antagonist N-allyl levallorphan-bromide (CM 32191) selectively prevents morphine antipropulsive action and buprenorphine in-vivo binding in the rat intestine
Authors: Bianchi G , Fiocchi R , Peracchia F , Petrillo P , Tavani A , Manara L
Published: April 2011

The assumed low ability of the the quaternary narcotic antagonist N-allyl levallorphanbromide (CM 32191) to cross the blood-brain barrier and its selectivity in relieving the peripherally-elicited antipropulsive action of morphine while preserving analgesia has been tested. To ascertain the extent of penetration of CM 32191 into the cns, its relative potency in preventing the in-vivo binding of high specific activity [3H]buprenorphine in the rat cns and small intestine was compared. Pretreatment was with CM 32191 at 16, 30 or 60 mg kg−1 s.c., 20, 60 or 120 min before buprenorphine, the concentrations of which in cerebrum and spinal cord were comparable with control values, but were consistently reduced in the intestine (longitudinal muscle with attached myenteric plexus). Pretreatment with naloxone (20 min, 0·5 or 1 mg kg−1 s.c.) lowered buprenorphine binding in intestine and cns. Neither narcotic antagonist produced significant changes in buprenorphine plasma concentrations. The peripheral selectivity of CM 32191, methyl naloxone and naloxone was examined by investigating in the same rats nociception in the hot plate (central opiate-sensitive mechanism) and the transit of a charcoal meal along the small intestine (local opiate-sensitive mechanism). Both effects were inhibited by morphine (5 mg kg−1 i.v.). Naloxone (10 min pretreatment, 0·5 or 1 mg kg−1 s.c.) did not selectively antagonize intestinal action of the morphine since the relief of charcoal transit inhibition was consistently associated with complete loss of analgesia. Pretreament (s.c. at 50 min) with the N-methyl quaternary analogue of naloxone, at low doses only, selectively prevented the slowing of transit by morphine without significantly impairing its antinociceptive action; higher doses (>16 mg kg−1) suppressed the antinociceptive action. In contrast, CM 32191 (16, 30 or 60 mg kg−1, 10, 50 or 110 min before morphine) always selectively antagonized constipation induced by the opiate and did not influence its action delaying hot-plate reaction.
The effect of intramolecular hydrogen bonding on the thermodynamics of partitioning of an isomer of the histamine H2-receptor antagonist metiamide
Authors: Mitchell R C , Dunkley D
Published: April 2011

The thermodynamics of transfer from water to 1−octanol of the 4 and 5 substituted N-methylimidazole isomers of the H2-receptor antagonist metiamide have been determined. The isomers have similar free energies of transfer but the enthalpy and entropy of transfer of the 4−isomer are substantially greater than those of the 5−isomer. This indicates that the 4−isomer forms an intramolecular hydrogen bond in the polar octanol phase.
Hypouricaemic effect after oral administration in chickens of polyethylene glycol-modified uricase entrapped in liposomes
Authors: Nishida Y , Kamatani N , Miyamoto T
Published: April 2011

Liposomal-entrapped methoxypolyethyleneglycol (PEG) modified uricase was used to study the plasma urate lowering effect after its oral administration to chickens. Plasma uric acid concentrations fell gradually and were accompanied by a rise in plasma uricolytic activity. Serum from chickens given PEG-modified uricase liposomes did not react with native uricase in immunodiffusion plates. These results suggested the clinical usefulness of liposome-entrapped PEG modified uricase in the treatment of hyperuricaemia.
Tropolone antagonism of the l−dopa-induced elevation of S-adenosylhomocysteine: S-adenosylmethionine ratio but not depletion of adrenaline in rat hypothalamus
Authors: Fuller Ray W , Perry Kenneth W , Hemrick-Luecke Susan K
Published: April 2011

Tropolone, an inhibitor of catechol O-methyl transferase, largely prevented the increase in SAH: SAMe ratio in rat hypothalamus following l−dopa injection. Tropolone did not prevent but instead enhanced the decrease produced by l−dopa of adrenaline concentration in rat hypothalamus. The results imply that the decrease in hypothalamic adrenaline concentration following l-dopa injection was not caused by the increase in SAH: SAMe ratio.
An in-vitro test for the duration of action of insulin suspensions
Authors: Graham D T , Pomeroy A R
Published: April 2011

A method is described which measures the prolongation effects of commercial insulin suspensions by monitoring the rate of solution of an insulin suspension into a phosphate buffer, pH 7·4, at 37°C. The method can rapidly categorize an insulin into the clinical classifications of either fast, intermediate or slow acting. It offers advantages of speed and sensitivity over the British Pharmacopoeial test for prolongation of insulin effect in fasted animals. Large differences between the dissolution rates of commercial samples of isophane insulin were observed which suggested a lack of bioequivalence.
Differential effects of caffeine on dihydroxyphenylacetic acid concentrations in various rat brain dopaminergic structures
Authors: Govoni S , Petkov V V , Montefusco O , Missale C , Battaini F , Spano P F , Trabucchi M
Published: April 2011

The behavioural and neurochemical effects of caffeine were examined in rats. The intraperitoneal administration of different doses of caffeine significantly decreased DOPAC concentrations in striatum, hypothalamus and frontal cortex, but increased them in nucleus accumbens. These observations suggest that the effects of caffeine on the central nervous system (cns) are at least partially mediated through an interaction with the dopaminergic system.
Amine oxidase activities in brown adipose tissue of the rat: identification of semicarbazide-sensitive (clorgyline-resistant) activity at the fat cell membrane
Authors: Barrand Margery A , Fox Sheila A , Callingham Brian A
Published: April 2011

Amine oxidase activity, previously described in homogenates of brown adipose tissue of the rat, has now been investigated in preparations of isolated fat cells. It was found that the specific activities of both monoamine oxidase A (MAO) and of the semicarbazide-sensitive clorgyline-resistant amine oxidase (SSAO) were higher in isolated fat cells than in the original whole tissue. Brown adipocytes therefore represent a major source of both these enzymes. In plasma membranes prepared from these isolated brown fat cells by borate extraction there was a similar enrichment of activity of SSAO and of the plasma membrane marker enzyme, phosphodiesterase I. However in preparations of cell membranes made by binding the cells to polycation-coated beads, enrichment of phosphodiesterase I activity was much greater than that of SSAO. It is suggested that the disposition of the enzyme within the cell membrane may account for the discrepancy in these results, i.e. the sidedness of the membrane may be important. Histochemical visualization of enzyme activity in whole tissue at the ultrastructural level was undertaken. Positive staining of mitochondria was achieved in the presence of the MAO substrate, tryptamine. Staining around the edges of the brown fat cells was observed with the SSAO substrates, tyramine and benzylamine. Staining was largely absent when substrate was omitted or after pretreatment with the irreversible SSAO inhibitor, hydralazine and the slowly reversible inhibitor, semicarbazide. It is not definitely proven that this staining represents sites of enzyme activity but the results are consistent with evidence from other studies indicating that SSAO in brown adipose tissue of the rat may be found predominantly at the fat cell surface. The significance of these findings in relation to the possible function of SSAO is discussed.
Binding of busulfan to plasma proteins and blood cells
Authors: Ehrsson Hans , Hassan Moustapha
Published: April 2011

The reversible and non-reversible binding of busulfan to plasma proteins and to blood cells has been evaluated in man. The reversible binding to plasma proteins was insignificant in both healthy subjects and in patients with chronic myelocytic leukaemia. The percentage of busulfan irreveribly bound to plasma ligands was 32·4. Busulfan was distributed evenly between blood cells and plasma. The fraction of busulfan irreversibly bound to the blood cells was 46·9%. The major portion of busulfan that is degraded in whole blood reacts with the blood cells and the main part of that binds to macromoelcular components in the cells.
Role of vagus in the antagonism of ouabain induced arrhythmias in dogs by β-adrenoceptor antagonists and related drugs
Authors: Alkondon M , Ray A , Sen P
Published: April 2011

The effects of propranolol and related drugs were investigated on ouabain-induced ventricular tachycardia (VT) in dogs with intact and ablated vagi. Propranolol and UM-272 completely antagonized the ouabain VT in dogs with intact vagi, whereas timolol was ineffective. Bilateral vagotomy completely abolished the effect of UM-272 and reduced the effect of propranolol. Diphenylhydantoin, however, reversed ouabain VT in dogs with both intact and ablated vagi. It is inferred that the vagus plays a significant role in the arrhythmolytic effect of propranolol and UM-272.
Improvement in the percutaneous absorption of beclomethasone dipropionate by γ-cyclodextrin complexation
Authors: Uekama K , Otagiri M , Sakai A , Irie T , Matsuo N , Matsuoka Y
Published: April 2011

Inclusion complex formation of beclomethasone dipropionate (BMDP) with γ-cyclodextrin (γ-CyD) in water and in solid state was assessed by solubility analysis and X-ray diffractometry. The solid complex of BMDP with γ-CyD in a molar ratio of 1:2 was prepared and its in-vitro release behaviour was investigated using an ointment release simulator. The release of BMDP from hydrophilic ointment was significantly improved by the γ-CyD complexation. Permeation and uptake studies indicated that the enhanced release of BMDP from the ointment may be due to the faster dissolution and the lower binding affinity of the complex in the ointment base. The vasoconstrictor activity of BMDP in man was found to be increased by γ-CyD complexation, suggesting an improvement in the percutaneous absorption of BMDP.
Enhanced delivery of mitomycin C derivatives through hairless mouse and rat skins
Authors: Hashida M , Mukai E , Kimura T , Sezaki H
Published: April 2011

The percutaneous permeation characteristics of two lipophilic mitomycin C derivatives with aromatic moieties were determined using excised hairless mouse and rat skins and compared with those of mitomycin C (MMC). 1a-N-Benzylmitomycin C penetrated more readily through both kinds of skin than MMC without metabolic conversion. 1a-N-Benzyloxycarbonylmitomycin C effected a 4-fold increase in the delivery of MMC through the rat skin and was completely converted to MMC by an enzyme in rat skin. However, saturation of the metabolic conversion activity was observed in the hairless mouse skin.