bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of anthraquinone derivatives on canine and rat intestinal motility
Authors: Garcia-Villar R , Leng-Peschlow Elke , Ruckebusch Y
Published: April 2011

The effects on gastrointestinal motility of 3 senna preparations containing 18% oxidized Ca-sennosides, 60% Ca-sennosides, or pure sennosides A + B were tested in dogs and rats as measured by electromyography. Oral administration of the oxidized products in the fasted animal increased the activity of the small intestine within 2 h and reduced both caecal and colonic contractions for 24 h. Severe diarrhoea was present 4–6 h after administration and lasted for at least 1 day. Ca-sennosides had a similar, but weaker effect while pure sennosides affected motility only 6–10 h after oral administration. The intracolonic administration of the oxidized products resulted in an immediate reduction of colon motility for 7–8 h and diarrhoea was present within 40 min. Intracolonic Ca-sennosides and sennosides A + B induced only small changes in the intestinal motility, but diarrhoea also appeared. The results confirm that pure sennosides act predominantly on large intestine motility after their degradation by colonic microorganisms. Oxidized products are already effective in the upper gastrointestinal tract. The early action of Ca-sennosides requires further investigation. Side effects after oral senna treatment such as griping or nausea may be caused by motility changes induced by the presence of small amounts of oxidized products in the drug.
Plasma concentrations of alphaxalone by gas chromatography: comparison with other gas chromatographic methods and gas chromatography-mass spectrometry
Authors: Sear J W , Holly J M P , Trafford D J H , Makin H L J
Published: April 2011

Existing methods for the measurement of plasma or tissue alphaxalone concentrations by gas chromatography are not wholly satisfactory because of the problems of interfering peaks and detector contamination by the silylation reagent. This paper describes an alternative gas chromatographic method using the nitrogen selective alkali flame ionization detector. Plasma samples from patients given Althesin (alphaxalone-alphadolone acetate) were extracted with light petroleum. O-Methyl oximes were formed using methoxyamine hydrochloride, and the O-methyloxime-3-acetate prepared by heating the extract with acetic anhydride-pyridine. Gas liquid chromatography was carried out on a column of 3% OV 17 on Celite 545 (mesh 80–100), initial temperature 235 °C and increasing by 1 °C min−1. Comparison has been made of the O-methyl oxime acetates with trimethylsilyl ethers using both gas chromatography and gas chromatography-mass spectrometry. The results of the two methods were not significantly different. The coefficient of variation for the O-methyloxime-3-acetates at a plasma concentration of 1·09 μl−1 was 6·9%. This method has an improved sensitivity and selectivity over the existing method, and allows determination of the plasma alphaxalone concentrations found in patients receiving Althesin-supplemented anaesthesia.
The application of differential pulse voltammetry at the glassy carbon electrode to multivitamin analysis
Authors: Ballantine J , Woolfson A D
Published: April 2011

Differential pulse voltammetry at the glassy carbon electrode has been applied to the determination of ascorbic acid, pyridoxine and folic acid in a multivitamin preparation. The individual vitamins all gave well-defined peaks in the anodic region with a linear response of peak current to concentration. The water-soluble vitamins were extracted into aqueous solution and folic acid into dibasic potassium phosphate solution. Before determination of pyridoxine, the ascorbic acid peak was depressed by reaction with formaldehyde. Iron (II) present in the multivitamin preparation did not interfere with the analysis. The voltammetric method compared favourably in terms of accuracy and precision with official methods: it was found to be much simpler, with sample manipulation kept to a minimum. The method was found to be generally applicable to the determination of the vitamins in several multivitamin preparations, or, in simplified form, to the determination of the individual vitamin preparations.
Effects of structural variations of non-ionic surfactants on micellar properties and solubilization: surfactants based on erucyl and behenyl (C22) alcohols
Authors: Arnarson Thórdis , Elworthy P H
Published: April 2011

Studies on erucyl alcohol ethoxylated with 24 units and on behenyl alcohol ethoxylated with 21 ethylene oxide units gave values of 10·2 times 103 and 25·4 times 103 for the micellar weights, 74 and 203 for the aggregation number, and 134 and 106 moles water mole−1 surfactant for the micellar hydration, respectively. The solubilization of azobenzene, cortisone acetate, griseofulvin, sulphadiazine, phenylbutazone, betamethasone, tolbutamide, and menaphthone was studied in 2% solutions of the above surfactants, and in cetomacrogol. Excluding sulphadiazine, a linear relationship was found between moles solubilized/mole surfactant, and (log P)/molar volume of solubilizate.
The filling of molten and thixotropic formulations into hard gelatin capsules
Authors: Walker S E , Ganley J A , Bedford K , Eaves T
Published: April 2011

Problems in the formulation and manufacture of conventional solid dose form products include the variation of fill weight and drug content, dissolution control of poorly water soluble drugs and dust generated during manufacture giving rise to cross contamination. We have examined the application of a liquid filling technique for the manufacture of hard gelatin capsules as a means of overcoming some of these. Filling materials are based on water-soluble hot melt polymers such as polyethylene glycol or water-dispersible thixotropic systems of pharmaceutical oils with thixotropic additives. A Zanasi LZ64 capsule filling machine was adapted to fill liquids using a liquid filling pump. No dust is generated during filling and 20 μg doses of drug can be accurately filled without extensive processing. The formulations are simple and do not require specialist ingredients such as lubricants, binders, disintegrants and flow aids. The method of manufacture is reduced to a simple mixing and direct filling operation. The system may be applied to promote the dissolution of poorly water soluble drugs using solid solutions or solid dispersions. Slow release formulations are also available using suitable retard excipients.
The use of liposomes as a model for drug absorption: β-lactam antibiotics
Authors: Kimura Toshikiro , Yoshikawa Michiyo , Yasuhara Masato , Sezaki Hitoshi
Published: April 2011

Liposomes were prepared from egg phosphatidylcholine-cholesterol-diacetylphosphate (80: 20: 5) and total lipid extracts of rat intestinal mucosa, and the permeability of the liposomal membrane to eight β-lactam antibiotics was studied by using a dynamic dialysis method. Although all the antibiotics used here are ionized and poorly lipid-soluble at pH 6·5, some of them are orally active and efficiently absorbed from the small intestine. The release rate constants from the aqueous dispersion of drug-entrapped liposomes were approximately in the order of their absorbability. Intestinal lipid liposomes were more permeable to the antibiotics than egg lecithin liposomes and the release rate constants for the drugs from intestinal lipid liposomes were strongly correlative with their absorption rate constants, except for cephalothin and ampicillin, the deviations of which could be explained by their surface activity. It is suggested that lipid components of the intestinal mucosa and the bilayer structure may play an important role in the absorption process of the antibiotics. The validity of liposomes as a model for the intestinal absorption of drugs is also discussed.
Long-term controlled delivery of levonorgestrel in rats by means of small biodegradable cylinders
Authors: Wise Donald L , Rosenkrantz Harris , Gregory John B , Esber Henry J
Published: April 2011

Hormone release rates from biodegradable cylindrical implants consisting of a physical matrix of [14 C]levonorgestrel and copolymers of [3 H]lactic and glycolic acids have been monitored in rats. Two copolymers were evaluated: one consisted of 90 parts L-lactide/10 parts glycolide (90L/10G) containing 33 or 50% hormone by weight, and the other of 50 parts DL-lactide/50 parts L-lactide (50DL/50L) containing 50% hormone. For each system, 4–6 rods (0·8 times 16 mm) providing 19 mg of steroid per rat were subcutaneously implanted into the scapular regions of 5 rats, and 14 C and 3 H in faeces and urine were determined weekly for 90–724 days. An initial burst of hormone release, peaking at approximately 90 μg day−1, occurred in the first two weeks. This was followed by an approximately zeroorder release for 14 C from all systems. Longer-term release rates were approximately 10–30 μg day−1 for the 90L/10G system containing 33% hormone, a more uniform rate of approximately 25 μg day−1 for the 50DL/50L system and the highest rate of approximately 40 μg day−1 for the 90L/10G system containing 50% hormone. 3 H and 14 C in residual implants of 90L/10G with 33% hormone removed from animals dying of natural causes during the test were assayed. For this system 3 H activity decreased by over 50% within 250 days, compared with < 25 % loss in 14 C activity. The amounts of 3 H and 14 C released were similar over much of the subsequent test period. At the end of the test both polymer and drug were essentially depleted. All animals with the 50DL/50L system died late in the test period. Between days 609 and 724 from 13·7-27·2% initial 14 C and from 10·0-22·1 % initial 3 H was measured in recovered rods. Microscopic inspection of recovered rods showed a loss of core material and tissue encapsulation. There were no signs of local tissue irritation or systemic toxicity.
Comparison of the effect of phenylbutazone, desonide and cyclophosphamide on four types of experimental pleurisy
Authors: Tarayre J P , Lauressergues H
Published: April 2011

The action of phenylbutazone, a non-steroid anti-inflammatory drug, desonide, a corticosteroid, and cyclophosphamide, an immunosuppressant agent, was studied on four types of experimental pleurisy: carrageenan-pleurisy in rats; passive reversed Arthus pleurisy in rats; Bordetella pertussis- delayed hypersensitivity pleurisy in rats and PPD (purified protein derivative)—delayed hypersensitivity pleurisy in guinea-pigs. For each compound, the action on the exudate and on the number of the different categories of leucocytes in the inflammation focus was evaluated. In carrageenan-inflammation, phenylbutazone reduced the oedema and the number of neutrophils and macrophages. Its favourable effect on exudative events in Arthus—and B. pertussis—reactions was not accompanied by high modifications at the cellular level. With the exception of PPD-pleurisy, desonide reduced the three other reactions. Its action related to the exudate and the various leucocyte types, except in the Arthus reaction in which only the number of neutrophils was decreased. The effect of cyclophosphamide was mainly in B. pertussis pleurisy in which it resulted in a decrease of oedema and a reduction in the number of mononuclears. For each compound, correlations between the effect on exudative and cellular phenomena are discussed.
Identification in human urine of Δ9-tetrahydrocannabinol-11-oic acid glucuronide: a tetrahydrocannabinol metabolite
Authors: Williams P L , Moffat A C
Published: April 2011

A Δ9 -THC metabolite has been identified in human urine as an ester linked glucuronide of Δ9 -THC-11-oic acid. Its identity was established by a comparison of mass spectra from the metabolite extracted from human urine and synthetically prepared material. Δ9 -THC-11-oic acid glucuronide was found to be responsible for the major part of RIA crossreactivity in urine with the Guildhay cannabinoid antiserum used in this study.
Radioimmunoassay of diazepam in samples of forensic interest
Authors: Rutterford Mary G , Smith R N
Published: April 2011

The radioimmunoassay of diazepam in biological fluids is described. The method is particularly applicable to samples encountered in forensic toxicology that may be haemolysed, decomposed and of small volume. The antiserum and tritiated diazepam that are used are commercially available. Polyethylene glycol (mol. wt 6000) is used to separate the bound and free fractions, and the free fraction is counted by extracting the tritiated diazepam into a toluene-based scintillant. Blood samples are extracted with ethyl acetate before analysis but urine samples may be assayed directly. The assay is convenient, quick and virtually specific for diazepam. The results correlate well with those obtained by gas chromatography.
The influence of various counter ions on the interaction of chlorhexidine with the hydrophilic contact lens polymer, poly(2-hydroxyethyl methacrylate)
Authors: Plaut B S , Meakin B J , Davies D J G
Published: April 2011

The commercially available salts of chlorhexidine were found to interact with the hydrogel poly (2-hydroxyethyl methacrylate) to different extents, the affinity for the polymer decreasing in the order acetate, gluconate, chloride. The uptakes of the acetate and gluconate salts were almost entirely irreversible over the concentration range studied. The influence of some alternative counter ions, namely amino acids and dicarboxylic acid salts, was examined and found to generate a three-fold variation in the extent of the chlorhexidine interaction. Uptakes were greatest for counter ions that were either hydrophobic in character or bore a net negative charge. Only two compounds, glycine and monosodium oxalate, were successful in reducing the extent of sorption below that observed for chlorhexidine hydrochloride.
Effect of saturable binding on the pharmacokinetics of drugs: a simulation
Authors: Øie Svein , Guentert Theodor W , Tozer Thomas N
Published: April 2011

The time-courses of both total and unbound drug concentrations with time were simulated under conditions of saturable binding to either plasma proteins or tissues, or both, following a single intravenous dose. The curves were either linear, convex, or concave, depending upon the extent of distribution and the intrinsic ability of an eliminating organ to remove drug from the body. Saturable binding should therefore be considered whenever data showing nonlinear semilogarithmic decline are to be interpreted.
Investigations into the binding of phenprocoumon to albumin using fluorescence spectroscopy
Authors: Otagiri M , Fleitman J S , Perrin J H
Published: April 2011

The fluorescence of phenprocoumon is enhanced following interaction with bovine and human serum albumin, allowing the binding parameters for two binding sites to be estimated by a modified Bjerrum method and the Scatchard method. The fluorescence is increased as the pH is raised to 9·0 and also on addition of the drugs ibuprofen and fenoprofen. Chloride ions, phenylbutazone and acenocoumarin seem to displace phenprocoumon from its primary binding site on human serum albumin. Investigations with the enantiomers of phenprocoumon show that the binding sites have some stereospecificity.
On the metabolism of clofibride, a hypolipaemic drug
Authors: Loiseau Gérard P , Millischer René J , Lohier Pierre V , Mardiguian Jean S , Gilede Anne-Marie Pieux , Ginocchio A V
Published: April 2011

The absorption and metabolism of clofibride, a new hypolipaemic drug of p-chlorophenoxyisobutyric type, were investigated in the CD rat, the beagle and the olive baboon monkey. Clofibride is rapidly and massively resorbed and hydrolysed into 4-chlorophenoxyisobutyric acid (CPIB) and 4-hydroxy-N-dimethylbutyramide (HMB). CPIB, in free and glucuroconjugated form, and its metabolite, 4-chlorophenol, in the form of the glucuronate ether, are found in the serum of the rat. HMB is rapidly metabolized. The half-life of CPIB, the main active metabolite, in the serum is about 12 h in the rat, 43 ± 9 h in the dog and 6 ± 1 h in the baboon. In the rat, peak hypocholesterolaemic activity occurs late—24 h after administration of the drug and 20 h after peak concentration of CPIB in the blood. The half-life of 4-chlorophenol glucuronate ether in the serum is about 4 h whereas that of HMB is about 3 h. In the rat, the elimination of clofibride takes place mainly via the urine since 70% of the dose administered is found in the form of free or conjugated CPIB, 10% in the form of HMB or one of its metabolites, in 48 h samples of urine. Over the same period, faecal elimination accounts for no more than 2% of the dose ingested. In addition, in this species, the CPIB, 30% of which is secreted via the biliary route without being eliminated in the faeces, undergoes an enterohepatic circulation.
The catecholamine mechanisms of prostaglandin E1-induced hypothermia in rats
Authors: Lin M T , Chandra A , Sun R , Kau C L
Published: April 2011

Intraperitoneal administration of prostaglandin E1 (PGE1) produced a hypothermia in rats at room temperature (22°C). The hypothermia in response to PGE1 was due to cutaneous vasodilatation and decreased metabolic heat production. Depletion of brain 5-hydroxytryptamine (with 5,6-dihydroxytryptamine and p-chlorophenylalanine) did not alter the PGE1-induced hypothermia. However, depletion of brain catecholamines (with 6-hydroxydopamine) and blockade of central catecholaminergic receptors (with phentolamine and propranolol) both greatly reduced the PGE1-induced hypothermia. The data indicate that PGE1 lowers body temperature in rats by acting on the central catecholaminergic systems.
Self-association of analgesics in aqueous solution: micellar properties of dextropropoxyphene hydrochloride and methadone hydrochloride
Authors: Attwood D , Tolley J A
Published: April 2011

The solution properties of several analgesics including dextropropoxyphene hydrochloride, methadone hydrochloride, dextromoramide acid tartrate and dipipanone hydrochloride have been examined using light scattering, conductivity, vapour pressure osmometry and surface tension techniques. A micellar pattern of association was established for dextropropoxyphene hydrochloride and methadone hydrochloride and critical micelle concentrations and aggregation numbers are reported. The hydrophobic contribution to the free energy of micellization of dextropropoxyphene was determined from measurements of the critical micelle concentration in the presence of added electrolyte.
Decrease in aspirin-induced gastric mucosal damage in rats by oral administration of the cytotoxic drugs melphalan and methotrexate
Authors: Berstock D A , Frank G J , Stamford I F , Bennett A
Published: April 2011

Gastric mucosal damage by aspirin and chemotherapeutic drugs was studied in Wistar rats. Aspirin 60 mg given by stomach tube caused substantial gastric mucosal damage as judged by visual examination of the stomachs removed four hours later. Melphalan and methotrexate given daily for four days had no significant macroscopic effect on the gastric mucosa, but reduced the damage caused by aspirin. This protective effect may involve a stimulation of prostaglandin synthesis by the stomach, increased mucus secretion, and/or inhibition of acid secretion.
The effect of dosage on the bioavailability of chlorothiazide administered in solution
Authors: Corrigan Owen I , O'Driscoll Katherine M
Published: April 2011

Chlorothiazide in solution was administered at four dose levels to three healthy male volunteers under controlled conditions. Excretion data indicated that the drug was poorly absorbed from the gastrointestinal tract. The 24 h recovery of the drug from urine fell from 33 to 6% as the dose was increased from 0·21 to 1·75 g per 70 kg of body weight. The cumulative amount of sodium excreted could be correlated with the cumulative amount of drug excreted, rather than with the dose administered. The electrolyte excretion response intensity could also be correlated with the amount of drug excreted. There was a poor linear relationship between response intensity and drug excretion rate. After higher doses the data suggested that the response was in the non-linear section of the dose response curve.
Vasoactive intestinal polypeptide (VlP)-sensitive adenylate cyclase in rat brain: regional distribution and localization on hypothalamic neurons
Authors: Kerwin R W , Pay Sarah , Bhoola K D , Pycock C J
Published: April 2011

The regional distribution of the vasoactive intestinal polypeptide (VlP)-sensitive stimulation of adenylate cyclase activity was studied in homogenates of rat brain. The order of sensitivity of this peptide on enzyme activity was: olfactory bulb > hippocampus > thalamus > occipital cortex ⋍ frontal cortex ⋍ midbrain ⋍ hypothalamus > striatum > cerebellum ⋍ brain stem > spinal cord. With neurotoxin-induced lesions the possible location of VIP-sensitive adenylate cyclase within the anterior hypothalamus was investigated. Intrahypothalamic 6-hydroxydopamine blocked the stimulatory effect of VIP on hypothalmic adenylate cyclase, but neither kainic acid nor 5,7-dihydroxytryptamine lesions had any effect. Similarly, there was a 71 % reduction in the sensitivity of VIP-sensitive adenylate cyclase activity in animals whose hypothalamic noradrenergic innervation had been interrupted by transection of the ascending dorsal and ventral bundles. Biochemical analyses of the lesions suggested that loss of VIP action on adenylate cyclase was associated with loss of hypothalamic noradrenaline-containing neurons. These results may give insight into those regions of rat brain where VIP may have a neurotransmitter role, and point to a possible noradrenergic localization of the VIP-sensitive adenylate cyclase within the hypothalamus.
On the ability of N-chloroethyl aporphine derivatives to cause irreversible inhibition of dopamine receptor mechanisms
Authors: Costall B , Fortune D H , Granchelli F E , Law S-J , Naylor R J , Neumeyer J L , Nohria V
Published: April 2011

The potential dopamine inhibitory properties of (-)N-(2-chloroethyl)-norapomorphine [(-)NCA], (-)N-(hydroxyethyl)norapomorphine [(-)NHA], (-)N-(2-chloroethyl)-norapocodeine[(-)NCC] and 6-[2-bis-(2-chIoroethyl)-amino]acetyl-11-acetoxy-2-hydroxy-10-methoxynoraporphine (I) were assessed in behavioural (ability to antagonize apomorphine climbing, stereotypy and circling after unilateral electrolesions of the striatum in the mouse, ability to initiate circling/asymmetry alone or after challenge with apomorphine when injected unilaterally into the striatum of rat) and biochemical (ability to inhibit the binding of [3H] (-)N-n-propylnorapomorphine, 3H-NPA, to rat striatal homogenates) tests. (-) NCA, 10–20 mg kg−1 s.c., antagonized apomorphine climbing for a period of 5 days, the response recovering to control values by the 7th day. 10 mg kg−1 s.c. (-)NHA, (-)NCC or I failed to modify apomorphine climbing. Similarly, 2–4 mg kg−1 s.c. (-)NCA caused a long-lasting inhibition of apomorphine circling in the mouse (up to 5 days) whilst (-)NHA, (-)NCC and I were inactive. (-)NCA (10–40 μg) (but not (-)NHA, (-)NCC or I) also caused ipsilateral circling/asymmetry when injected unilaterally into the striatum of rat: this effect was enhanced by apomorphine. However, all agents, including (-)NCA, failed to consistently modify apomorphine stereotypy in the mouse. Non-labelled (-)NPA, (-)NCA and (-)NHA were shown to inhibit the ‘specific’ binding of 3H-NPA to rat striatal homogenates; (-)NCC and I were ineffective. A single washing removed the (-)NHA inhibition whilst repeated washing caused only a modest reversal of the inhibition afforded by (-)NCA. It is concluded that N-chloroethylation in the aporphine series can abolish dopamine agonist action and confer a long-lasting dopamine antagonist potential.
Aerodynamic size distribution, hygroscopicity and deposition estimation of beclomethasone dipropionate aerosol
Authors: Hiller F C , Mazumder M K , Wilson J D , Bone R C
Published: April 2011

Aerodynamic size distribution and aerodynamic mass per dose of beclomethasone dipropionate aerosol were measured at 24 and 95% relative humidity. At high humidity, the count median aerodynamic diameter was unchanged, mass median aerodynamic diameter increased from 2·01 μm to 2·68 μm, particle number/dose from 41·3 times 106 to 78·3 times 106, and aerodynamic mass per dose from 23·7 to 60·0μ g. The quantity of active ingredient estimated to be in the 23·7μg aerodynamic mass at low humidity was 19·7 μg. From data previously available describing average deposition fraction as a function of aerodynamic diameter, 6·7 μg or 13% of the total dose of 50μg produced by the metered dose canister would be expected to deposit in the lower respiratory tract.
Light scattering studies of the solubilization of some esters of p-aminobenzoic acid by lysophosphatidylcholine
Authors: Hunt M J , Saunders L
Published: April 2011

Light scattering equipment has been constructed using a vertically polarized helium-neon laser and a phase-sensitive detection system. The apparatus has been used to determine the micellar weight of lysophosphatidylcholine (LPC), giving values of 1·33 times 105 in water and 1·47 times 106 in 0·05 M sodium chloride; the sols showed some degree of polydispersity. The light scattering apparatus has also been used to study the solubilization by LPC of three n-alkyl esters of paraminobenzoic acid. These compounds caused a considerable increase in the scattered light, particularly at higher LPC concentrations.
Influence of phenobarbitone pretreatment on disposition of amidopyrine and its metabolites in rat
Authors: Lockwood G F , Houston J B
Published: April 2011

Plasma concentration-time profiles for amidopyrine and its primary desmethyl metabolite have been determined in control rats and in rats pretreated with phenobarbitone. The kinetics of both compounds indicate enhanced clearance following pretreatment. Metabolite excretion in urine, bile and breath support the plasma data. It would appear that phenobarbitone pretreatment results in quantitative but not qualitative changes in the metabolism of amidopyrine in rat.
Evidence for thermoregulatory dopaminergic receptors located in the preopticus medialis nucleus of the rat hypothalamus
Authors: Colboc O , Costentin J
Published: April 2011

Systemic administration of apomorphine induces hypothermia in anaesthetized rats as well as in conscious rats exposed to an ambient temperature of 22 °C. The central nature of this effect is confirmed by the antagonism exerted by haloperidol and the lack of antagonism with domperidone. Dopamine receptors involved in the hypothermic effect of apomorphine seem to be located in the preopticus medialis nucleus (p.o.m.n.) of the hypothalamus since: (i) injections of apomorphine (5 ng), dopamine (100 ng) or (+)-amphetamine (50 ng) into this nucleus induce hypothermia, (ii) haloperidol injected into the p.o.m.n. antagonizes the hypothermic effect of a systemic administration of apomorphine, (iii) heat lesions of the p.o.m.n. strongly reduce the hypothermic effect of a systemic injection of apomorphine.
Influence of calcium on noradrenaline release evoked by 5-hydroxytryptamine, tyramine and potassium from goat pial arteries
Authors: Marin J , Sanchez C F
Published: April 2011

The release of tritium (3 H) evoked by tyramine, potassium (K+) and 5-hydroxytryptamine (5-HT) from goat pial arteries preloaded with [3 H]noradrenaline (3 H-NA) was studied. In normal Krebs-bicarbonate solution (KBS) all these agents caused a transient increase in radioactivity release over the basal spontaneous outflow. The pattern of release evoked by 5-HT was similar to that induced by tyramine with a slow onset and decline, but different from that induced by K+ which produced a rapid peak of 3 H release followed by a quick fall. The removal of Ca2+ from the medium did not modify the efflux of radioactivity caused by tyramine, but the 3 H efflux produced by K+ was markedly reduced. Nevertheless, in this Ca2+ -free medium the 3 H release evoked by 5-HT was partially, but significantly, decreased. These results indicate that K+ evokes NA release by a Ca2+ -dependent process, probably of an exocytotic nature, while tyramine mediates NA release by means of a Ca2+ -independent mechanism. However, 5-HT possesses a Ca2+ -dependent and a tyramine-like component.
Dissolution rates of sulfamethoxazole utilizing sugar glass dispersions
Authors: Ghanem A , Meshali M , Ibraheem Y
Published: April 2011

Solid glass dispersions of sulfamethoxazole have been prepared by fusion using different classes of sugars, A marked increase in the dissolution rate of sulfamethoxazole in the solid dispersions was observed compared with that of the drug alone. During the fusion process, interaction took place between sulfamethoxazole and those sugars with carbonyl groups. The bacteriological activity of sulfamethoxazole was not changed by the interaction compared with dispersions in which the interaction did not occur.
Sustained-release dosage forms of microencapsulated isoniazid
Authors: Jalŝenjak I , Nixon J R , Senjkovic R , Ŝtivic I
Published: April 2011

The preparation and release characteristics of microcapsules of isoniazid have been studied. The differing techniques of microencapsulation are assessed and the dissolution of drug from suspended and tableted microcapsules prepared using the chosen technique has been monitored for in vitro release.
The effect of lipid-depletion on the kinetic properties of rat liver monoamine oxidase-B
Authors: Fowler C J , Oreland L
Published: April 2011

The extraction of lipids from rat liver mitochondrial membranes by 2-butanone treatment inhibited the activity of membrane-bound monoamine oxidase -A but not -B. For the -B form, the apparent Michaelis constants of the enzyme towards oxygen and the maximum molecular turnover numbers obtained when β-phenethylamine and benzylamine were used as substrates were not significantly changed by the lipid-depletion procedure, but the values of the Michaelis constant towards benzylamine was significantly increased after lipid- depletion. The differential sensitivity of β-phenethylamine and benzylamine oxidation to inhibition by Tris-HCI was not changed after lípid-depletion. The results are consistent with the hypothesis that the mitochondrial membrane lipids, while essential for the actìvìty of the -A form of the enzyme in rat liver, play a more subtle modulatory role in the activity of the -B form.
The effects of the optical isomers of propranolol on functional refractory period in rat isolated myocardium
Authors: Tomlinson D R , Haworth S C , Harmsworth N J , Ross A M
Published: April 2011

The two optical isomers of propranolol caused a concentration-dependent increase in functional refractory period of the rat isolated left atrium. In this property the isomers were equipotent. Noradrenaline (1 times 10−7 M) decreased the functional refractory period. This effect was completely reversed by (-)-propranolol. The (+)-isomer was much less potent than (-)-propranolol in antagonizing the effects of noradrenaline on functional refractory period.
Effect of prenatal Phenytoin administration on brain tryptophan metabolism of rat offspring during the preweaning period
Authors: Elmazar M M A , Sullivan F M
Published: April 2011

Serum 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) concentrations in control rat offspring increased progressively during the preweaning period reaching adult values by day 21. It has been shown that prenatal phenytoin administration (100 mg kg−1 orally, days 7–19 of pregnancy) increased serum tryptophan and brain tryptophan, 5-HT and 5-HIAA of rat offspring at 3 days of age but not at 4, 15 or 21 days of age. The effect of prenatal phenytoin administration on the offspring at 3 days of age was not observed when these pups were cross-fostered to control mothers at 2 days of age suggesting that the alteration in brain tryptophan metabolism during the development of tryptaminergic neurons in rat offspring, as a result of prenatal phenytoin administration is mediated through changes in lactation or nursing ability of the mothers. It is important that such non-specific factors are controlled when studying the effect of prenatally administered drugs on neonatal brain transmitter concentrations.
Carrageenan-induced activation of human platelets is independent of phospholipase A2 and of formation of thromboxanes
Authors: Vargaftig B B , Fouque F , Chignard M , Dumarey C
Published: April 2011

Aggregationof washed rabbit platelets by thrombin and by carrageenan is accompanied by the activation of phospholipase A2 and by the synthesis of thromboxanes. Accordingly, aggregation, the accompanying release reaction and the activation of phospholipase are blocked by p-bromophenacyl bromide and by CB 874 (2,3-dibromo (4′-cyclohexyl-3′-chloro)-phenyl-4- oxo-butyric acid), two recognized inhibitors of the enzyme. Since these two reagents also inhibit aggregation and the release reaction induced by thrombin and by carrageenan on washed human platelets, it might have been anticipated that the mechanisms of aggregation of the platelets from the two species are similar. Nevertheless, no thromboxanes A2 or B2, nor activation of phospholipase A2 could be demonstrated with the use of carrageenan on human platelets, under conditions where thrombin was effective. It is concluded that carrageenan activates the human platelets by phospholipase A2- and thromboxane A2-independent mechanisms, and that the inhibitors of phospholipase A2 may block platelet functions by mechanisms other than inhibition of the expected enzyme.
Self-association of analgesics in aqueous solution: association models for codeine, oxycodone, ethylmorphine and pethidine
Authors: Attwood D , Tolley J A
Published: April 2011

Light scattering, vapour pressure osmometry, conductivity and surface tension techniques have been used to examine aqueous solutions of several narcotic analgesics for evidence of association. Contrary to a previous report, no significant association could be detected in solutions of morphine sulphate and codeine phosphate. Other drugs which showed no evidence of aggregation in water included morphine hydrochloride, ethylmorphine hydrochloride, oxycodone hydrochloride and dihydrocodeine tartrate. Self-association of ethylmorphine hydrochloride, oxycodone hydrochloride and codeine phosphate was observed in the presence of 0·5 mol dm−3 electrolyte, the pattern of association conforming to that of a stepwise association process with all association constants of equal value. The association of pethidine hydrochloride in 0·5 mol dm−3 sodium chloride could be represented by an association scheme in which association constants KN increased sequentially with aggregation number N according to the relation KN = K(N — 1)/N.
Dosage uniformity in hydrocortisone ointment B.P
Authors: Orr N A , Hill E A , Smith J F
Published: April 2011

The content uniformity of hydrocortisone in seven commercially available brands of hydrocortisone ointment B.P. 1% has been investigated. Fifty 5 mg samples were assayed by high pressure liquid chromatography and the results indicated that for 95% confidence levels only two of the ointments exhibited no positive skewness, one exhibited a significant degree of positive skewness and four exhibited a highly significant degree of positive skewness. The extent of the skewed distributions is discussed in relation to previously published particle/ agglomerate distributions for these ointments. The content uniformity in terms of the coefficient of variation CE calculated from the h.p.l.c. data is compared with the coefficient of variation CP that can be predicted from mixing theory on the basis of the particle/agglomerate distribution of the hydrocortisone. The departure from normality in drug content uniformity in the ointment is attributed to the hydrocortisone particles not being individually available for randomization, a large number being in an agglomerated form. That is, the manufacturing process is failing to achieve the full potential of the formulation by dispersing all of the agglomerates. Theoretical and experimental models predict that percutaneous absorption of drug may be enhanced over areas, where agglomerates are located, possibly not only resulting in localized toxicity but increased systemic availability. Drug content variability in small samples (5 mg) of topical steroid formulations could also effect the degree of skin blanching response in Mackenzie-Stoughton type tests since 5 mg portions containing in excess of twice the labelled strength were found. Regulatory control of content uniformity should be considered for certain topical steroids if unintentional over-dosage on small discrete areas is to be avoided.
Four benzodiazepine radioimmunoassays are described, the most sensitive of which can detect sub-therapeutic levels of bromazepam, chlordiazepoxide, clobazam, demoxepam, desalkylflurazepam, desmethyldiazepam, diazepam, flunitrazepam, lorazepam, medazepam, nitrazepam, oxazepam, prazepam, temazepam and triazolam. The standard curve for diazepam has a concentration range of 0–2·5 ng ml The assay is particularly applicable to blood samples of forensic interest that may be haemolysed or decomposing. A 75 μI sample is required. The antiserum and [3 H]flunitrazepam used are commercially available
Authors: Robinson Katherine , Rutterford Mary G , Smith R N
Published: April 2011

Four benzodiazepine radioimmunoassays are described, the most sensitive of which can detect sub-therapeutic levels of bromazepam, chlordiazepoxide, clobazam, demoxepam, desalkylflurazepam, desmethyldiazepam, diazepam, flunitrazepam, lorazepam, medazepam, nitrazepam, oxazepam, prazepam, temazepam and triazolam. The standard curve for diazepam has a concentration range of 0–2·5 ng ml The assay is particularly applicable to blood samples of forensic interest that may be haemolysed or decomposing. A 75 μI sample is required. The antiserum and [3 H]flunitrazepam used are commercially available.
Rate constants for drug release from micellar solutions of non-ionic surfactants
Authors: Collett J H , Dickinson N A
Published: April 2011

The release of a weak acid from micellar solutions containing different concentrations of two structurally related non-ionic surfactants was estimated using a dynamic dialysis apparatus. In all cases the effect of the surfactant was to reduce the amount of weak acid transferred. The data have been subjected to compartmental analysis using non-linear regression analysis. Rate constants for exchange across the dialysis membrane were independent of surfactant concentration. As surfactant concentration increased the rate constants for transfer from the non-micellar region did not show a marked change.
Availability of tritium from non-aqueous solutions of [1,2-3H]methyltestosterone, administered orally to rats
Authors: James K C , Nicholls P J , Sanders L M
Published: April 2011

The solvent-water distribution coefficients of 17α-methyltestosterone have been determined in selected alkanes, alkanols and alkane-alkanol blends. The oral availability of tritium from solutions of [3 H]methyltestosterone in these solvents and blends was studied in rats by measuring radioactivity in plasma, faeces and urine. Disappearance of radioactivity from the gut and biliary recirculation of 3 H were also examined. Variation of the solvent led to marked changes in the absorption of radioactivity, suggesting a possible method of varying bioavailability from soft gelatin capsules. Neither distribution coefficients nor tritium concentrations changed significantly from one homologue to another, but there was a marked difference when the alkane series was compared with the alkanol series. Blends of octane and octanol, together with the pure solvents, provided a suitable spread of distribution coefficients and tritium concentrations, but no simple relationship could be established between the two properties.
Some factors influencing the metabolism of benzylamine by type A and B monoamine oxidase in rat heart and liver
Authors: Parkinson David , Lyles Geoffrey A , Browne Barbara J , Callingham Brian A
Published: April 2011

The ability of MAO-A and MAO-B to metabolize benzylamine in vitro has been investigated in mitochondrial preparations from rat liver and heart. Although under normal circumstances benzylamine appeared to be metabolized exclusively by MAO-B in the rat liver, a contribution by both MAO-A and a clorgyline-resistant enzyme component was revealed when the MAO-B activity was much reduced by pretreatment of the mitochondria with appropriate concentrations of deprenyl. These three enzyme activities also contributed to benzylamine deamination in rat heart mitochondria. However, binding studies with [3 H]pargyline, which provided an estimate of the respective concentrations of MAO-A and MAO-B active centres in heart mitochondria, indicated a ratio between MAO-A and MAO-B, markedly different from that shown by plots of inhibition of benzylamine metabolism by various concentrations of clorgyline. The interpretation of these clorgyline plots is discussed in terms of the kinetic constants of both MAO-A and MAO-B, and the relative amounts of each enzyme. It is proposed that although the turnover rate constant for benzylamine metabolism by MAO-A is much smaller than that shown by MAO-B, in those tissues containing a large ratio of MAO-A:MAO-B content, the metabolism of benzylamine by MAO-A can be detected.
The effect of the particle size of an inert additive on the surface roughness of a film-coated tablet
Authors: Rowe R C
Published: April 2011

The effect of the particle size of a model inert additive—a dolomite, commercially available in a wide range of grades with varying particle sizes—on the surface roughness of a coated tablet has been studied using a stylus surface roughness measuring instrument. With all grades with a maximum particle size below 10–15 μm there was only a marginal increase in roughness on the addition of the material at low concentrations with a marked increase at concentrations in excess of 20–30% v/v. With the largest particle size material (mean size 18 μm) there was a marked increase in surface roughness at low concentrations with a decrease at higher concentrations. The different trends were due to the influence of the inherent roughness of the tablet substrate used. The results illustrate the potential of this accurate, rapid, simple and non-destructive technique in the optimization of film formulations during product development.
Mechanism of smooth muscle relaxation by tiropramide
Authors: PLANA R R VIDAL Y , CIFARELLI A , SETNIKAR I
Published: April 2011

Experiments on rabbit isolated colon show that a carbachol-induced contraction is accompanied by a decrease in cAMP content of the smooth muscle. (±)-α-(Benzoylamino)-4-[2-(diethylamino)-ethoxy]-NN-di-propylbenzen-propanamid (tiropramide, CR 605), a new tyrosine derivative with antispastic properties, increases cAMP concentrations within the same dose range that produces smooth muscle relaxation with or without carbachol (0·1 μm). These effects are potentiated by 1 mM theophylline, a phosphodiesterase inhibitor. In a purified microsomal preparation from rabbit colon smooth muscle, corresponding to sarcoplasmic reticulum, tiropramide induced a dose-dependent increase Ca2+ binding in the presence of ATP and Mg2+. Tiropramide inhibited phosphodiesterase activity in rabbit colon homogenates in a range of doses about ten times that producing relaxation, cAMP content enhancement and increase Ca2+ binding to sarcoplasmic reticulum. The effects of tiropramide on the carbachol-stimulated rabbit colon in the presence of theophylline, indomethacin or PGE1 are more in agreement with an action of tiropramide as inhibitor of cAMP catabolism than as a result of a prostaglandin-mediated effect. These observations suggest that the smooth muscle relaxant activity of tiropramide arises from drug-induced increase of cAMP concentrations possibly because of inhibition of cAMP catabolism. This effect is accompanied by the binding to the sarcoplasmic reticulum of Ca2+, preventing its interaction with the contractile proteins of the smooth muscle. A direct effect of tiropramide-enhanced cAMP content on contractile proteins in the smooth muscle cannot be excluded.
On the mechanism of salicylate-induced hypothrombinaemia
Authors: PARK B K , LECK J B
Published: April 2011

The mechanism of salicylate-induced hypothrombinaemia has been investigated in the rabbit. Administration of methyl salicylate produced a significant decrease in prothrombin complex activity, in the activity of clotting factors II, VII and X but no significant change in factor V activity. Metabolic studies with [3H]vitamin K1 showed that salicylate increased the plasma concentration ratio of [3H]vitamin K1-epoxide: [3H]vitamin K1. The results are consistent with the concept that salicylate produces its anticoagulant effect, like the coumarin anticoagulants, by interruption of the physiologically important vitamin K1-epoxide cycle at the epoxide reductase.
Inhibition of prostaglandin biosynthesis by clidanac and related compounds: structural and conformational requirements for PG synthetase inhibition
Authors: TAMURA SHIGEO , KUZUNA SEIJI , KAWAI KIYOHISA
Published: April 2011

The inhibition of prostaglandin (PG) biosynthesis by clidanac (6-chloro-5-cyclohexyl-1-indancarboxylic acid, TAI-284), its metabolites and some analogues has been examined using various microsomal preparations as enzyme source. Clidanac and some analogues were among the most potent inhibitors. The (+)-isomer of clidanac was shown to be 1000 times more potent than the (−)-isomer in inhibiting PG synthetase activity. The cis-3′-hydroxyl metabolite which retains anti-inflammatory activity comparable to that of clidanac had much less inhibitory activity. Structure-activity studies with clidanac analogues showed that the position of halogen substitution in 1-indancarboxylic acid is of considerable significance for the conformational requirement for binding to the enzyme.
Immobility test: effects of 5-hydroxytryptaminergic drugs and role of catecholamines in the activity of some antidepressants
Authors: BORSINI F , BENDOTTI C , VELKOV V , RECH R , SAMANIN R
Published: April 2011

Fenfluramine and m-chlorophenylpiperazine, two drugs purported to enhance central 5-hydroxytryptaminergic transmission, and metergoline, a 5-HT antagonist, did not modify the duration of immobility induced in rats made to swim in a restricted space. Nomifensine, desipramine and amineptine, three antidepressants known to block neuronal catecholamine uptake, significantly reduced the duration of immobility. Penfluridol, a dopamine antagonist at central receptors, counteracted the effect of nomifensine and amineptine but not that of desipramine. Propranolol and phenoxybenzamine respectively reduced the effects of desipramine and nomifensine but did not modify amineptine's effect. Metergoline pretreatment did not counteract the effect of any drug. The results indicate that various antidepressants can reduce the duration of immobility in rats by activating dopaminergic and/or noradrenergic mechanisms in the brain. Either α- or β- noradrenergic receptors could contribute to the anti-immobility effects, depending on the drug used. The immobility test appears to be insensitive to drugs activating or reducing 5-HT-ergic mechanisms in the brain.
The measurement of phenol coefficients by flow microcalorimetry
Authors: BEEZER ANTHONY E , HUNTER WILLIAM H , STOREY DAVID E
Published: April 2011

Microcalorimetric bioassay procedures have been applied to the determination of phenol coefficients and dilution coefficients. The derived values are compared with those from a standard AOAC test procedure. The microcalorimetric results indicate close agreement with AOAC values, good reproducibility (±2%), rapidity (30 min per test), potential for automation and the determination of in-use dilutions of disinfectants.