bluuebunny/crossref_metadata_2025 huggingface dataset:
Control of the composition of gentamicin sulphate by proton magnetic resonance spectrometry
Authors: Calam D H , Gilbert J N T , Lightbown J W , Powell J W , Thomas A H
Published: April 2011

The proportions of the main components present in gentamicin sulphate complex, gentamicins C1, C1a and C2, can be monitored by 1H nuclear magnetic resonance (nmr) spectrometry. The method depends on measurement of the peak heights of signals for N-methyl and C-methyl groups present in all three components and of those present in C1 and C2 only, followed by calculation of peak height ratios to control composition within acceptable limits. The precision and reproducibility of the method have been established through two collaborative studies each involving seven laboratories. In the second study, with an improved procedure, the mean variance between laboratories with 10 samples was 3·4 × 10−4 for the N-methyl ratio of the peak at δ 2·75 to that at δ 2·95, and 1·25 × 10−3 for the C-methyl ratio of the peak at δ 1·25 to that at δ 1·35. Within laboratories the mean variance for triplicate determinations was 7·4 × 10−5 and 8·9 × 10−5 respectively. The data presented here form the experimental basis for the test controlling the composition of gentamicin sulphate in the British Pharmacopoeia 1973: Addendum 1975, and for the introduction into the British Pharmacopoeia of nmr spectrometry as an analytical technique. The reference standards and all batches of gentamicin sulphate intended for therapeutic use in the United Kingdom examined by this procedure comply with the limits laid down.
The mechanism of the hypothermic effect of amantadine in rats and mice
Authors: Brown F , Davies J A , Redfern P H
Published: April 2011

Amantadine (25–100 mg kg−1, i.p.) given to rats at an ambient temperature of 4°, or mice at 21°, caused a marked fall in rectal temperature. Prior administration of pimozide (1–2 mg kg−1, s.c.) did not block hypothermia due to amantadine in rats or mice; in contrast, hypothermia due to apomorphine (2 mg kg−1, i.p.) and piribedil (10–40 mg kg−1, i.p.) in rats was blocked by pimozide pretreatment. Amphetamine (5 mg kg−1, i.p.) given 2 h after reserpine (2 mg kg−1, i.p.) caused a reversal of the hypothermic effect of reserpine in mice, but a reversal was not obtained with amantadine (50 mg kg−1, i.p.). Direct injection of amantadine (4–8 mg kg−1) into the cerebral ventricles (i.c.v.) of mice caused marked hypothermia which was not blocked by pimozide, but intravenous injection of the same dose of amantadine did not cause hypothermia. Rimantadine, a congener of amantadine but without anti-parkinsonian activity, also caused pimozide insensitive hypothermia in mice at doses of 50 mg kg−1, intraperitoneally or 2–4 mg kg−1, intracerebroventricularly. The main conclusion drawn from these results is that in causing hypothermia amantadine acts in the cns but not on dopamine receptors.
A mammalian muscle with the pharmacological characteristics of slow tonic muscle
Authors: Dale M Maureen , Muid R
Published: April 2011

The guinea-pig isolated cremaster muscle gave tetrodotoxin-resistant dose-related contractures with acetylcholine, carbachol and the depolarizing neuromuscular blocking agents. The dose-response curve to suxamethonium in tetrodotoxin 2 × 10−7m could be shifted to the right with tubocurarine 10−6m. KCl, 0·1 m, produced slow sustained contractures of the muscle. With the cremaster nerve-muscle preparation tetanic contractions at 20 Hz were maintained over several minutes. Tetrodotoxin eliminated the twitch response to single shock nerve stimulation but not the sustained increase in tension produced by suxamethonium. The results suggest either that there is a component of slow tonic muscle in the guinea-pig cremaster or that the cremaster consists of a type of focally innervated muscle which has pharmacological responses qualitatively different from those of most focally innervated muscles so far described.
Effect of carbenoxolone on lipolysis in rat adipose tissue
Authors: Lambert B , Godard C , Jacquemin C
Published: April 2011

Carbenoxolone slightly but significantly decreased the release of FFA from rat epididymal fat pads. The antilipolytic action of carbenoxolone was not blocked by 10−3m 3-isobutyl-1-methylxanthine, a potent inhibitor of phosphodiesterase. The findings suggest that carbenoxolone exerts its antilipolytic activity by acting on adenylate cyclase, thereby decreasing cyclic AMP concentrations and the activity of the hormone-sensitive lipase in adipose tissue.
The inhibition by clorgyline of 5-hydroxytryptamine deamination by the rat liver
Authors: Fowler C J , Callingham B A
Published: April 2011

The inhibition of the monoamine oxidase activity in the rat liver by the substrate selective inhibitor clorgyline has been investigated with 5-hydroxytryptamine as substrate. The results obtained are consistent with a theoretical model whereby the inhibition of enzyme activity by clorgyline follows a reversible association phase leading to an irreversible ‘suicide’ reaction. The relative concentrations of enzyme and inhibitor are of the same order, and can account both for the failure of the reaction to go to completion, and for the differences in the apparent sensitivity of enzyme preparations to inhibition by clorgyline. The possible value of this type of inhibition as a means of assay for monoamine oxidase active centres is discussed.
The measurement of the adhesion of film coatings to tablet surfaces: the effect of tablet porosity, surface roughness and film thickness
Authors: Rowe R C
Published: April 2011

The effect of tablet porosity, surface roughness and film thickness on the adhesion of hydroxypropyl methyl cellulose films to placebo tablet substrates have been studied using a specially designed tensile tester (Fisher & Rowe, 1976). There were direct relations between measured adhesion and tablet porosity and also surface roughness and tablet porosity. The effect of film thickness on the measured adhesion is complex with an initial decrease with thicknesses up to 35 μm and then a gradual increase with thicknesses up to 140 μm due to differences in in the stress distibution within the film during testing. A knowledge of these effects is necessary if results from various sources are to be compared. The findings illustrate the potential capability of the extrapolation of measured adhesion results to zero porosity and zero thickness values in order to obtain a measure of the true or intrinsic adhesion at any film/tablet interface without the confusing elements of tablet porosity, surface roughness and residual stresses in the film.
On methods of expressing dissolution rate data
Authors: Goldsmith J A , Randall N , Ross S D
Published: April 2011

The value of the Weibull, logarithmic-logistic, and logarithmic-normal plots in expressing dissolution rate data is considered for the combinations of zero and first-order release with sink and non-sink conditions, and for actual dissolution rate data of diazepam from tablets in a medium of pH 2.
Investigation of possible interactions between substance P and transmitter mechanisms in the substantia nigra and corpus striatum of the rat
Authors: Starr Michael S
Published: April 2011

The effect of substance P (SP) on the uptake and release of radiolabelled dopamine (3H-DA), 5-hydroxytryptamine (3H-5-HT) and γ-aminobutyric acid (3H-GABA) was studied in slices of rat substantia nigra and corpus striatum. SP, 10−9 to 10−5m, failed to modify the uptakes of these compounds during incubations (10–90 min) with slices of either brain region. SP, 10−6m, had no apparent effect on the spontaneous output of any of these compounds in either substantia nigra or corpus striatum. In the corpus striatum, SP seemed to potentiate the potassium-stimulated outflow of 3H-DA and 3H-5-HT, but not 3H-GABA, while the releases from substantia nigra were unaffected. Morphine (10−3m), but not met-enkephalin (5 × 10−6m), weakly antagonized K+-evoked release of 3H-DA in the corpus striatum. These results are discussed with reference to the possible interaction of SP with transmitter mechanisms at presynaptic sites in the central nervous system.
Quisqualamine, a novel γ-aminobutyric acid (GABA)-related depressant amino acid
Authors: Evans R H , Francis A A , Hunt K , Martin M R , Watkins J C
Published: April 2011

A new substance, quisqualamine, the decarboxylated analogue of quisqualic acid, predictably depressed electrical activity of neurons of the frog and rat spinal cord in vitro and of the mouse spinal cord in vivo. In the in vitro preparations, the action of quisqualamine was associated with a prolonged depolarization of primary afferent terminals which was sensitive to blockade by picrotoxin and bicuculline and which was also depressed by strychnine. This suggests an interaction of quisqualamine with presynaptic receptors for both GABA and β-alanine. Post-synaptic actions of quisqualamine, which were less marked than those at pre-synaptic sites, also appeared to be predominantly GABA-mimetic in vitro, though a sensitivity to the GABA-antagonist bicuculline could not be demonstrated in vivo.
Multiple-scored tablets. Weight and content uniformity of subdivisions and the distribution of active constituent within and between tablets
Authors: Walker John , Abdulsalam Aminah , Theobald Anthony E , Subrahmanyam Rany , Verma Subash K
Published: April 2011

Using three brands of multiple-scored levodopa tablets B.P. (500 mg) and one brand of sulphamethoxypyridazine tablets B.P. (500 mg) the weight and content uniformity of the subdivisions has been examined. It is shown that quartering of such tablets can result in sub-units which do not conform to recognized standards of weight uniformity, and in some instances content uniformity may be questionable. The homogeneity of distribution of active constituent between tablets has been determined and compared with that within tablets (between quarters of individual tablets). Statistical evaluation of the results is presented.
The effect of repeated administration of diftalone on enzyme induction
Authors: Garnham J C , Saunders L , Stainton-Ellis D M , Franklin C , Volans G , Turner P , Natunen T
Published: April 2011

Plasma concentrations of diftalone have been examined in normal volunteers after a single dose (500 mg) and after 500 mg doses given twice daily for one week. An increase in post dosing urinary excretion of D-glucaric acid showed a correlation with the ratio of calculated to observed areas under the plasma concentration, time curve following the final dose in the multiple dosing studies, indicating that hepatic microsomal enzymes are induced after repeated administration of the drug. Single dose studies in the presence of aluminium hydroxide and sodium bicarbonate showed that the antacids had no significant effect on the absorption of diftalone.
Species differences in the in vitro metabolic reduction of the amphetamine metabolite, 1-phenyl-2-propanone
Authors: Coutts R T , Jones G R , Townsend R E
Published: April 2011

Marked differences were observed, in the ability of fortified 9000 g liver homogenate supernatants from three species to reduce 1-phenyl-2-propanone to the corresponding alcohol. This metabolic keto-reduction was negligible in homogenates from the rat and extensive in the rabbit; guinea-pig liver homogenates had intermediate ability. Metabolic oxidation of 1-phenyl-2-propanol was negligible in all three species. The amount of deamination of amphetamine and of N-n-propylamphetamine was approximately equal, in vitro, in rats and guinea-pigs but two to three times greater in liver homogenates from rabbits. Approximately three times more deaminated products were formed from the in vitro metabolism of N-n-propylamphetamine than from amphetamine metabolism by all three species.
The evaluation of cardiovascular drugs in the anaesthetized, unrestrained rat
Authors: Purdy Ralph E , Ashbrook Donald W
Published: April 2011

A method is reported which allows continuous long-term drug administration and simultaneous blood pressure measurement in the unanaesthetized unrestrained rat. The external jugular vein and abdominal aorta were cannulated and the opposite ends of the cannulae were passed subcutaneously and exteriorized at the back of the head. They were then passed through a spring attached at the lower end to the skull and, at the upper end, to a counter-weighted cantilever. In rats so prepared, infusion of angiotensin amide 200 ng kg−1 min−1 caused a rise of blood pressure which lasted the 48 h infusion period. Heart rate decreased initially but recovered within 6 h. Angiotensin amide 30 ng kg−1 min−1, infused up to seven days, was without effect on blood pressure or heart rate, and both doses of angiotensin amide failed to alter cardiac catecholamine turnover. Hydralazine, mecamylamine and clonidine reduced blood pressure to 63, 62 and 84% of control respectively while clonidine induced a transient increase before its depressor effect. Heart rate was increased by hydralazine to 138%, and decreased by clonidine to 74% of control, and was unaffected by mecamylamine. The magnitude of pressor response to noradrenaline, tyramine and angiotensin was reduced by hydralazine and increased by mecamylamine. Clonidine increased the pressor response to angiotensin but had no effect on that to noradrenaline or tyramine.
Theory of the mean absorption time, an adjunct to conventional bioavailability studies
Authors: Cutler D J
Published: April 2011

The theory is outlined of a procedure for characterizing the time-course of drug absorption by determining the mean absorption time. The procedure requires data of the type normally collected in bioavailability studies.
The relation between molecular connectivity and gas chromatographic retention data
Authors: Millership J S , Woolfson A D
Published: April 2011

The recently developed topological index, molecular connectivity (&cH), has been correlated using multiple regression analysis with gas chromatographic retention time (Rt) for various series of compounds. For saturated and unsaturated aliphatic hydrocarbons, and aliphatic aldehydes, good correlation with log Rt was achieved by one-parameter linear equations in terms of the first-order connectivity index. (1&cH). The equation for aliphatic alcohols required an additional parameter, the valence connectivity (v&cH) for satisfactory correlation. One-parameter equations using 1&cH also gave good correlation with log Rt for three series of drug molecules, amphetamines, barbiturates and phenothiazines. In all cases the equations generated gave good agreement between calculated and observed log Rt values.
The character of the antagonism by polyphloretin phosphate of contractions to prostaglandins E1 and F2α in guinea-pig ileum
Authors: Petkov V , Radomirov R , Petkov O , Todorov S
Published: April 2011

Polyphloretin phosphate (PPP) produced a dose-dependent decrease in the tone and reduction of the spontaneous phasic contractions of the longitudinal muscle of guinea-pig isolated ileum. PPP (100 μg ml−1) after a 2 min contact with the ileum decreased the contractile effects of PGE1 0·1 μM by 40·6 ± 7·4%, of PGE1 0·01 μM by 86·7 ± 3·3% and of PGF2α 0·1 μM by 62·2 ± 8·6%. After 10 min contact of PPP the contractile effect of PGE1 0·1 μM was decreased by 47·7 ± 4·7% and that of PGF2α0·1 μM by 89·6 ± 1·7%. When the contact was longer, PPP showed a pronounced after-effect in respect to the effects of PGE1 and particularly of PGF2α. PPP significantly reduced contractions to 5-HT and BaCl2, but not to acetylcholine, histamine or substance P. The type of antagonism of PGE1 by PPP was examined using cumulative concentration-effect curves for PGE1 in the presence of increasing concentrations of PPP. We conclude that on guinea-pig ileum PPP acts as a non-competitive antagonist of PGE1 and PGF2α.
The effect of microcapsule size on the oxidative decomposition of core material
Authors: Nixon J R , Nouh A
Published: April 2011

The factors that affect the size of microcapsules and the oxidation of their benzaldehyde core have been examined. The pH of the preparation changed the overall size of the microcapsules which reached a maximum diameter at pH 4·1. The size of the core droplets also varied with the preparative pH and their oxidation rate depended on the bulk droplet size rather than their surface area. A rapid oxidation of benzaldehyde associated with the microcapsule wall resulted in a preliminary peak in the oxidation curve. Explanations for these phenomena are discussed.
The wetting of powders of acetylsalicylic acid, salicylic acid, phenacetin and paracetamol
Authors: Fell J T , Efentakis E
Published: April 2011

The wetting of powders of acetylsalicylic acid, salicylic acid, phenacetin and paracetamol has been assessed using methanol-water mixtures to give a range of surface tensions. The results have been interpreted in terms of the critical surface tension, adhesion tension and spreading coefficients. The critical surface tension values are surprisingly low which may be due to adsorption of the methanol at the solid surface, exposing its CH3 group to the liquid. The adhesion tension and spreading coefficient values could be useful guides in formulation.
Structure activity relation for some 1,4-benzodiazepinones: correlation between rate constants for reduction by sodium borohydride and antileptazol ED 50
Authors: Ramanujam V M Sadagopa , Trieff Norman M
Published: April 2011

Significant correlation in 11 different 1,4-benzodiazepinones has been established between log k2 (the second order rate constant for the reduction of the ‘azepinones’ by sodium borohydride) and their ED50 against leptazol-induced seizures in mice. The results suggest a possible involvement of the carbonyl group at the receptor site.
The antitussive actions of the drug Ru 20201 given as an aerosol to cats
Authors: Korpas J , Nosalova G , Widdicombe J G
Published: April 2011

The effect of the drug Ru 20201 (1,2,3,4,4a,9b-hexahydro-8,9b-dimethyl-4-[3-(4-methylpiperazin-1-yl)propionamido]dibenzofuran-3-one upon mechanically-evoked cough from the laryngopharyngeal and tracheobronchial areas in nine unanaesthetized cats has been examined. Inhalation of 2 ml of an aerosol of a 10% solution in water suppressed coughing for 30 min. The effect was greatest on the number of cough efforts. The expiratory component of cough was suppressed more than was the inspiratory one. The effect was greater on cough from the laryngopharyngeal than from the tracheobronchial area.
Involvement of mesolimbic and extrapyramidal nuclei in the motor depressant action of narcotic drugs
Authors: Costall B , Fortune D H , Naylor R J
Published: April 2011

The ability of narcotic drugs to induce motor depression from the mesolimbic nucleus accumbens (ACB) and extrapyramidal caudate-putamen (CP) was investigated using the bilateral intracerebral injection technique. Fluphenazine and procaine were used as control agents. Firstly, drugs were injected alone into the ACB or CP and catalepsy was assessed. Fentanyl (2·5–10μg), sufentanil (0·25–1 μg) and carfentanil (0·05–0·5μg) were shown to be potent cataleptogens when injected into both the ACB and CP, the responses being dose-dependent and achieving maximum intensity. Morphine (1–50 μg) also induced a marked dose-dependent catalepsy, but only after injection into the ACB. In contrast, pethidine and methadone, in doses up to 160 μg, caused only weak and inconsistent responses from the ACB and CP. Similar injections of procaine (50–200 μg) were ineffective, but fluphenazine (25–200 μg) induced a moderate dose-dependent response from both the ACB and CP, although onset of action was more rapid and the duration markedly longer for the latter injections. Secondly, drugs were injected peripherally and intracerebrally to determine their ability to antagonize the marked hyperactivity induced by intra-ACB dopamine in the presence of nialamide. Two agents shown to induce catalepsy from the ACB, fluphenazine and morphine, antagonized dopamine hyperactivity when they were administered peripherally or directly into the ACB (0·1–0·2 mg kg−1, i.p. or 3·1–25 μg fluphenazine and 1–5 mg−1 kg, s.c. or 1–5 μg morphine), but only a weak antagonism occurred at much larger doses after intra-CP injections (100 μg fluphenazine and 50 μg morphine). Larger doses of intra-ACB pethidine (160 μg) and procaine (100–200 μg) also antagonized the dopamine response, but methadone was inactive. Again, the most potent and effective drugs in this test were fentanyl (1–5 μg), sufentanil (0·25–0·5μg) and carfentanil (0·05–0·1 μg). It is suggested that the ACB, and not the CP, is the site at which morphine acts to cause motor depression, whilst other narcotic drugs are able to act in both areas (although there is some indication of a further unspecified site of action for methadone). In contrast, the neuroleptic fluphenazine appears to differentially affect motor function via the ACB and CP, antagonizing a dopamine hyperactivity in the former and primarily inducing catalepsy from the latter nucleus.
Opiate-receptor mediated changes in monoamine synthesis in rat brain
Authors: Garcia-Sevilla J A , Ahtee Liisa , Magnusson T , Carlsson A
Published: April 2011

The effects of morphine, β-endorphin, naloxone and naltrexone on the rate of tyrosine and tryptophan hydroxylation were investigated in vivo by measuring the accumulation of dopa and 5-hydroxytryptophan (5-HTP) in different brain regions of rats after inhibition of the aromatic L-amino acid decarboxylase. The cerebral concentrations of tyrosine and tryptophan were also measured. Morphine (3–30 mg kg−1) increased the accumulation of dopa dose-dependently (25–50%) in the dopamine-rich areas (limbic forebrain and corpus striatum). In the noradrenaline-predominant parts of the brain (containing hemispheres, diencephalon and lower brain stem) only the highest dose of morphine (30 mg kg−1) significantly increased dopa formation (47%). Similarly to morphine, intracerebroventricularly injected β-endorphin (5–10 βg per rat) increased the formation of dopa. This increase was doubled in limbic forebrain, corpus striatum and cerebral hemispheres. Doses of 10 to 20 μg of β-endorphin were needed to increase dopa accumulation in the diencephalon and the lower brain stem. Naloxone antagonized the β-endorphin-induced increases in dopa. But naloxone and naltrexone (10–100 mg kg−1) decreased the dopa formation in the dopamine-rich areas (about 20–25 %) but not in the noradrenaline-predominant areas. Morphine (30 mg kg−1) and β-endorphin (5 μg per rat) increased the accumulation of 5-HTP whereas naloxone and naltrexone (10 mg kg−1) tended to decrease its formation. Morphine and β-endorphine increased the concentrations of tyrosine and tryptophan, and naloxone decreased the cerebral tryptophan concentration. These results show that the effects of a narcotic agonist (morphine) and of pure narcotic antagonists (naloxone and naltrexone) on the synthesis of dopamine and 5-HT are opposite to each other. Furthermore, the effects of β-endorphine on brain monoamine synthesis are remarkably similar to those of morphine. Thus, it is probable that opiate receptors and their endogenous ligands are involved in the regulation of dopamine and 5-HT synthesis.
Effects of temperature on the tensile strength of pharmaceutical powders
Authors: Britten J R , Pilpel N
Published: April 2011

Measurements have been made of the tensile strengths of fatty acids, lactose and of an oxtetracycline and a paracetamol tablet formulation at temperatures between −20 and +90°. The measurements were made on compressed tablets and on consolidated beds of powders, using a diametral compression tester and a split plate tensile tester which had been designed to operate over this range of temperature. The tensile strengths of all the materials increase with temperature and values are given for the activation energies of bonding between particles.
Chlorhexidine kinetics of hydrophilic contact lenses
Authors: MacKeen Donald L , Green Keith
Published: April 2011

An average chlorhexidine concentration of 4·5 μg mg−1 lens (wet weight) was measured in HEMA-based contact lenses after 16 days of the following treatment. The lenses were maintained 16 h daily in 1·5 ml of a solution containing Chlorhexidine digluconate 0·005%, and then worn by adult albino rabbits 8 h daily. Similarly maintained, but unworn lenses contained approximately 23 μg Chlorhexidine mg−1 wet lens weight after 16 days. A plot of the results indicates that continued exposure to Chlorhexidine following initial immersion increased its concentration in unworn lenses while that in the worn lenses reached a peak at 8 days, then decreased slightly in the subsequent days of wearing. Continuous exposure of lenses to the disinfecting solution (1 lens/167 ml) in which the Chlorhexidine concentration was maintained at 0005% for 16 days gave a maximal concentration of 44 μg mg−1 wet lens weight. The comparatively small concentration in a worn lens results from: (1) daily loss from the lens during wear, a large percentage of which is apparently absorbed to tear proteins which subsequently flow from the eyes via the canaliculi; (2) limited uptake because of the small immersion volume employed in routine storage; and (3) the possible competition between Chlorhexidine and tear components for lens binding sites or establishment of an equilibrium condition between uptake and release.
Distribution of pellets in the gastrointestinal tract. The influence on transit time exerted by the density or diameter of pellets
Authors: Bechgaard Helle , Ladefoged Karin
Published: April 2011

The influence on transit time exerted by the density or diameter of pellets has been established in six ileostomy subjects. An increase in density from 1·0 to 1·6 significantly increased the average transit time of pellets in the small intestine. The average transit time for the light and heavy pellets being 7 and 25 h respectively. The diameter of pellets is of minor significance. The findings suggest the use of density as a means of modifying the period of absorption of controlled-release pellets.
Content uniformity of potent drugs in tablets
Authors: Orr N A , Sallam E A
Published: April 2011

The type of distribution of low dosage drugs that occurs in batches of commercially available tablets has been examined. The uniformity of content of ethinyloestradiol tablets 10 μg B.P. from different sources, assessed by single tablet assay showed that three batches exhibited some positive skewness and one marked positive skewness. At the high level of dilution required, the mixing theory indicates that particles of drug must be very fine if acceptable content uniformity is to be obtained. Cohesion of particles impairs the efficiency of the mixing process. It is shown theoretically that unless the drug is dispersed into its component particles the shape of the distribution curve for the content of drug per tablet, in a batch of tablets, will be positively skewed. The relation between the tensile strength of the powdered drug and the degree of skewness of the drug content is also discussed. A positively skewed distribution for tablets containing a small amount of potent drug is unacceptable because this can lead to the presence of relatively large doses of drug in a single tablet. Where one unexpectedly high result occurs in the quality control of the content uniformity of tablets containing potent drugs it is suggested that sufficient single tablet assays be performed to allow the shape of the distribution curve to be assessed. A test for skewness should be included in compendial standards.
The effects of a decarboxylase inhibitor, benserazide, on both thermoregulation and chlorpromazine-induced hypothermia in rats
Authors: Lin M T , Chow C F , Chern Y F
Published: April 2011

Intraperitoneal administration of a peripheral decarboxylase inhibitor benserazide (Ro4–4602) to unanaesthetized rats produced alterations in body temperature which depended on ambient temperature. In the cold, hypothermia was brought about by a decrease in metabolic heat production. At room temperature, a dose-dependent hypothermia was preceded by a slight hyperthermia. The hypothermia was due to an increase in skin temperature (tail) and a decrease in metabolic heat production, while the hyperthermia was due to a decrease in skin temperatures (both tail and footsole) and an increase in metabolic heat production. In the heat, hyperthermia responses to benserazide were associated with decrease in skin temperature (both tail and footsole). Benserazide treatment produced no significant change in brain 5-HT content. Chlorpromazine-induced hypothermia was greatly enhanced after pretreatment of the animals with benserazide at room temperature (22°).
Hypertension: its effect on the stimulated release of dopamine-β-hydroxylase in the rat
Authors: Algate D R , Leach G D H
Published: April 2011

Plasma dopamine- β-hydroxylase (DBH) concentrations have been postulated as providing an index of sympathetic nerve activity. Using a microspectrophotometric assay system, plasma DBH concentrations have been measured in emergent blood from autoperfused heart, spleen and mesentery of normotensive, deoxycorticosterone (doca)/NaCl-treated, Goldblatt (1 kidney) renal and spontaneously hypertensive rats following sympathetic nerve outflow stimulation. Changes in plasma DBH concentrations as a result of sympathetic nerve outflow stimulation rates of 1–25 Hz for the mesentery and spleen and 1–4 Hz for the heart, were found to be frequency-dependent in all groups. Significantly greater amounts of DBH were found in the perfusate from the spleen (1–25 Hz) and mesentery (3–25 Hz) but not the heart (0·5–4 Hz) of renal hypertensive rats compared with normotensive controls. Significantly greater concentrations of DBH were released from the spleen but not the mesentery in all hypertensive groups following high stimulation frequencies of 12 and 25 Hz. It is concluded that there is a relation between plasma DBH concentrations and sympathetic nerve activity. Furthermore, greater amounts of the enzyme are released from the spleen and mesentery of chronic renal hypertensive rats following sympathetic nerve stimulation.
Comparative study of the dopamine-sensitive adenylate cyclase in the striatum and hypothalamus of rat brain
Authors: Roufogalis B D , Thornton M , Wade D N
Published: April 2011

Stimulation by dopamine of adenylate cyclase in homogenates of rat brain striatum was enhanced in the presence of ATP (0.6-3 mm) and GTP (10–100μM). The stimulation by dopamine appeared to be the result of its antagonism of inhibition of adenylate cyclase by GTP or higher concentrations of ATP. Stimulation of the enzyme by dopamine was also dependent on MgCl2, and was maximal at MgCl2 concentrations of at least two fold excess over ATP. While ATP did not inhibit the adenylate cyclase in homogenates of the ventral hypothalamus, GTP (10–100 μM) significantly stimulated it. Dopamine stimulated the adenylate cyclase in the hypothalamus. This action was blocked by chlorpromazine (10 μM) and phentolamine (100 μM) but not by an analogue of chlorpromazine having no neuroleptic activity or by propranolol (100 μM).
Percutaneous absorption: interfacial transfer kinetics
Authors: Albery W John , Hadgraft Jonathan
Published: April 2011

A new rotating diffusion cell is described in which a solute diffuses through a rotating filter. The transport of the solute to both sides of the filter is controlled by the rotation. The filter is filled with an organic phase. The rate of transfer of the solute through the filter is determined by the transport and by the kinetics of the interfacial transfer reactions. Since the transport is controlled the rate constant for the transfer reaction can be measured. Results for eleven different systems are reported and it is found that the rate constants are all smaller than 10−4 ms−1.
The mechanical strength of film-coated tablets
Authors: Fell J T , Rowe R C , Newton J M
Published: April 2011

The mechanical strength of film-coated tablets has been assessed using the diametral compression test. The results show that the influence of the film is more complex than that suggested by Stern (1976). The film may increase the breaking load of the core itself by acting as a padding material during the test and also by filling in surface irregularities. The film may also have enough intrinsic strength and elasticity to hold the core together once it has broken. The maximum breaking load to completely fracture the coated tablet is related to film properties, but the relation is not a simple one.
Improved gas-chromatographic method and micro-extraction technique for the measurement of nicotine in biological fluids
Authors: Feyerabend C , Russell M A H
Published: April 2011

A rapid and sensitive method for the measurement of nicotine in plasma, urine, saliva and breast milk is described. An internal standard (quinoline) is added to the samples and these are made alkaline and extracted with diethyl ether. The solvent is evaporated to small bulk and extracted with dilute acid which is then made alkaline. The nicotine is finally extracted into butyl acetate and an aliquot of this extract is injected onto a gas-chromatograph fitted with a nitrogen detector. Quantitation relies on comparison of peak areas and the calibration curve is linear over the concentration range 0.5 to 100 ngml−1. Nicotine concentrations as low as 0.1 ng ml−1 can be measured. In addition, a micro-method is described which requires only 100 μl of sample and yields an accurate result in 5 min.
A spectropolarimetric assay of (−)-adrenaline in compendial formulations
Authors: Davidson A G
Published: April 2011

A method is described for the determination of (−)-adrenaline in certain formulations containing adrenaline hydrogen tartrate at concentrations down to 0.18 mg ml−1 (1:10000 adrenaline). The assay is based upon a spectropolarimetric measurement at 249 nm of sample solutions, suitably treated to remove interfering substances. The rotation of the sample solutions is corrected for the rotation of the tartaric acid species which is determined by a difference rotation measurement on equimolar sample solutions at pH 1.1 and pH 5.6. The concentration of (−)-adrenaline in the sample is calculated from the net rotation at 249 nm due to the (−)-adrenaline and the total concentration of adrenaline ((+)- and (−)-isomers) determined by a published spectrofiuorimetric method. The assay is specific for (−)-adrenaline in the presence of (+)-adrenaline, (+)-tartaric acid, adrenaline sulphonic acid and low levels of adrenochrome.
Effects of drugs on the formation of 3-methoxytyramine, a dopamine metabolite, in the substantia nigra, striatum, nucleus accumbens and tuberculum olfactorium of the rat
Authors: Westerink Ben H C
Published: April 2011

3-Methoxytyramine (3-MT) was assayed with a sensitive and rapid liquid chromatographic separation on a Sephadex G 10 column in combination with a fluorimetric detection in a continuous flow system. The method made it possible to measure pargyline-induced 3-MT concentrations in various regions of a single rat brain. After haloperidol, morphine or sulpiride treatment, pargyline-induced 3-MT concentrations in the striatum, nucleus accumbens, tuberculum olfactorium and substantia nigra of the rat were comparable with reported changes of homovanillic acid concentrations. Dose-response curves for 3-MT increase in various brain regions after (+)-amphetamine pretreatment were studied. The effect of (+)-amphetamine on 3-MT formation was much more pronounced in nerve terminal areas, especially in the mesolimbic structures. The influence of apomorphine, γ-hydroxybutyric acid, haloperidol, reserpine or combined treatment of haloperidol and (+)-amphetamine revealed pronounced differences on regional 3-MT concentrations, indicating important differences between the regulation of dopamine metabolism in the substantia nigra and nerve terminal areas.
Comparative evaluation of six techniques for determining the Michaelis-Menten parameters relating phenytoin dose and steady-state serum concentrations
Authors: Mullen P W , Foster R W
Published: April 2011

Using randomly generated data within set error limits, the Michaelis-Menten parameters Dmax and Km relating steady-state serum phenytoin concentrations (Css) and dose (D) were determined by 5 graphical techniques and an iterative computer fit to the hyperbolic equation. The best mean estimates of Dmax and Km were provided by the latter. Assuming the experimental error to be in Css the results indicate that the most reliable graphical technique is that based on the equation CSS = Dmax -CSS/D - Km. However, considering its obvious simplicity and relative reliability the direct linear plot is recommended for clinical use.
Effect of paracetamol on amylobarbitone hydroxylation in man: a gas chromatographic method for simultaneous estimation of underivatized paracetamol and barbiturates
Authors: Kinsella Helen C , Smith Susan , Rogers H J , Toseland P A
Published: April 2011

A rapid and specific technique for the simultaneous gas chromatographic estimation of underivatized paracetamol and barbiturates using an alkali flame ionization detector is described which is suitable for both forensic and pharmacokinetic investigations. An improved method for estimation of 3-hydroxyamylobarbitone is also detailed. These techniques were used in an investigation of the effects of oral administration of 1 g paracetamol 8 hourly on the formation of 3-hydroxyamylobarbitone from a single oral dose of 200 mg sodium amylobarbitone. No significant changes were found in the plasma concentrations and total body clearance of amylobarbitone nor was there any alteration in the urinary elimination of 3-hydroxyamylobarbitone.
The gastrointestinal absorption of paracetamol in the rat
Authors: Bagnall W E , Kelleher J , Walker B E , Losowsky M S
Published: April 2011

The absorption of [3H]paracetamol by rat small intestine, colon and stomach was studied in vivo and in vitro. Small intestinal in vivo studies, using a wide range of drug concentrations, showed that absorption was efficient and uniform throughout the small bowel, no site showing preferential absorption. Double reciprocal and direct plots indicated first order kinetics. The pattern was not observed when uptake was occurring from high concentrations of paracetamol in suspension. Gastric and colonic in vivo studies showed that there was appreciable absorption of [3H]paracetamol from these sites. In vitro studies using everted intestinal sacs showed no effect on paracetamol transfer when the incubation temperature was lowered to 10 °C or when iodoacetate (5 times 10−2m) and 2.4 dinitrophenol (5 times 10−4m) was added to the incubation medium. There was, however, a significant reduction in transfer of paracetamol against a concentration gradient of 10:1 applied across the mucosa. These data suggest that the uptake of paracetamol is by a passive transport process and confirm the efficiency of paracetamol absorption observed indirectly by others.
Additivity of action between polysorbate 80 and polymyxin B towards spheroplasts of Pseudomonas aeruginosa NCTC 6750
Authors: Brown M R W , Geaton E M , Gilbert P
Published: April 2011

When polymyxin B and polysorbate 80 were used together against spheroplasts of Pseudomonas aeruginosa, the activities were found to be additive. These substances have previously been reported to act synergistically against P. aeruginosa, but little or no intrinsic activity towards intact cells has been attributed to polysorbate 80. We suggest that in addition to enhancing polymyxin B penetration to the cytoplasmic membrane, polysorbate 80 may also act as an antimicrobial agent when polymyxin-induced damage to the outer membrane facilitates the surfactant's passage through the cell envelope.
The granulation of ternary mixtures containing lactose and boric acid with different starches
Authors: Jaiyeoba K T , Spring M S
Published: April 2011

Ternary mixtures of lactose, boric acid and starch have been granulated by massing and screening. The properties of the granules have been compared with those resulting from granulation of blends of lactose and boric acid without starch. Potato, maize and rice starches have been studied as the third component at concentrations similar to those employed in tablet formulations. The starches caused a reduction in both mean granule size and granule strength. The effect is dependent on the proportions of the excipients. Increasing the amount of binder solution used gave bigger, stronger granules but did not compensate for the effects produced by the starches.
Sustained release of a dual antimalarial system
Authors: Wise Donald L , Gresser Joseph D , McCormick Gerald J
Published: April 2011

The sustained release of a dual drug system in a biodegradable carrier was evaluated in rhesus monkeys and mice. The two drugs were sulphadiazine (WR-7557) (3H-labelled) and 2,4-diamino-6-(2-naphthylsulphonyl)quinazoIine (WR-158122) (14C-Iabelled). The carrier was a polymer of L-lactide (90 parts by weight) and glycolide (10 parts), with a molecular weight of 46 000. The dual system injected was a blend of two preparations, each 50% (w/w) of the appropriate drug in the polymer, in a weight ratio of ten parts of the sulphadiazine system to one part of the WR-158122 system. This blend, as cryogenically ground particles, was injected intramuscularly into three monkeys; a fourth monkey received an equivalent dose of a 10:1 mixture of the pure drugs. Excretion of radioactivity in urine and faeces was measured over 13 weeks. Similar studies were done with mice. In monkeys, 14C-labelled material derived from WR-158122 was excreted at a nearly uniform rate; expressed as WR-158122, the rate of excretion from the pure drug mix was approximately 50 μg day−1 from week three to week 13, while the drug/polymer matrix released the drug at approximately 26 μg day−1 during this period. Recovery of tritiated materials derived from sulphadiazine was approximately 82% of the injected dose in the first three weeks and only a slight difference in release characteristics of the pure drug mix and the mixed drug/polymer matrices was observed. Results of studies with both mice and monkeys were generally consistent.
Characterization of receptors on postganglionic cholinergic neurons in the guinea-pig isolated ileum
Authors: Ennis Christine , Janssen P A J , Schnieden H , Cox B
Published: April 2011

Dopamine, apomorphine, noradrenaline and isoprenaline reduced the response of the isolated guinea-pig ileum to exogenous acetylcholine by a maximum of 40%. Propranolol reversed this inhibition whilst phentolamine and pimozide were ineffective, suggesting that the drugs were acting on a post-synaptic β-adrenoceptor. The same agonists were more effective as inhibitors of the response to transmural electrical stimulation of the ileum, lower doses producing almost complete inhibition. This inhibition was partially antagonized by phentolamine, pimozide and propranolol. Clonidine proved to be the most potent inhibitor of the response to transmural electrical stimulation, whilst phenylephrine was ineffective. pA2 determinations showed that phentolamine was a potent antagonist of clonidine but a weak antagonist of apomorphine whilst for pimozide the opposite was true. The results suggest that there are two populations of prejunctional receptors on the cholinergic nerves innervating the smooth muscle of the guinea-pig ileum. One receptor is similar to a classical prejunctional α-adrenoceptor and the other resembles a central dopamine receptor.
The non-specific membrane binding properties of ΔA9-tetrahydrocannabinol and the effects of various solubilizers
Authors: Roth Sheldon H , Williams Peter J
Published: April 2011

The binding of [3H]δ9-tetrahydrocannabinol to crude and purified synaptosomal membrane suspended in either Krebs solution or 10mM sodium phosphate buffer was examined. The membrane/buffer partition coefficient was found to be 12 500, and was constant over a free concentration range of 10−8 to 10−6m. Binding was similar in both suspending media, and to both crude and purified synaptosomal membrane. The solubilizing agent Cremophor E.L. (8 μg ml−1) decreased the partition coefficient by one-half, and by greater than 99 % at 0.4 mg ml−1. Similar effects were observed with Tween 80, while ethanol caused a maximum decrease of 60%. Membrane concentrations of THC were calculated at various effective concentrations reported in the literature, and were within the range predicted by the Meyer-Overton rule of anaesthesia. An apparent non-specific interaction with neuronal membranes and effective membrane concentrations of the order 2 times 10−1 to 1 times 10−2 mol kg−1 suggests THC may exert some of its effects by a mechanism analogous to the general anaesthetics, and thus may be classified as a partial anaesthetic.
Acidic metabolites of Δ1-tetrahydrocannabinol isolated from rabbit urine
Authors: Nordqvist Marianne , Lindgren Jan-Erik , Agurell Stig
Published: April 2011

The in vivo metabolism of Δ1-tetrahydrocannabinol (Δ1-THC) was investigated in the rabbit after i.v. administration. Thirteen acidic metabolites were isolated from rabbit urine and identified by gas chromatography-mass spectrometry and by proton magnetic resonance spectroscopy. One additional metabolite was tentatively identified. All but three were new metabolites and all but one were oxidized in the pentyl side chain. The metabolites included dicarboxylic acids, monocarboxylic acids and mono- or dihydroxylated derivatives thereof. However, the dicarboxylic acid metabolites were the most prominent.
Plasticization of cellulose ethers used in the film coating of tablets
Authors: Entwistle C A , Rowe R C
Published: April 2011

Plasticizer/polymer interactions have been studied by measuring the intrinsic viscosities of both ethyl cellulose and hydroxypropyl methylcellulose in a series of dialkyl phthalates and in a series of liquid glycols respectively. A correlation was found between the intrinsic viscosity of the polymer/plasticizer solutions and the tensile strength, elongation at rupture and work done in stressing to failure of cast films—the mechanical properties being at a minimum when the intrinsic viscosity was at a maximum. This correlation held only within a homologous series of plasticizers and none was found for plasticizers of different structures. A relationship was found between the lowering of a calculated glass transition temperature of hydroxypropyl methylcellulose in the presence of the plasticizers propylene glycol, polyethylene glycol 200 and glycerol and the intrinsic viscosity of the corresponding solutions—the higher the viscosity the greater the lowering of the transition temperature.
Relative effects of different surfactants on intestinal absorption and the release of proteins and phospholipids from the tissue
Authors: Whitmore D A , Brookes L G , Wheeler K P
Published: April 2011

The actions of anionic, cationic and non-ionic surfactants on the absorptive capability of rat jejunal tissue in vivo were compared with their effects on the amounts of protein and phospholipid released from the mucosal surface under the same conditions. Release of a comparatively small amount of protein was accompanied by large increases in the absorption rates of both L-valine and salicylate, whereas much larger quantities of phospholipid were released before any increase in absorption was observed. Much of the released material appeared to be derived from mucus which was partly degraded after exposure to the higher concentrations of surfactants. The liberation of cholesterol by high concentrations of anionic surfactants suggested that some disruption of the mucosal membrane occurred under those conditions. The relative potency of the surfactants in stimulating both absorption of the solutes and the release of polypeptides and lipids followed the order: anionic > non-ionic > cationic. The possible pharmaceutical relevance of these findings is discussed.