bluuebunny/crossref_metadata_2025 huggingface dataset:
An analysis of the mechanism of 5-hydroxytrypt-amine-induced vasopressor responses in ganglion-blocked anaesthetized dogs
Authors: FENIUK W , HARE J , HUMPHREY P P A
Published: April 2011

5-Hydroxytryptamine (5-HT) administered intravenously (i.v., 1–30 μg kg−1) to ganglion-blocked anaesthetized dogs produced dose-related increases in diastolic blood pressure and we have analysed the mechanism involved. Cyproheptadine and methysergide (10–100 μg kg−1 i.v.) were potent and specific antagonists of the 5-HT induced rise in blood pressure, while the α-adrenoceptor blocking agent phentolamine (0·3–3 mg kg−1 i.v.) also caused dose-related inhibition. Syrosingopine pretreatment converted the vasopressor action of 5-HT to a vasodepressor action and acute bilateral adrenalectomy caused a marked reduction in the 5-HT-induced rise in blood pressure. In two dogs, 5-HT (30 μg kg−1 i.v.) markedly increased the venous plasma concentrations of noradrenaline and adrenaline. We concluded that the 5-HT-induced rise in diastolic pressure in the ganglion blocked anaesthetized dog is due largely to the release of catecholamines of which a substantial component is from the adrenal gland. The rise in diastolic blood pressure is specifically blocked by low doses of cyproheptadine and methysergide suggesting that the release of catecholamines is mediated by specific 5-HT receptors located mainly within the adrenal medulla.
Animal modelling of human polymorphic drug oxidation—the metabolism of debrisoquine and phenacetin in rat inbred strains
Authors: AL-DABBAGH S G , IDLE J R , SMITH R L
Published: April 2011

The metabolism of debrisoquine (5mg kg−1 orally) was investigated in females of 7 strains of rat. Two major metabolic pathways, those of 4- and 6- hydroxylation were found to be polymorphic. The DA strain eliminated in urine only 7–10% of the dose as 4-hydroxy-debrisoquine together with 31–55% debrisoquine while the corresponding values for the Lewis strain were 44–55% and 11–17% respectively. Accordingly, DA and Lewis rats were proposed as models for the human PM (poor metabolizer) and EM (extensive metabolizer) drug oxidation phenotypes. To further test this model, DA and Lewis rats were given phenacetin (200 mg kg−1 orally). This underwent O-de-ethylation to paracetamol (52–55%) and aromatic 2-hydroxylation (7–8%) in Lewis rats. The corresponding findings in DA rats were 35–40% O-de-ethylation and 12–13% 2-hydroxylation. It is suggested that, with respect to both debrisoquine and phenacetin, Lewis and DA inbred rat strains afford a model of oxidative drug metabolism for the human EM and PM phenotypes respectively.
Uniformity of content requirements for tablets and capsules
Authors: KENDALL C E , LOW G K-C , HAILEY D M
Published: April 2011

Present pharmacopoeial requirements for uniformity of content of tablets and capsules are based on tests by attributes. A test for uniformity of content based on the root mean square deviation about target (ST) is more reliable than the pharmacopoeial tests and has the added convenience of using a single statistic to control both the mean content and the variation about the mean. Implications of the use of the statistic ST in uniformity requirements are discussed.
Analysis of moisture sorption hysteresis in hard gelatin capsules, maize starch, and maize starch: drug powder mixtures
Authors: YORK PETER
Published: April 2011

Moisture sorption and desorption isotherms at 25°C for hard gelatin capsules, maize starch and 50:50 mixes of maize starch: barbitone and maize starch: sodium barbitone have been measured. The sorption hysteresis observed in all four systems studied has been analysed according to the hypothesis of Young & Nelson (1967a) which distinguishes three locations for moisture—monolayer adsorbed moisture, normally condensed moisture and absorbed moisture. Hysteresis is explained by a separation of absorption and desorption isotherms for absorbed moisture and different patterns of moisture distribution are demonstrated in the four systems examined.
The stability of trifluorothymidine: hydrolysis in buffered aqueous solutions
Authors: JONES M F
Published: April 2011

The decomposition of trifluorothymidine in aqueous solution, and borate and phosphate buffers has been studied using an h.p.l.c. method. In aqueous solution accelerated studies demonstrate that a storage life, to 10% loss, of more than 30 years at 4°C is predicted, but steam sterilization causes extensive breakdown. Considerable differences occur in the kinetics and routes of decomposition in borate and phosphate buffers in the pH range 4–8. Hydroxide ion attack producing 5-carboxy-2′-deoxyuridine is suppressed in borate buffers. Complex kinetics of decomposition in phosphate buffer are found and possible explanations suggested. Steam sterilization in buffered solution also leads to unacceptable breakdown.
Apparent diffusion coefficient of sodium phenobarbitone in ethylcellulose microcapsules: effects of capsule size
Authors: SENJKOVIČ R , JALŠENJAK I
Published: April 2011

Ethylcellulose microcapsules of sodium phenobarbitone with a thick wall were prepared and fractionated. The apparent diffusion coefficient of sodium phenobarbitone was measured for the transport of the drug from the core of microcapsules into the surrounding sink condition. The apparent diffusion coefficient decreased with decreasing capsule size. Apart from structured water in and around the capsule wall, the volume fraction of pores in the membrane has been suggested as the source of the observed trend.
Fluorescence spectroscopic analysis of the hydrogen bonding properties of catecholamines, resorcinolamines, and related compounds with phosphate and other anionic species in aqueous solution
Authors: DE VENTE J , BRUYN P J M , ZAAGSMA J
Published: April 2011

Fluorescence spectroscopic analysis based upon the difference in fluorescent behaviour of several phenol, catechol and resorcinol derivatives in 0·2 M phosphate and water, at different pH values ranging from 7·4 to 1·0, produced evidence for the existence of complexes between phosphate anions and these compounds. This complex formation was also found with acetate, citrate and glutamate but not with sulphate and borate. A comparison of different ligand structures revealed that the complex formation observed with unsubstituted phenol, catechol or resorcinol was not influenced by ethyl substitution; however, ethylamine or ethanolamine substitution favoured the formation of the complex. The findings indicate the formation of 1:1 intermolecular complexes between mono- and dihydroxyphenethylamines and several anionic species with participation of two hydrogen bonds. The predictions of a theoretical model describing this interaction are confirmed by the experimental data. Association constants of isoprenaline with phosphate and glutamate were found to be 5·1 and 26·6 litres mol−1 respectively; for the complexes of m-tyramine and terbutaline with phosphate, association constants of 15·3 and 6·9 litres mol−1 respectively, were obtained.
The metabolism of bifluranol by rat, dog and ferret
Authors: POPE D J , GILBERT A P , EASTER D J , CHAN R P , TURNER J C , GOTTFRIED S , PARKE D V
Published: April 2011

The synthesis of monohydroxy- and dihydroxy-bifluranol, and of glucuronide and sulphate conjugates of bifluranol are described. Bifluranol administered orally to rats, ferrets and dogs at a dosage of 50 to 200 μg kg−1 is mostly excreted in the faeces as unchanged bifluranol and bifluranol monosulphate, disulphate and monoglucuronide. The bifluranol is well absorbed and is mostly excreted in the bile, as six different conjugates, including a glucuronide sulphate found in all 3 species, and a glucuronide phosphate found only in ferret and dog bile. Hydroxylation of the aromatic rings occurs in the rat, to an extent of about 8% of the dose, but was not detected in ferret or dog.
Synthesis of N-oxide derivatives of metyrapone and their detection as in vitro metabolites
Authors: CROOKS PETER A , DAMANI LYAQUATALI A , COWAN DAVID A
Published: April 2011

A variety of possible N-oxidation products of 2-methyl-1, 2-bis(3-pyridyl)propan-1-one (metyrapone) have been synthesized by peracid oxidation, and characterized using various spectroscopic techniques. Specific and sensitive chromatographic techniques have been developed for the separation and identification of its in vitro metabolites. Incubation of metyrapone with rat or mouse hepatic microsomes, in the presence of a NADPH-regenerating system, leads to the formation of metyrapol (keto-reduction), and two mono-N-oxides.
β1-Adrenoceptors mediating relaxation of the guinea-pig trachea: experiments with prenalterol, a β1-selective adrenoceptor agonist
Authors: JOHANSSON ULF , WALDECK BERTIL
Published: April 2011

In the presence of 17 β-oestradiol, prenalterol, a β1-selective adrenoceptor agonist, caused a dose-dependent relaxation of the isolated, pilocarpine-contracted guinea-pig trachea. This effect was blocked by the antagonists propranolol (non-selective) and practolol (β1-selective) but not by IPS 339 [(t-butylamino-3-ol-2-propyl)oximino-9-fluorene HCl] (β2-selective). The relaxing effect of terbutaline, a β2-selective adrenoceptor agonist, was more efficiently blocked by IPS 339 than by practolol. These data support the hypothesis that the guinea-pig trachea contains both β1- and β2-adrenoceptors mediating relaxation and that the β1-adrenoceptors are selectively stimulated by prenalterol. The efficacy of prenalterol was less than that of terbutaline, thus confirming its partial agonistic activity. In the absence of 17 β-oestradiol, the ability of prenalterol to relax the pilocarpine-contracted trachea was lost. It is suggested that 17 β-oestradiol may act as a functional antagonist to pilocarpine as it caused a partial relaxation itself.
Interference of pentobarbitone with the contraction of vascular smooth muscle in goat middle cerebral artery
Authors: MARÍN JESUS , RICO MERCEDES L , SALAICES MERCEDES
Published: April 2011

Pentobarbitone (10−5 to 10−3 M) decreased the basal tone of vascular smooth muscle of goat middle cerebral artery in a dose-dependent manner as well as relaxing established contractions induced by noradrenaline (NA) (10−5 M), 5-hydroxytryptamine (5-HT) (10−5 M) and KCl(120 mM). Preincubations with pentobarbitone reduced the contractions evoked by these three agents in a dose-dependent way. It also decreased Ca2+-induced contractile responses in K+-depolarized arteries and 5-HT-Ca2+ and NA-Ca2+ contractions dose-dependently. Contractions induced by K+ were more sensitive to the depressant actions of the drug than those produced by NA and 5-HT. The small contractions evoked by K+ and 5-HT in Ca2+-free medium were also reduced in its presence. The antagonism Ca2+-pentobarbitone was insurmountable. These results suggest that the drug interferes with Ca2+ entry and Ca2+ release from cell stores, and therefore with the smooth muscle contractions.
The tetrahydrocannabinol and tetrahydrocannabinolic acid content of cannabis products
Authors: BAKER P B , TAYLOR B J , GOUGH T A
Published: April 2011

Cannabinoid acids readily decarboxylate to the corresponding cannabinoid. Methods are available for the determination of Δ9-tetrahydrocannabinol (THC) and its acids (THCA) and published data on the levels of these compounds in cannabis are summarized. Using gas and liquid chromatography, fresh cannabis (64 samples) and cannabis resin (26 samples) from different countries were examined. Wide variations in the relative amounts of THCA and THC in cannabis were found. For cannabis resin, a wide range of values was also found (0·5: 1 to 6·1: 1), the lower values being in resins from the Indian sub-continent and the higher values in resins from the Mediterranean area. Total THC values were in the range 1·–10·6% in cannabis and 6·0–12·5% in cannabis resin.
Effect of dyes on the photodecomposition of pyridoxine and pyridoxamine
Authors: MIZUNO NOBUYASU , FUJIWARA ASAMI , MORITA EMIKO
Published: April 2011

Erythrosine, eosine Y, rose bengal, mercurochrome, methylene blue, azure A and azure B accelerated the photodecomposition of pyridoxine and pyridoxamine at pH 5–9, but fluorescein and acid red did not. The photodecomposition of pyridoxine in the presence of erythrosine was greatest at pH 9·0, The singlet oxygen generated by light-excited dyes played a role as a mediator in the decomposition of pyridoxine but the degradation products of erythrosine had no effect. The photodecomposition of pyridoxine and pyridoxamine in the presence of dyes was depressed by aminopyrine, sulpyrine and tryptophan. Pyridoxine 3, 4′-dioctanoate was stable in the presence of erythrosine.
Effect of temperature changes on the densification and compression of griseofulvin and sucrose powders
Authors: ONYEKWELI A O , PILPEL N
Published: April 2011

A study has been made of the effect of varying the temperature between +60° and −25°C on the densification and low pressure compression of griseofulvin, sucrose and mixtures of the two powders. Densification and compression of the materials were facilitated as they were cooled in the range of homologous temperatures (ratio of the experimental temperature in°K to melting point of the material in°K) from 0·7 to 0·5. This was attributed to a reduction in the cohesive forces operating between the particles. Values are given for the activation energies of densification and compression derived by plotting the logarithms of these properties versus the reciprocal of the absolute temperature. For both materials and their mixtures the activation energies were in the range of about 1 to 10 kJ mol−1 showing that physical rather than chemical forces were operating between the particles.
The prolongation of the in vitro dissolution of a soluble drug (phenethicillin potassium) by microencapsulation with ethyl cellulose
Authors: ALPAR H OYA , WALTERS V
Published: April 2011

Microcapsules of phenethicillin potassium as a model water-soluble drug, coated with ethyl cellulose, have been prepared (core: wall ratios 1:1, 1:2 and 1:3) in which the taste has been masked, the odour almost eliminated and the release retarded. Sieve analysis showed that with decreasing core: wall ratios there was a trend towards increasing amounts of larger sized microcapsules. At constant core: wall ratios in vitro release of drug was generally greatest from the larger microcapsules. This result correlated with the surface areas of the microcapsules which became less as the asymmetry of the microcapsules diminished with decrease in microcapsule size. There was a linear relation between the amount of ethyl cellulose and the time for 60% release of drug, and the release pattern was analogous to that from insoluble porous matrices. Scanning electron micrographs showed the microcapsules to be irregularly shaped with circular surface pores, and they did not alter in shape or size during dissolution. Tableting of 1:1 core: wall ratio microcapsules significantly further retarded the dissolution.
The in vivo metabolism of Althesin (alphaxalone + alphadolone acetate) in man
Authors: HOLLY J M P , TRAFFORD D J H , SEAR J W , MAKIN H L J
Published: April 2011

Gas chromatography-mass spectrometry has been used to study the metabolism of Althesin (alphaxalone and alphadolone acetate) in man. Two metabolites, 20α-reduced alphaxalone and alphadolone, as well as the two parent steroids, have been detected in the plasma during and after an infusion of Althesin. The main urinary metabolites were alphaxalone and 20α-reduced alphaxalone, with smaller amounts of alphadolone, all of which were excreted mainly as the glucuronide conjugates. No alphadolone acetate was detected in the urine. In 3 patients in whom bile was collected over the 1st 24 h post-operation from an indwelling T-tube, it has not been possible using the methods described to detect in bile the presence of the parent steroids, or any of their probable metabolites.
The influence of initial packing on the compression of powders
Authors: SHEIKH-SALEM M , FELL J T
Published: April 2011

The influence of the initial packing density on the compression properties of lactose and sodium chloride has been studied. Differences in initial packing density are eliminated for both materials at relatively low pressures. The results have been analysed by the equations of Kawakita (1956), Heckel (1961), and Cooper & Eaton (1962). The constants derived from the Cooper & Eaton equation are dependent on the choice of low pressure data. The Kawakita constants are influenced by the initial packing of the powder. The Heckel treatment uses data at pressures above the point where the initial packing exerts an influence. Hence the constants are independent of the initial packing. If comparisons are to be made between processing treatments or mixtures which change the initial packing of the powder, the Heckel equation would appear to offer the most valid approach.
The systemic bioavailability of buprenorphine by various routes of administration
Authors: BREWSTER DAVID , HUMPHREY MICHAEL J , MCLEAVY MICHAEL A
Published: April 2011

The systemic bioavailability of buprenorphine has been studied in female rats following single doses (200 μg kg−1) administered by one of six different routes. Relative to the 100% bioavailability from the intraarterial route the mean bioavailabilities were intravenous, 98%; intrarectal, 54%; intrahepatoportal, 49%; sublingual, 13%; and intraduodenal, 9·7%. Area under the curve analysis of buprenorphine concentrations in blood showed the relative fractions of drug extracted (first pass) by gut, liver and lung to be 0·80, 0·50 and 0·02 respectively, In situ absorption studies showed that the poor availability of intraduodenally administered buprenorphine is not due to slow or incomplete absorption.
A pre-junctional action of 5-hydroxytryptamine and methysergide on noradrenergic nerves in dog isolated saphenous vein
Authors: WATTS A D , FENIUK W , HUMPHREY P P A
Published: April 2011

Electrical stimulation (2 Hz for 2 min) of dog isolated saphenous vein strips pre-incubated with tritiated noradrenaline increased the overflow of tritium of which about 80% was noradrenaline. 5-Hydroxytryptamine (5-HT; 1·0 × 10−9-1·0 × 10−7 mol litre−1) and methysergide (3·0 × 10−8-3·0 × 10−8 mol litre−1) inhibited the induced overflow of total tritium by a maximum of 78 ± 4% and 47 ± 7% respectively (mean ± s.e. mean, n = 6 for each). Methysergide was about 30 times less potent than 5-HT and the maximum inhibition obtained was less than with 5-HT. Both compounds inhibited electrically-induced contractions and overflow of tritiated noradrenaline. Their inhibitory actions on tritium overflow were little affected by phentolamine (1·0 × 10−8 mol litre−1) or cyproheptadine (1·0 × 10−8 mol litre−1), nor was the inhibitory effect of methysergide on electrically induced contractions antagonized by atropine, mepyramine, cimetidine or propranolol. The findings suggest that the prejunctional inhibitory effect of methysergide may be mediated via stimulation of a 5-HT receptor which, unlike the D-receptor, is not blocked by cyproheptadine. The possibility that the pre-junctional 5-HT receptor in the dog saphenous vein is the same as the post-junctional receptor in this preparation is discussed.
Amine oxidase in human blood vessels and non-vascular smooth muscle
Authors: LEWINSOHN RACHEL
Published: April 2011

The pattern of amine oxidation was studied in human blood vessels at various stages of development, and in tissues with muscular layers made up predominantly or exclusively of smooth muscle. Specific activity of benzylamine oxidase, present in all vascular tissues examined, was higher in vessels than in other tissue; the enzyme, in organs rich in nonvascular smooth muscle, though lower than in blood vessels, was significantly higher than in striated muscle or connective tissue. The localization of benzylamine oxidase activity in smooth muscle, as opposed to connective tissue, may have important physiological implicacations.
Effect of indomethacin on the blood pressure and plasma catecholamine responses to acute endotoxaemia
Authors: FEUERSTEIN G , DIMICCO J A , RAMU A , KOPIN I J
Published: April 2011

Injection of E. coli endotoxin (7 mg kg−1 i.v.) to pentobarbitone anaesthetized cats resulted in prolonged decrease of systemic blood pressure and increases in plasma concentrations of adrenaline, noradrenaline and 6-ketoprostaglandin (PG) F1α. Indomethacin pretreatment (10 mg kg−1 i.v.) attenuated the decrease in blood pressure following endotoxin injection. Plasma adrenaline, noradrenaline and 6-keto-PG F1α were significantly lower in the indo-methacin-treated cats. These data indicate that the superior haemodynamic status of the indomethacin pretreated animals exposed to endotoxic shock is not the result of potentiation of the peripheral sympathetic response.
Thermic and tremorogenic effects of thyroliberin (TRH) in reserpine-treated mice—the non-involvement of GABA-ergic mechanisms
Authors: BJÖRKMAN SVEN , LEWANDER TOMMY , KARLSSON JAN-ANDERS , KOSKINEN LARS-OWE , ZETTERSTRÖM TYRA
Published: April 2011

Administration of thyroliberin (TRH) to reserpinized mice causes tremor and counteracts the hypothermia in a dose-dependent fashion. The thyroliberin response is inhibited by γ-hydroxybutyric acid (GHB) and baclofen, but not by other, more specific GABA-ergic agents, such as THIP, γ-acetylenic GABA, and sodium valproate. Picrotoxin neither potentiates nor inhibits the thyroliberin actions. Nor are the thyroliberin effects dependent on cholinergic, monoaminergic or histaminergic mechanisms. The results repudiate a current hypothesis, that the peptide actions may be mediated by GABA-ergic pathways in the brain.
Changes in seizure susceptibility after successive treatments of mice with tryptophol and ethanol
Authors: FUKUMORI RYUJI , MINEGISHI AKEMI , SATOH TETSUO , KITAGAWA HARUO
Published: April 2011

Changes in leptazol (pentetrazol) seizure susceptibility after successive treatments of mice with tryptophol, a neutral metabolite of indoleamine, in combination with ethanol have been examined. Mice treated with tryptophol plus ethanol became highly susceptible to convulsions. There was little or no difference in seizure susceptibility in mice treated with tryptophol or ethanol alone, compared with the corresponding controls. In the mice treated with tryptophol plus ethanol, a much higher brain tryptophol level was observed, compared with that in mice treated with tryptophol alone. There appeared to be a good correlation between the reduction of the length of the seizure latency time and the time for which the brains were exposed to high levels of tryptophol. These results suggest that elevation of the levels of neutral indoleamine metabolites in the brain may have resulted in the increase in the seizure susceptibility.
The prediction of the bulk densities of powder mixtures, and its relationship to the filling of hard gelatin capsules
Authors: NEWTON J M , BADER F
Published: April 2011

From measurements of the properties of individual components, it has been found possible to predict the maximum tapped bulk density of two component mixtures of a range of particle size fractions of acetylsalicylic acid and lactose in varying proportions. This has been extended to the prediction of bulk density of such mixtures when filled into hard gelatin capsules by a system which results in the powders existing at the maximum tapped bulk density. Consequently the capsule fill weight can also be predicted for such systems. The method is less satisfactory for the prediction of the bulk density and capsule fill weight, when the capsules are filled by a process involving compression of the powder within the capsule shell.
Effects of acute and subacute treatment with ergot drugs on the GABA system in specific brain regions
Authors: PERIČIČ DANKA
Published: April 2011

The effect of dihydroergotoxine and dihydroergotamine on Γ-aminobutyric acid (GABA) levels, the aminooxyacetic acid (AOAA)-induced accumulation of GABA, and the in vitro activity of L-glutamate decarboxylase (GAD) have been examined in various regions of rat brain. Dihydroergotoxine (1 mg kg−1) decreased the concentration of GABA and enhanced the AOAA-induced accumulation of GABA in the caudate nucleus and cingulate cortex. Dihydroergotoxine 10·0 mg kg−1 decreased the AOAA-induced accumulation of GABA in the substantia nigra. The repeated treatment with dihydroergotoxine, 0·05 mg kg−1 for eight days, also decreased the concentration of GABA in the cingulate cortex and diminished the AOAA-induced accumulation of GABA in the substantia nigra. The administration of 0·1 mg kg−1, but not higher doses; of dihydroergotamine, enhanced the AOAA-induced accumulation of GABA in the cingulate cortex. Dihydroergotamine (10·0 mg kg−1) decreased the concentration of GABA in the cingulate cortex and increased the AOAA-induced accumulation of GABA in the caudate nucleus. The activity of GAD in the cingulate cortex, but not in the caudate nucleus, was enhanced after a high dose of dihydroergotamine. Observed increases in the AOAA-induced accumulation of GABA indicate that dihydroergotoxine and dihydroergotamine in at least some brain areas cause an apparent increase in GABA syn-synthesis in vivo, which is presumably a compensatory phenomenon due to a diminished GABAergic transmission under the influence of these drugs.
The effects of cadmium ions on blood pressure, dopamine-β-hydroxylase activity and on the responsiveness of in vivo preparations to sympathetic nerve stimulation, noradrenaline and tyramine
Authors: FADLOUN Z , LEACH G D H
Published: April 2011

Changes in sympathetic nervous function of the rat caused by acute and chronic treatment with cadmium (Cd2+) have been studied in vivo by measurement of changes in blood pressure and plasma dopamine-β-hydroxylase (DBH) activity. In anaesthetized animals, acute injection of Cd2+ (0·1–1 μm) caused an initial fall followed by a rise in both diastolic and systolic blood pressure, plasma DBH activity increased in a dose-dependent manner. Animals subjected to repeated treatment with Cd2+ (0·5, 1 μm) daily for 12 days became markedly hypertensive, the increases in the systolic pressure being greater than those seen in the diastolic pressure. In pithed animals the blood pressure responses of the treated animals to electrical stimulation of the lower sympathetic outflow (T10-L1) and tyramine injection (35, 70, 140 nmol kg−1) were markedly decreased, whilst responses to low doses of noradrenaline (NA) (7, 15, 30 nmol kg−1) were potentiated compared with untreated animals. In addition, plasma DBH activities following sympathetic outflow stimulation and tyramine administration were markedly increased and decreased respectively compared with untreated controls. The data suggest that a correlation exists between changes in sympathetic nervous function and the induction of hypertension caused by Cd2+.
A comparative study on the performance of asbestos-free depth-filters for removal of pyrogens from infusion fluids
Authors: BAGGERMAN C , BRANDSEMA C , HUMER M , VISSER J
Published: April 2011

Three asbestos-free depth-filters were compared with traditionally used asbestos-containing depth-filters for chemical integrity, physical integrity and pyrogen retention. With chemical and physical integrity only minor differences between the various filter types were seen. One asbestos-free depth-filter, based on charcoal, showed poor pyrogen-retention; this might be due to a high flow rate used. Asbestos-free depth-filters based on kieselguhr or on a mixture of kaolin and alumina proved to be good alternatives; these filters have proved to be suitable for the removal of pyrogens from electrolyte- or carbohydrate-containing infusion fluids.
A semi-empirical model of aerosol deposition in the human respiratory tract for mouth inhalation
Authors: GONDA IGOR
Published: April 2011

A mathematical model for regional deposition of aerosols following inhalation via mouth has been developed. The model is in the form of algebraic equations which make it particularly efficient for computation of deposition of polydisperse aerosols. The parameters of the model were derived from average experimental data for‘head’ and tracheobronchial deposition which were supplemented by results of previous theoretical calculations and mass balance considerations. An example is presented to illustrate an application of the model to a problem in formulation of inhalation aerosols. To make the calculations more reliable for particular patho-physiological groups of patients, some modifications of the parameters used in the model are necessary. The model may be suitable, e.g. for testing the changes in regional deposition which would be likely to result from modification of particle size and related formulation properties of inhalation aerosols.
Circular dichroic examination of the interaction of some planar acidic drugs with tryptophan-modified human serum albumin
Authors: VALLNER J J , PERRIN J H
Published: April 2011

The single tryptophan region in human serum albumin was investigated for its involvement in binding planar hydrophobic and acidic drug molecules. The lone tryptophan was alkylated with a selective and specific agent, 2-hydroxy-5 nitrobenzyl bromide. The subsequent interaction of four drug molecules with tryptophan modified, and normal albumin was examined by circular dichroism (CD). In all cases the CD signal of tryptophan modified albumin was perturbed at low drug concentrations. The predominantly α-helical structure of the albumin remained intact. It is suggested that the primary binding site of these four acidic planar drugs does involve the tryptophan region.
Optical isomerization of R(−)-clidanac to the biologically active S(+)-isomer in guinea-pigs
Authors: TAMURA SHIGEO , KUZUNA SEIJI , KAWAI KIYOHISA , KISHIMOTO SHOJI
Published: April 2011

Optical isomerization of clidanac (RS-6-chloro-5-cyclohexyl-1-indancarboxylic acid, I), an anti-inflammatory drug having a chiral centre in its molecule, was evaluated in guinea-pigs. After oral administration of R(−)-I, the biologically active S(+)-isomer was detectable in the plasma, in the early stages. At 3 h after dosing R(−)-I, the plasma contained above 90% of the S(+)-isomer. Little conversion of S(+)-I to R(−)-I was observed. This may account for the equivalent in vivo activities of R(−)- and S(+)-I in this species. Determination of the enantiomeric composition required derivatization of the enantiomers to their diastereomeric amides after which thin layer chromatography (t.l.c.) was used for the separation. The quantitative determination of the compounds so-separated was accomplished by in situ measurements of the u.v.-reflectance. The t.l.c.-u.v.-densitometric procedure was also used to determine the plasma concentration of I.
Secoverine hydrochloride is a muscarinic antagonist in human isolated gastrointestinal muscle and myometrium
Authors: SANGER G J , BENNETT A
Published: April 2011

Secoverine is a new antimuscarinic agent thought to be selective for smooth muscle. We have found it to be a potent anticholinergic antagonist of acetylcholine in strips of human gastrointestinal and uterine muscle. The pA2 values in gut longitudinal and circular muscle and myometrium were 9·1, 9·3 and 8·6 respectively.
The postsynaptic effects of antidepressant drugs in the rat anococcygeus muscle
Authors: DOGGRELL SHEILA A , VINCENT LYNN
Published: April 2011

The effects of antidepressants of tricyclic (amitriptyline, nortriptyline, protriptyline, doxepin, imipramine, and desipramine) and atypical (maprotiline, nomifensine, tandamine, viloxazine, CGP 6085A, and YM-08054-1) structures on contractile responses to exogenously applied acetylcholine and (−)-noradrenaline were studied in rat isolated anococcygeus muscle previously incubated with 6-hydroxydopamine. Atropine, amitriptyline, protriptyline, doxepin, imipramine, maprotiline and nortriptyline inhibited contractile responses to acetylcholine whereas desipramine, nomifensine, tandamine, viloxazine, CGP 6085A and YM 08054-1 did not. The contractile responses to (−)-noradrenaline were inhibited by low concentrations of tricyclic antidepressants and by higher concentrations of the atypical agents. These results illustrate that, in the preparation, the order of potency of antidepressants as muscarinic and as postsynaptic α-adrenoceptor antagonists is similar. The ability of tricyclic, but not atypical agents, to increase the concentration of noradrenaline bound to postsynaptic α-adrenoceptors may be severely limited by the antagonistic effect these agents have at this receptor.
Membrane damage by bile salts: the protective function of phospholipids
Authors: MARTIN GARY P , MARRIOTT CHRISTOPHER
Published: April 2011

The direct toxicity of sodium deoxycholate (SDC) and lysophosphatidylcholine (LPC) to biological membranes was assessed by measurement of goldfish overturn time. When phosphatidylcholine (PC) was incorporated into the aqueous media, the toxicity of both SDC and LPC was reduced, as indicated by increased overturn time. Fish were also pretreated for various times in media containing (a) 1 mM SDC and (b) 1 mM SDC with 1 mM PC. Subsequent transfer to solution, 100 mg litre−1 quinalbarbitone sodium showed that reciprocal overturn times for fish treated using method (a) increased linearly with duration of pretreatment up to a limiting value, obtained after 20 min exposure; 40 min exposure to 1 mM SDC was directly toxic. Fish pretreated using regimen (b) survived longer when challenged with barbiturate, and the reciprocal overturn times were a linear function of time of pretreatment up to at least 40 min. PC also provided protection against membrane damage caused by the synthetic surfactant sodium dodecyl sulphate. Mixed micelle formation between PC and surfactant is thought to account for the protective effects. The results are of significance in the consideration of reflux hypotheses for the aetiology of gastric ulceration and also to the possible formulation of drug delivery systems intended to enhance absorption whilst minimizing gastrointestinal damage.
Presynaptic α-block and inhibition of noradrenaline and 5-hydroxytryptamine reuptake by a series of compounds related to mianserin
Authors: NICKOLSON VICTOR J , WIERINGA JOOP H
Published: April 2011

A structure-activity relationship study was undertaken for a variety of structural analogues of the tetracyclic antidepressant mianserin. Presynaptic α-blocking activity in vitro was evaluated measuring the potentiation of depolarization-induced noradrenaline (NA) release from rat cerebral cortex slices. Inhibition of NA and 5-hydroxytryptamine reuptake was measured in rat hypothalamic or striatal synaptosomes, respectively. Presynaptic α-blockade was only found in molecules with an overall bent shape. Flat rigid molecules or flexible ones were not active. Six-membered, chair-formed D-rings (containing the -NCH3 moiety) appeared better than 5- or 7-membered ones. Heteroatom substitution, but not hydroxylation or methylation, of the bridge between the two aromatic rings left presynaptic α-blockade unaffected. N-Demethylation and aromatic methyl- or chlorine-subsitution reduced presynaptic α-blockade. In pyridine ring-substituted analogues the localization of the heteroatom appeared to be crucial. 5-Hydroxytryptamine reuptake inhibitory activity was only found in desmethylmianserin. NA reuptake inhibition was found in many mianserin analogues, especially those with an exocyclic -N(CH3)2 moiety. Structure activity relationships for NA reuptake inhibition differed from those for presynaptic α-blockade and were generally less stringent. For both properties simple additivity relationships appeared to be absent.
Pressor effect of L-threo-3,4-dihydroxyphenylserine in rats
Authors: ARAKI HIROMASA , TANAKA CHIKAKO , FUJIWARA HIROSHI , NAKAMURA MASAFUMI , OHMURA IPPEI
Published: April 2011

The pressor effect of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) in rats and its decarboxylation in vivo have been examined. On i.v. administration, it produces a slow-onset and long-lasting pressor response, but no significant change in heart rate or e.c.g. The pressor effect was markedly reduced by inhibition of peripheral decarboxylase and by blockade of α-adrenoceptors. The slow-onset and long-acting pressor effect was also evident when the drug was given orally, while intracerebroventricular administration produced a long-lasting decrease in blood pressure. Noradrenaline (NA) concentrations in the plasma were significantly increased by both i.v. and oral administration of L-threo-DOPS. Elevation of plasma NA concentration by L-threo-DOPS given i.v. was suppressed by inhibition of decarboxylase. The plasma concentration of the drug was highest immediately after its i.v. administration. Its pressor effect was enhanced in rats made hypotensive by chemical sympathectomy with 6-hydroxydopamine (6-OHDA), compared with control rats, nevertheless, L-threo-DOPS produced the same increase in plasma NA concentrations in sympathectomized rats as in the controls. These results indicate that L-threo-DOPS is gradually converted to NA by L-aromatic amino acid decarboxylase in vivo. These findings suggest that L-threo-DOPS may be clinically useful as an oral pressor agent for the treatment of certain disorders related to hypotension.
Tests for foreign particles in metered-dose aerosols
Authors: LEA A R , DREW R M , WONG S S L , HAILEY D M
Published: April 2011

A simple method for the determination of foreign particulate matter in metered-dose aerosols (MDA's) has been developed. The method compares favourably with a procedure currently used in pharmaceutical industry and has the advantage of providing information on container to container variation. A linear relationship between log particle count and particle size was found for a number of MDA's, although there was considerable product-to-product variation. On the basis of the results obtained in this study, commercially available MDA's would in general comply with a limit for foreign particles greater than 100 μm of not more than 150 particles per container with the sum of the mean count and twice the standard deviation not more than 200.
The design and use of an instrumented mG2 capsule filling machine simulator
Authors: JOLLIFFE I G , NEWTON J M , COOPER D
Published: April 2011

The problems of instrumenting a continuous motion dosator nozzle capsule filling machine (mG2 type) are discussed and the construction of an mG2 simulator is described. A standard filling turret is employed with mechanical modification so that the dosator does not rotate. This allows instrumentation in the form of a strain gauged dosator piston, to measure compression and ejection stresses during filling, as well as distance transducers, to measure the corresponding piston and dosator movements. An experimental method is described for using this machine to study the filling of lactose powders.
Time-course of the effects of chronic Δ9-tetrahydrocannabinol on behaviour, body temperature, brain amines and withdrawal-like behaviour in the rat
Authors: TAYLOR D A , FENNESSY M R
Published: April 2011

The effects of clomipramine HCl (15 mg kg−1 i.p.) on behaviour, body temperature and brain amines were investigated in rats that had been chronically treated twice daily with increasing doses of Δ9-tetrahydrocannabinol (Δ9-THC, 2–6 mg kg−1 i.v.). Δ9-THC produced a biphasic change in behaviour, stimulation followed by depression, and a pronounced hypothermia. Tolerance developed rapidly to these effects of Δ9-THC. Chronic treatment with Δ9-THC reduced the levels of homovanillic acid, 5-hydroxytryptamine and noradrenaline. The level of dopamine was not altered with chronic treatment and tolerance appeared to develop to the increased level of 5-hydroxyindoleacetic acid induced by Δ9-THC. Injection of clomipramine, 12–14 h after 2, 5 or 10 days of Δ9-THC treatment induced characteristic changes in the rats behaviour which consisted of writhes, backward kicking, wet shakes, jumps, ataxia and front paw and whole body tremor. The severity of the behavioural changes appeared to be dependent on the period of Δ9-THC administration and they were not accompanied by a change in body temperature or consistent changes in brain amines or metabolites. The results indicate that physical dependence on Δ9-THC may occur since clomipramine is able to precipitate changes in behaviour, indicative on an abstinence syndrome, in rats chronically treated with Δ9-THC. It is suggested that tryptaminergic mechanisms are altered during chronic Δ9-THC treatment and that clomipramine induces the behavioural changes by interacting with an altered tryptaminergic system.
On the preferred rotameric conformation for dopamine agonist action: an illusory quest?
Authors: COSTALL B , LIM S K , NAYLOR R J , CANNON J G
Published: April 2011

Putative dopamine agonists from the 2-aminotetrahydronaphthalene and trans-octahydrobenzo (f) and (g) quinoline series were shown to inhibit the spontaneous locomotor activity of mice. Marked potency differences were observed between the α- and β-rotameric conformations, compounds having the α-rotameric conformation having the greater potency. Thus, 2-di-n-propylmino-5,6-dihydroxytetrahydronaphthalene was 339 times more potent than the 6,7-dihydroxy isomer, and 2-n-propylamino-5,6-dihydroxy-compound was respectively 79 times and 179 times more potent than 6,7-hydroxy- and 7,8-dihydroxycompounds. trans-7,8-Dihydroxy-1-n-propyl-1,2,3,4,4a,9,10,10b-octahydrobenzo(f)quinoline was 11 times more potent than the β-rotamer, the 6,7-dihydroxy compound, and within the trans-octahydrobenzo(g)quinoline series the α-rotameric N-propyl derivative was 467 times more potent than the β-rotamer, and the α-rotameric >N–H analogue was 46 fold more potent than the β-rotamer. Thus, the α-rotamer appears the more potent in causing the present functional dopaminergic change. The dopaminergic nature of the response was indicated by its sensitivity to spiroperidol but not to yohimbine or prazosin. The possibility that a difference in behavioural potency between the α- and β-rotamers may reflect a differential metabolism by catechol-O-methyl transferase was assessed by administration of different agonists after pyrogallol pre treatment. This potentiated the activity of 2-di-n-propylamino-6,7-dihydroxytetrahydro-naphthalene but not that of the 5,6-dihydroxy analogue. However, changes in the effects of N-propyl derivatives of trans-octahydrobenzo(f) and (g)quinoline were not marked and, in all experiments, pyrogallol treatment failed by orders of magnitude to shift the dose-response curves of the β-rotamers to indicate a comparable potency to the α-rotameric forms.
Multiple compression of powders in a tablet press
Authors: ARMSTRONG N A , ABOURIDA N M A H , KRIJGSMAN L
Published: April 2011

Lactose, magnesium carbonate, phenacetin, microcrystalline cellulose and directly compressible starch compacts were repeatedly compressed in a tablet press, the tablets not being ejected from the die between compressions. When the interval between compressions was 1.3 s, all substances showed a decrease in the maximum force exerted by the tablet press, this being attributed to the formation of a structure of lower porosity. As the intervals between compressions is increased, the decrease in force is reduced, and in the case of microcrystalline cellulose and directly compressible starch, the force exerted at the second compression is greater than that exerted by the first.
A high performance liquid chromatographic method for determination of the radiochemical purity of iodohippuric acid [123I] injection
Authors: MILLAR A M
Published: April 2011

A method for the separation of the radiopharmaceutical iodohippuric acid ([123I]IHA) from the two impurities produced in the labelling reaction, iodide (123I−) and iodobenzoic acid ([123I]IBA) has been developed using reversed-phase high performance liquid chromatography (h.p.l.c). The effect of eluent pH on the separation of the three compounds was studied. An eluent consisting of methanol: 0.1 M acetic acid (30:70) adjusted to pH 4.0 with NaOH gave optimum phase capacity ratios of −0.21 for I−, 0.93 for IHA and 1.54 for IBA. On the chromatograph used, this corresponded to an analysis time of 4 min per sample. To recover 123I− from the column with a good peak shape, it was found necessary to include sodium iodide (1 mg/100 ml) in the eluent. The recoveries of 123I− 123IHA and 123IBA from the column were found to be 100.6% (s.d. 1.3), 100.2% (s.d. 2.1) and 98.1% (s.d. 1.2) respectively (n = 10 for each compound). H.p.l.c. was compared with the standard thin layer chromatographic (t.l.c.) method of analysis on 10 preparations of [123I]IHA which gave a mean radiochemical purity of 99.1% (± 0.2 s.e.) by h.p.l.c. and 98.3% (± 0.2 s.e.) by t.l.c. This difference was found to be significant (P <0.05) and an explanation for this difference is proposed. A coefficient of variation of 0.1% on the results from the repeated analysis (n = 20) of one preparation of [123I]IHA, demonstrated that the h.p.l.c. method was capable of very high precision.
Clonidine-induced potentiation of reflex vagal bradycardia in anaesthetized cats
Authors: CONNOR HELEN E , DREW G M , FINCH L
Published: April 2011

The interactions between clonidine and the selective α1- and α2-adrenoceptor antagonists, prazosin and yohimbine, on the angiotensin-induced reflex vagal bradycardia have been investigated in propranolol-treated chloralose-anaesthetized cats. Clonidine (1–10 μg intracisternally) had little effect on the pressor responses to angiotensin, only slightly increased the peak but markedly increased the duration of the reflex bradycardia. Neither prazosin nor yohimbine (200 μg intracisternally of either antagonist) had any effect on the reflex bradycardia to angiotensin. Yohimbine greatly diminished the clonidine-induced potentiation of the response, but prazosin was without effect. Clonidine appears to potentiate the vagal reflex bradycardia by stimulating central α2-adrenoceptors.
Involvement of histaminergic mechanisms in the cataleptogenic effect of morphine in mice
Authors: MULEY M P , BALSARA J J , JADHAV J H , CHANDORKAR A G
Published: April 2011

Intraperitoneally administered morphine induced catalepsy in mice. Morphine pretreatment however, failed to antagonize apomorphine-induced cage climbing behaviour thereby ruling out the possibility of its possessing DA receptor blocking activity. Pretreatment with L-histidine, a precursor of histamine, and atropine, potentiated the cataleptic effect of morphine whilst pretreatment with chlorcyclizine, an H1 receptor blocker, and naloxone, a morphine antagonist, antagonized morphine-catalepsy. Pretreatment with metiamide, an H2 receptor blocker, and methysergide, a 5-HT antagonist, did not significantly alter the cataleptic effect of morphine. The results with L-histidine and chlorcyclizine suggest an involvement of central histaminergic mechanisms in the cataleptogenic effect of morphine in mice. Further, as the cataleptic effect of morphine was also antagonized by naloxone it appears that the interaction of morphine with the central histaminergic mechanisms is mediated through specific opiate receptors.
Specification of limits for particulate contamination in pharmaceutical dosage forms
Authors: HAILEY D M , LEA A R , KENDALL C E
Published: April 2011

Limits for the control of particulate contamination in large volume parenteral solutions and metered-dose aerosols are discussed. It is suggested that it would be desirable to use limits based on measurement of both the mean and the standard deviation of the particle counts obtained for each of the containers tested. Use of the statistic sT, assuming a target value of zero, is considered to be an appropriate means of measuring the container to container variation in particulate contamination.