bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for more than one type of 5-hydroxytryptamine receptor in the human colon
Authors: Burleigh D E
Published: April 2011

The actions of methysergide, a 5-hydroxytryptamine (5-HT) antagonist, have been examined on muscle strips taken from the circular and longitudinal layers of the human colon. Relaxations of the longitudinal muscle to 5-HT were antagonized by concentrations of methysergide known to be selective. Relaxations of the circular muscle to 5-HT were unaffected by similar concentrations of methysergide. Responses of both types of muscle to 5-HT were partially reduced by tetrodotoxin. Furthermore there was evidence for 5-HT receptors in circular colonic muscle which were unaffected either by selective concentrations of methysergide or tetrodotoxin.
Analysis of the β-receptor mediated effect on slow-contracting skeletal muscle in vitro
Authors: Waldeck Bertil
Published: April 2011

Subtetanic contractions of the guinea-pig isolated soleus, a slow-contracting skeletal muscle, were evoked by transmural field-stimulation. Isoprenaline caused a dose-dependent depression of the contractions. This effect was inhibited by propranolol and H 35/25 (1-(p-tolyl-2-isopropylamino-1-propanol) but not by practolol. Similar results were obtained for terbutaline. Tazolol and H 80/62 (1-isopropylamino-3-(p-hydroxyphenoxy)-2-propanol HCl), selective β1-agonists, had no effect per se but inhibited the effect of terbutaline. Adrenaline, noradrenaline, and dopamine all caused a dose-dependent decrease in the force of the soleus contractions, their potencies being in that order. Tyramine did not appreciably affect the contractions nor did it inhibit the effect of terbutaline. Pretreatment with reserpine, if anything, increased the response to terbutaline. It is concluded, in conformity with previous in vivo studies, that the adrenergic receptor mediating the effect on the soleus muscle contractions is of the β2-type. Indirect sympathomimetic effects do not contribute to the responses observed on the isolated soleus muscle.
A comparison of the dissolution rates of caffeine tablets in a rotating-basket with those in a Sartorius dissolution tester
Authors: Kitazawa Shikifumi , Johno Ikuo , Minouchi Tokuzo , Ito Yoko , Okada Jutaro
Published: April 2011

Uncoated caffeine tablets of four different hardnesses were tested for dissolution rate by the Sartorius (S.S. method) and by the rotating basket method of the U.S.P. XVIII. In both methods the dissolution rate decreased with increasing hardness, and the rate obtained with the S.S. method was always less than that by the U.S.P. method. This result cannot be explained as being due only to the difference in the volume of dissolution medium. Also it was difficult to ensure that the characteristic changes in the process of dissolution paralleled the curves obtained from a plot of % caffeine dissolved vs time. Accordingly, the dissolution rate constants were calculated from the slope of each straight line in a plot of In W∞/(W∞ - W) vs time.
The effect of age and thyroid hormones upon the ability of the chick heart to deaminate monoamines
Authors: Fowler C J , Callingham B A
Published: April 2011

The effect of age and thyroid hormones upon the ability of chick heart homogenates to metabolize monoamines has been investigated. 5-Hydroxytryptamine is entirely metabolized by a monoamine oxidase (MAO) with the characteristics of MAO-A, whereas some of the tyramine and all of the benzylamine are oxidatively deaminated by a clorgyline-resistant, but semicarbazide-sensitive enzyme, with a similar subcellular distribution to that of MAO. The remainder of the tyramine deamination is brought about by MAO-A and MAO-B. The specific activities of both clorgyline-sensitive and resistant enzymes are increased by the same proportion by increase in age or by treatment with (-)-thyroxine, and decreased by 2-thiouracil. The significance of these results is discussed.
The central and peripheral effectiveness of two oxotremorine-antagonists determined using oxotremorine-induced tremor and salivation
Authors: Eicholzer Alfred , Ögren Sven-Ove
Published: April 2011

Two oxotremorine antagonists have been examined using oxotremorine as the tremor and salivation inducer and the ratios between the central and peripheral nervous systems determined. Under these conditions these compounds are still more effective antagonists centrally than peripherally. Differences in distribution to the various muscarinic receptors involved is believed to be the major factor in determining this separation of central and peripheral activities.
A model for the selective mode of action of the irreversible monoamine oxidase inhibitors clorgyline and deprenyl, based on studies of their ability to activate a Ca2+-Mg2+ ATPase in defined lipid environments
Authors: Houslay Miles D
Published: April 2011

Clorgyline and deprenyl activated the pure Ca2+-Mg2+ ATPase from rabbit muscle sarcoplasmic reticulum when it was in a defined lipid environment of either dimyristoyl lecithin or dipalmitoyl lecithin, apparently by fluidizing the phospholipid that surrounds the protein (the phospholipid annulus). Activation was only significant at temperatures when the annulus placed rigid constraints upon the protein. There was a two order of magnitude difference in the concentration at which the drugs achieved their effect which is thought to be related to their abilities to perturb the phospholipid annulus since it could not be attributed simply to the small differences in their partition coefficients. Clorgyline, which was more potent than deprenyl at effecting fluidization of the phospholipid annulus of the Ca2+-Mg2+ ATPase in the defined lipid environments, activated species ‘B’ monoamine oxidase at concentrations at which it began to inhibit the species ‘A’ enzyme. Deprenyl did not activate the species ‘A’ enzyme at any concentration tested. It is suggested that, in tissues where there are multiple forms of mitochondrial monoamine oxidase, the selective action of clorgyline and deprenyl arises from a modification of the single inhibitor binding site on a protein species to yield species ‘A’ enzyme and species ‘B’ enzyme. One form of this modification to give the species ‘A’ monoamine oxidase would be a masking of the inhibitor binding site by lipid such that it could be readily penetrated by clorgyline but less readily so by deprenyl. The other form of the modification would yield the species ‘B’ enzyme, which like the ‘chaotrope-treated’ enzyme and presumably ‘nascent’ monoamine oxidase, would expose the inhibitor binding site to the aqueous environment in which deprenyl would be the more efficacious inhibitor.
The effect of metyrapone on granuloma induced by carrageenan-impregnated sponges in normal and essential fatty acid deficient rats
Authors: Parnham M J , Adolfs M J P , Bonta I L
Published: April 2011

Treatment of normal rats with metyrapone (20 mg kg−1 day−1, s.c.) for 5 days, starting on the day before implantation, inhibited the production of granuloma, induced by carrageenan-impregnated sponges, determined 8 days after implantation. Exudate volume and prostaglandin (PG) production were unaffected. In essential fatty acid deficient (EFAD) rats, metyrapone did not alter the already existing adrenal hyperplasia due to EFAD and did not affect either granuloma formation or exudate production. The results are discussed in relation to earlier work using adrenalectomy and with regard to the effect of EFA deficiency on adrenal corticosteroid production. It is suggested that metyrapone is a more useful tool than adrenalectomy in studying the role of endogenous corticosteroids.
Platelets in inflammatory exudates
Authors: Bolam J P , Smith M J H
Published: April 2011

In exudates of implanted sponges in the rat there are apparent accumulations of blood platelets, assessed by the light microscope, and of radioactivity from labelled platelets administered systemically. The use of more specific techniques for platelet detection showed no evidence of intact blood platelets in the exudate and the radioactivity was not associated preferentially with cellular components in the exudate.
Permeability of human epidermis to phenolic compounds
Authors: Roberts M S , Anderson R A , Swarbrick J
Published: April 2011

The permeability of human epidermis to many phenolic compounds can be related to octanol/water partition coefficients. For a series of compounds having similar diffusion coefficients and showing an increase in lipophilic character, the maximum flux will be obtained with the less lipophilic compounds because the solubility decreases more rapidly than the partition coefficient increases. The penetration of some phenolic compounds is concentration dependent, a constant permeability coefficient being observed below a threshhold concentration above which the permeability coefficient increases with concentration. The increase in the permeability coefficient is attributed to ‘damage’ to the epidermis and a reduction in its diffusional resistance. A relation between the ability of a substance to damage the skin and the lipophilic character (or more generally the penetration flux) of the substance was found. A number of substances do not appear to ‘damage’ the skin due to insufficient substance partitioning or penetrating into the stratum corneum. This ‘cut-off’ in effect is generally observed for the more lipophilic substances. For a series of compounds, maximum damage will be obtained with the less lipophilic compounds in accordance with the predicted concentrations of the substance in the stratum corneum. Phenolic compounds appear to interact with the skin by protein denaturation although for the more lipophilic compounds some degree of ‘plasticization’ of the lipids is evident.
Estimation of the degree of crystallinity in digoxin by X-ray and infrared methods
Authors: Black D B , Lovering E G
Published: April 2011

The X-ray procedure for estimation of the degree of crystallinity in digoxin is based upon measurement of the total X-ray scattering and the scattering from crystalline regions of the drug. The infrared procedures are based upon measurement of the peak height ratios, 1775/1618 and 3095/1618 cm−1. Correlation between results obtained by the two methods is good. These methods are of value in the physico-chemical characterization of digoxin, particularly as the properties may be altered by comminution.
The effect of composition and ageing on the dissolution rates of chlorpropamide-urea solid dispersions
Authors: Ford James L , Rubinstein Michael H
Published: April 2011

Discs of chlorpropamide and urea have been prepared by (a) melting and (b) compression. Intrinsic and relative dissolution rates of the discs have been measured and the dissolution process investigated microscopically. Higher dissolution rates were found from melts than from physical mixes. The optimum dissolution rate composition found was for a melt composed of 30% w/w chlorpropamide which possessed an intrinsic dissolution rate 930 times greater than for the pure drug. Sphere formation, during dissolution rate measurement has been observed and a likely mechanism proposed to account for its occurrence. Dissolution rates generally increased with age for most melt compositions.
The effect of bromocriptine on locomotor activity and cerebral catecholamines in rodents
Authors: Dolphin A C , Jenner P , Sawaya M C B , Marsden C D , Testa B
Published: April 2011

The locomotor activity in mice induced by bromocriptine was suppressed by drugs inhibiting both dopaminergic and noradrenergic pre- and post-synaptic actions. The onset of locomotor activity was preceded by a period of decreased activity which lengthened with increasing dose. Both increased and decreased turnover of noradrenaline and decreased turnover of dopamine was shown by measurement of the dopamine metabolites homovanillic acid, dihydroxyphenylacetic acid (DOPAC) and the noradrenaline metabolite MOPEG-SO4 and following pretreatment of animals with α-methyl-p-tyrosine. The increased activity caused by bromocriptine did not correlate with a consistent biochemical change, but the period of behavioural suppression appeared to be associated with an increased noradrenaline turnover. Bromocriptine potently inhibited the noradrenaline-stimulated adenylate cyclase system from mouse limbic forebrain suggesting that the increased in vivo turnover of noradrenaline may be due to a post-synaptic receptor blockade. The involvement of cerebral dopamine receptors was substantiated by the ability of bromocriptine to displace [3H]haloperidol from binding sites in rat striatal preparations. The findings are interpreted as indicating a complex involvement of both noradrenaline and dopamine pre-and post-synaptic components in the locomotor activity produced by bromocriptine, possibly due to the involvement of a partial agonist action or an active metabolite.
Changes in vascular reactivity in experimental hypertensive animals following treatment with indapamide
Authors: Finch L , Hicks P E , Moore R A
Published: April 2011

Indapamide at doses of 8–16 mg kg−1 day−1, orally, lowered arterial blood pressure (9–26 mm Hg) in conscious renal hypertensive cats during a two week treatment period. The antihypertensive effect was sustained for 5–7 h after dosing and was not accompanied by reflex tachycardia. Antihypertensive responses to injection of clonidine (20 μg, i.c.v.) were significantly enhanced one week after the completion of indapamide treatment but had returned to normal two weeks later. In DOCA/saline hypertensive rats, administration of indapamide 10 mg kg−1 day−1, orally, or hydrochlorothiazide, 5 mg kg−1 day−1, intraperitoneally, for 10 days produced similar falls in blood pressure (40–45 mm Hg) as measured by an indirect method. Pressor responses to intravenous noradrenaline or tyramine or electrical stimulation of the sympathetic outflow in the pithed rat preparation were much reduced by pretreatment with indapamide (10 mg kg−1, orally) for 10 days. However, cardiovascular reactivity was unaffected by hydrochlorothiazide pretreatment (5 mg kg−1 day−1, i.p.). Isolated perfused mesenteric artery***/preparations from indapamide-treated rats showed no changes in reactivity to noradrenaline, 5-hydroxytryptamine or adenosine-5′-triphosphate from those of control DOCA/saline hypertensive rats. Isolated portal veins from rats pretreated with indapamide showed contractile responses to noradrenaline similar to those of control animals although the frequency of spontaneous contractions was reduced in the former group. The results support a vascular site of action for indapamide and suggest a mode of action different from that of hydrochlorothiazide.
Effects of pulmonary metabolites of prostaglandins E2 and F2α on guinea-pig respiratory tract
Authors: Lo Pia Yong
Published: April 2011

The effects of three pulmonary metabolites of prostaglandins E2 and F2α on the guinea-pig tracheal muscle in vitro and on lung resistance in vivo were investigated. Prostaglandin F2α, 13, 14-dihydro PGF2α and 13,14-dihydro 15-oxo PGF2α produced contractions on the tracheal muscle in vitro. 15-oxo PGF2α relaxed some tracheal preparations but stimulated others, the stimulant action having a threshold dose range some 10–25 times lower than the relaxant doses. Prostaglandin F2α and 13,14-dihydro PGF2α increased lung resistance in anaesthetized guinea-pigs. Prostaglandin E2 and its three pulmonary metabolites produced relaxation of guinea pig trachea in vitro and decreased lung resistance in vivo. All three metabolites were less active than PGE2 in both the systems. The in vitro effects of PGF2α and its metabolites were selectively blocked by polyphloretin phosphate.
Degradation of (—)-ephedrine in solution and during extraction with diethyl ether
Authors: Beckett A H , Jones G R , Hollingsbee D A
Published: April 2011

Significant losses occurred during the extraction of small quantities of ephedrine from aqueous media using either regular or analytical grades of diethyl ether. The losses were, at least in part, caused by reaction of the ephedrine with aldehydic impurities in the ether; three substituted oxazolidines were identified, using g.l.c. and g.l.c.-ms. These and one other oxazolidine were synthesized and characterized by g.l.c, g.l.c.-ms, nmr and infrared spectroscopy. Alternative mechanisms for ephedrine breakdown were considered. Ephedrine was separately oxidized by three different oxidizing agents and also irradiated by ultraviolet light; the products were characterized by g.l.c, g.l.c.-ms. A method for the purification of diethyl ether is recommended to minimize ephedrine breakdown.
Red cell cyanide
Authors: Vesey Cyril J , Wilson John
Published: April 2011

The amount of cyanide released on acidifying whole blood was much greater than the total from the plasma and red cells assayed separately, and varied directly with plasma thiocyanate concentrations. This artifactual formation of cyanide by whole blood was reduced by exposure to carbon monoxide. Incubation of haemolysates of washed red blood cells showed that optimum cyanide production from thiocyanate occurred at pH 4·5 with none at pH 7·4; spectrophotometric study confirmed the involvement of haemoglobin. It is doubtful whether this activity of haemoglobin is of normal physiological importance and it is probable that the evidence for the enzyme, ‘thiocyanate oxidase’ was based on this artifact of assay. Plasma cyanide is probably the metabolically relevant measurement, since the red blood cells act as a ‘cyanide sink’. Where values for whole blood cyanide are required we recommend separate assay of plasma and saline washed red blood cells.
Changes in muscarinic ligand binding to intestinal muscle strips produced by pre-exposure to hypotonic conditions
Authors: Elliott J M , Tayler P J , Young J M
Published: April 2011

The extent of the binding of [3H]propylbenzilylcholine mustard (3H-PrBCM) to muscarinic receptors in longitudinal muscle strips from guinea-pig small intestine is increased by nearly 50 % when the strips are preexposed to distilled water before measurement of 3H-PrBCM binding in Krebs-Henseleit solution. The apparent rate constant for 3H-PrBCM-receptor complex formation is more than double that of intact strips. The curves for the inhibition of 3H-PrBCM binding by methylatropinium bromide in normal and treated strips are superimposable, but, in contrast, distilled water pretreatment shifts the inhibition curve for carbachol to lower concentrations by a factor of 5–6. The inhibition curve for methyl-furmethide is also shifted, by a factor of approximately 4, but the effect on the curve for hexyltrimethylammonium (C6TMA) is slight. The relative inhibition produced by benzhexol in the two preparations was variable. Comparison of the rate of equilibration of benzhexol with muscarinic receptors in intact and in distilled water pretreated muscle indicates that this inconsistency is unlikely to be due to incomplete equilibration.
Modification by monoamine oxidase inhibitors of the analgesic, hypothermic and toxic actions of morphine and pethidine in mice
Authors: Botting Regina , Bower Susan , Eason C T , Hutson P H , Wells Linda
Published: April 2011

A single injection of phenelzine 100 mg kg−1 given 18 h before, decreased the analgesia and hypothermia induced by morphine, but potentiated the analgesic and hypothermic effects of pethidine, when the analgesics were administered either intraperitoneally or intracerebroventricularly. The modification of pethidine analgesia and hypothermia, but not morphine analgesia, was antagonized by methysergide (10 mg kg−1, s.c). The LD50 of pethidine, but not that of morphine, was 30–40 % lower in mice treated with phenelzine tranylcypromine or iproniazid 6 h before the test. The increased lethality of a single dose of pethidine induced by phenelzine was also prevented by methysergide. Pretreatment of mice with 100 mg kg−1 phenelzine was followed by a significant rise in both brain tryptophan and 5-hydroxytryptamine (5-HT) concentrations which lasted for 24 h. Therefore, the changes in pethidine effects could have been due to raised brain tryptophan and 5-HT concentrations.
Problems associated with analysis and interpretation of small molecule/macromolecule binding data
Authors: Plumbridge Terence W , Aarons Leon J , Brown Jeffrey R
Published: April 2011

In the analysis of binding data, arbitrary transformations such as the Scatchard plot, may give misleading estimates of the binding parameters. The statistically correct approach is to determine values of K and n by non-linear regression of the actual dependent variable against the actual independent variable. In the case of the spectrophotometric titration method the dependent variable is the absorbance and the independent variable is the composition of the drug/macromolecule mixture. The method relies on an accurate estimate of the extinction coefficient of the bound drug and this is best treated as a parameter to be estimated in the regression analysis. In testing models by data fits alone it is emphasized that whilst a model may be rejected if it does not fit the data, a good fit does not ensure uniqueness and confirmatory, independent evidence must be sought.
Effects of bromocriptine on adenylate cyclase and phosphodiesterase activities of rat striatum
Authors: Pagnini Giuseppe , Camanni Franco , Crispino Antonio , Portaleone Paolo
Published: April 2011

The activity of 2-bromo-α-ergokryptine (bromocriptine) (5 mg kg−1, i.p.) on adenylate cyclase and on phosphodiesterase (PDE I-PDE II) of rat striatum, has been examined both in vitro and in vivo. In vitro and in vivo bromocriptine stimulated adenylate cyclase activity, but reduced the stimulating effect of dopamine on adenylate cyclase activity. Bromocriptine showed a dose-dependent biphasic action on phosphodiesterases in vitro while in vivo it stimulated them. The results obtained proved bromocriptine to have an agonist-antagonist action at striatal dopamine receptor level, with a relevant effect on the cAMP system.
Salicylic acid fails to inhibit generation of thromboxane A2 activity in platelets after in vivo administration to the rat
Authors: Vargaftig Bernardo B
Published: April 2011

Arachidonic acid-induced aggregation of rat platelets and the accompanying generation of thromboxane A2 activity were inhibited by aspirin, whereas 20 times higher doses of salicylic, gentisic and salicyluric acids were inactive. Salicylic acid administered to the rats before aspirin prevented the inhibition of the cyclo-oxygenase-mediated effects of arachidonic acid. These results do not support the hypothesis that the anti-inflammatory activity of salicylic acid is due to inhibition of prostaglandin synthetase (cyclo-oxygenase) by an unknown metabolite and indicate that salicylic acid displays an anti-inflammatory activity independent inhibition of prostaglandin biosynthesis.
Studies on the role of ACTH and of 5-HT in anxiety, using an animal model
Authors: File Sandra E , Vellucci Sandra V
Published: April 2011

The effects of ACTH (5 & 7·5 μg/100 g) were studied using a new animal model of anxiety. ACTH had an anxiogenic effect that was maximal during a 10 min test period starting 3 min after injection. The behavioural effects of ACTH were counteracted by chronic administration of chlordiazepoxide (5 mg kg−1 for 5 days) and by acute administration of ethanol (0·4 g kg−1). These anxiolytic drugs decreased the turnover of 5-HT in the midbrain, hypothalamus and cerebral cortex, whereas ACTH increased 5-HT turnover in the midbrain and hypothalamus. It is therefore proposed that anxiety results from the action of ACTH, possibly on 5-HT pathways in the midbrain and hypothalamus.
Biopharmaceutical properties of liquid and tablet antacids: in vivo studies using the intragastric pH-measurement technique
Authors: Brouwers J R B J , Tytgat G N J
Published: April 2011

Three types of liquid and tablet antacids have been studied in vitro and in vivo: aluminium hydroxide, aluminium hydroxide-magnesium carbonate and hydrotalcite. The effects on gastric pH of antacid suspensions and antacid chewing tablets having identical active ingredients have been studied in 36 volunteers, the sequence of both forms of administration being randomized. Gastric acid secretion was continuously stimulated during the experiment by a pentagastrin infusion. Antacid chewing tablets gave inferior results when compared with the same antacid in liquid. Antacid suspensions are therefore preferred in the treatment of acid-peptic disease.
The diffusion of nandrolone through occluded and non-occluded human skin
Authors: Foreman M I , Clanachan I , Kelly I P
Published: April 2011

Diffusion constants have been measured for nandrolone in human cadaver skin in vitro under conditions which approximate to both the occluded and non-occluded topical therapeutic situation. The results suggest that occlusion affects the diffusion parameters only marginally, if at all, but appears to reduce the ability of the stratum corneum to ‘irreversibly’ bind a fraction of the applied dose. Studies of nandrolone diffusion in freshly excised human epidermis yield similar results to those from measurements on cadaver skin, and it has also been found that epidermal samples excised from non-involved sites of human psoriatic patients behave under these conditions in essentially the same way as normal epidermis.
Circling behaviour in the rat following unilateral injections of p-chlorophenylalanine and ethanol-amine-O-sulphate into the substantia nigra
Authors: Tanner Trevor
Published: April 2011

Circling behaviour following the unilateral intranigral injection of the γ-aminobutyric acid (GABA) transaminase inhibitor ethanolamine-O-sulphate, (EOS), or the tryptophan hydroxylase inhibitor p-chlorophenylalanine (pCPA) was compared, both for spontaneous circling and for circling induced by apomorphine administration. EOS-injected rats exhibited spontaneous contralateral rotation for up to 3 h after such injections. pCPA-injected rats showed only a slight ipsilateral postural asymmetry, both groups of rats elicited ipsilateral rotation upon apomorphine challenge. Increased ipsilateral dopamine release within the corpus striatrum accompanied this response. It is proposed that GABA and 5-HT may be closely related in modifying the nigrostriatal impulse flow.
The synthesis and urinary estimation of N-hydroxyaprobarbitone
Authors: Gilbert John N T , Nelmes Philip T J , Powell John W
Published: April 2011

N-Hydroxyaprobarbitone (I) has been synthesized by oxidation of aprobarbitone, characterized, and a method developed for its estimation in urine. It has shown to be no more than a minor metabolite (<4%) in the human metabolism of aprobarbitone.
Survival of plasmid-containing strains of Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus in phenylmercuric nitrate and thiomersal
Authors: Pinney R J
Published: April 2011

Strains of Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus harbouring plasmids that confer mercury resistance grew in nutrient broth containing concentrations of phenylmercuric nitrate (PMN) that were inhibitory to isogenic plasmid-less strains. Decimal reduction times of P. aeruginosa and S. aureus in aqueous PMN solution were also increased by the presence of plasmids. The viable count of a plasmid-containing P. aeruginosa strain in Davis and Mingioli's minimal medium (DM) containing 10 μg ml−1 PMN fell by approximately 99% after 5 h. The count then remained constant for two weeks, when growth recommenced. This pattern of death followed by growth was also observed with the P. aeruginosa strain in DM + 10 μg ml−1 thiomersal.
Melanocyte-stimulating hormone—mimetic action of the phenothiazines
Authors: Carter R J , Shuster Sam
Published: April 2011

We have compared the melanophore-stimulating action of four phenothiazines, trifluoperazine, perphenazine, chlorpromazine, and prochlorperazine, with α-MSH on the skin of the lizard Anolis carolinensis, using a new rate method of bioassay. The dose-response curves for the phenothiazines were parallel to that of α-MSH, and when given together α-MSH and chlorpromazine were additive. The phenothiazines may therefore stimulate melanosome dispersion in the lizard skin by the same mechanism as α-MSH; a MSH-mimetic action of phenothiazines may similarly explain their pigmentary action in man. The pigmentary potency of the phenothiazines corresponded with their therapeutic potency in man; this is in keeping with a neuro-regulatory role for MSH peptides and suggests a possible therapeutic use for them.
The effect of various topical antibiotic and antibacterial agents on the middle and inner ear of the guinea-pig
Authors: Parker F L , James G W L
Published: April 2011

The topical application of antibiotics and anti-inflammatory agents is used to reduce inflammation of the middle ear mucosa and irradicate infection. Many of the antibiotic and anti-inflammatory preparations so used contain compounds known to be or are potentially ototoxic. Eighteen antibiotic, antibacterial, antifungal and anti-inflammatory compounds and four commonly used solvents were screened for the absence of ototoxicity and inflammation to the middle ear mucosa. All compounds were injected intra-tympanically and sensory hair cell loss recorded graphically. Inflammation of the middle ear mucosa was assessed macroscopically. Of the 18 compounds only three, penicillin, carbenicillin and nystatin were free of hair cell toxicity and inflammatory effects on the middle ear mucosa. Only one of the commonly used solvents was free of side effects.
Inhibitors of gastric lesions in the rat
Authors: Hayden Linda J , Thomas G , West G B
Published: April 2011

The production by stress of gastric lesions in rats was inhibited by metiamide and by mepyramine. Lesions induced by indomethacin treatment were inhibited by mepyramine but not by metiamide. Those induced by aspirin treatment in pylorus-ligated rats were not affected by either antihistamine drug. Oral glutamine inhibited lesion production in all three systems whereas aspirin orally markedly potentiated it. Sodium salicylate inhibited both indomethacin-induced lesions and those produced by aspirin in pylorus-ligated rats. On the other hand, copper salicylate inhibited stress-induced lesions and it, like copper aspirinate, also markedly reduced the extent of lesions produced by aspirin. On the basis of these results, stress-induced lesion production offers a suitable animal model for testing anti-ulcer drugs as it is, like most human gastric ulcers, inhibited by H2-receptor inhibitors like metiamide.
Actions of procaterol (OPC-2009), a new β2-adrenoceptor stimulant, on pulmonary resistance, contractions of the soleus muscle, and cardiovascular system of the anaesthetized cat
Authors: Yamashita Shuji , Takai Masaaki , Yabuuchi Youichi
Published: April 2011

The β-adrenoceptor stimulant actions of procaterol hydrochloride [5-(1-hydroxy-2-iso-propylaminobutyl)-8-hydroxycarbostyril hydrochloride hemihydrate] were compared with those of isoprenaline, orciprenaline and salbutamol on pulmonary resistance, contractions of the soleus muscle, heart rate and diastolic blood pressure in the anaesthetized cat. All four drugs reduced the 5-HT-induced increase in pulmonary resistance, decreased the tension of incomplete tetanic contractions of the soleus muscle and the diastolic blood pressure, and increased the heart rate in a dose-related manner. The duration of the bronchodilator action of procaterol was far longer than that of orciprenaline or salbutamol while isoprenaline had the shortest duration. Procaterol was about 1·5 times more potent, and orciprenaline and salbutamol about 80 and 10 times less potent than isoprenaline in reducing the 5-HT-induced increase in pulmonary resistance and in decreasing the tension of incomplete tetanic contractions of the soleus muscle. Procaterol, orciprenaline and salbutamol were 3·5, 91·9 and 43·9 times less potent than isoprenaline in increasing the heart rate. Procaterol, orciprenaline and salbutamol were 3·4, 130·2 and 12·9 times less potent than isoprenaline in decreasing the diastolic blood pressure. Calculation of selectivity for bronchial vs cardiac β-adrenoceptors indicates that procaterol and salbutamol have a similar degree of selectivity for β2-adrenoceptors mediating the bronchodilation, and that orciprenaline was an essentially unselective stimulant. Furthermore, the results support the suggestion that at present it is not possible to separate the bronchodilating and tremor-enhancing properties of β-adrenoceptor stimulants.
Tryptamine-induced drug effects insensitive to serotoninergic antagonists: evidence of specific tryptaminergic receptor stimulation?
Authors: Quock Raymond M , Weick Barton G
Published: April 2011

The drug effects of tryptamine and 5-hydroxytryptophan (5-HTP) in the rabbit were compared following monoamine oxidase inhibition and various drug pretreatments. Both agents evoked hyperthermia and behavioural excitation; tryptamine but not 5-HTP also produced forepaw clonic activity. Serotoninergic receptor blockers abolished the effects of 5-HTP but only weakly influenced tryptamine responses. Both tryptamine and 5-HTP effects were potentiated by fluoxetine. Methergoline, a putative tryptaminergic receptor blocker, antagonized tryptamine-induced hyperthermia and forepaw clonus but did not influence 5-HTP responses. It is postulated that while 5-HTP produces its effects through a serotoninergic mechanism, some of the responses to tryptamine result from activation of a specific tryptamine-sensitive mechanism.
Some pharmacological actions of acetylsecohemicholinium
Authors: Hemsworth B A , Cholakis J M
Published: April 2011

The effects of the acetylated derivative of HC-3 (acetylsecohemicholinium; AcHC-3) have been studied at cholinergic nerve terminals and compared with the effects of the parent compound. AcHC-3 blocked neuromuscular transmission in nerve-muscle preparations; it was shown to be less effective than HC-3 in producing a pre-junctional block in the rat diaphragm but was more effective than HC-3 in eliciting a post-junctional blocking effect in the chick biventer muscle. On the frog rectus abdominis muscle AcHC-3 caused a substantial potentiation of the contractures elicited by acetylcholine but did not by itself cause a contracture of the muscle. AcHC-3 inhibited the synthesis of acetylcholine by cholinergic nerve ending particles and inhibited the uptake of [14C]choline into brain synaptosomal fractions to a similar extent to HC-3. AcHC-3 was shown to be a substrate for cholinesterase enzymes although the rate of hydrolysis was much less than the rate of hydrolysis of acetylcholine. It is concluded that AcHC-3 is effective in inhibiting cholinergic transmission and this acticn is exerted by the open chain (seco) compound and is not due to the hydrolysis of the AcHC-3 by cholinesterases to form the active HC-3 molecule.
Interaction of cortisol-21-palmitate with liposomes examined by differential scanning calorimetry
Authors: Fildes F J T , Oliver J E
Published: April 2011

Liposomes have been suggested as carriers for corticosteroids in the local treatment of arthritis by intra-articular injection. The long chain 21-esters of Cortisol such as the palmitate or octanoate are taken up and retained by liposomes in higher concentration than cortisol itself. Differential scanning calorimetry has been used to show that the cortisol ester is anchored in the liposome phospholipid bilayer by the acyl side chain. In addition, the limiting concentration of cortisol-21-palmitate which can be incorporated into dipalmitoyl phosphatidylcholine liposomes has been measured by observing changes in the DSC spectrum at different steroid concentrations. Steroid in excess of this concentration limit forms a separate phase which can be identified by nuclear magnetic resonance. For optimum effect, the treatment of arthritis with liposomes must be carried out with liposomes containing steroid below the limiting concentration.
In vitro and in vivo defoaming action of three antacid preparations
Authors: Stead J A , Wilkins R A , Ashford J J
Published: April 2011

The defoaming activity of three tablet antacids (hydrotalcite, hydrotalcite/dimethicone and aluminium hydroxide/dimethicone) powdered to 60 mesh was measured in vitro using a new static/dynamic technique. Their antacid actions and that of aluminium hydroxide gel B.P.C. were also measured using a modified Fuch's test. Combination of dimethicone with hydrotalcite conferred good defoaming activity with little effect on pH profile whilst combination of aluminium hydroxide with dimethicone markedly altered both. Additionally, the defoaming actions of the three commercial antacids were assessed in vivo. Radiographs were taken after administration of antacid, a foaming mixture and a normal barium meal. The radiographs were then ranked blind by 5 radiologists. The rankings assigned the significantly greatest (Mann-Whitney U-test) defoaming effect to the hydrotalcite/dimethicone combination, there being no difference between the other two preparations. The in vitro results were thus confirmed.
Correlation of physicochemical properties with absorption and metabolism of some tricyclic drugs
Authors: Gescher A , Po A Li Wan
Published: April 2011

Octanol and dodecane partition coefficients, surface activity and adsorbability to activated charcoal were determined for six tricyclic psychotropic drugs with N-dimethylalkyl side chains. Surface activity correlated well with the partition coefficients, and all drugs obeyed the Langmuir adsorption isotherm. A correlation between the reciprocal of the death time of gold fish exposed to drugs and partition coefficients was observed. The extent to which the drugs were N-demethylated as measured by formaldehyde formed in rat liver homogenate incubations correlated with their adsorbability to activated charcoal but not with their ability to inhibit aniline-p-hydroxylase, nor was there a linear correspondence between N-demethylation and drug lipophilicity as indicated by partition coefficients or surface activity.
Rat brain and serum lithium concentrations after acute injections of lithium carbonate and orotate
Authors: Kling Mitchel A , Manowitz Paul , Pollack Irwin W
Published: April 2011

Eight hours after intraperitoneal injections of 1·0, 2·0, and 4·0 m equiv Li kg−1, the serum and brain lithium concentrations of rats were significantly greater after lithium orotate than after lithium carbonate. While little serum lithium remained at 24 h after injection of 2·0 m equiv kg−1 lithium carbonate, two-thirds of the 2 h serum lithium concentration was present 24 h after lithium orotate. Furthermore, the 24 h brain concentration of lithium after lithium orotate was approximately three times greater than that after lithium carbonate. These data suggest the possibility that lower doses of lithium orotate than lithium carbonate may achieve therapeutic brain lithium concentrations and relatively stable serum concentrations.
Corticosterone concentrations in mice during ethanol drinking and withdrawal
Authors: Tabakoff Boris , Jaffe Randal C , Ritzmann Ronald F
Published: April 2011

Consumption of an ethanol-containing diet by mice resulted in a significant increase in circulating concentrations of corticosterone which was maintained for 8 days. There were no changes in the concentrations of plasma corticosterone binding globulin. Ethanol withdrawal symptoms followed the removal of ethanol from the diet and circulating corticosterone concentrations were further increased. There was no correlation between blood ethanol and glucocorticoid concentrations during the chronic ethanol treatment. Stress related to ethanol consumption may be of greater importance than the circulating ethanol concentrations in producing the elevation in plasma glucocorticoids.
Antidotal effects of dimethyl sulphoxide against paracetamol-, bromobenzene-, and thioacetamide-induced hepatotoxicity
Authors: Siegers C-P
Published: April 2011

In mice the hepatotoxic effects of paracetamol (0·5–1·0 g kg−1, orally) as evidenced by increased serum enzyme activities of the aminotransferases and sorbitol dehydrogenase were dose-dependently inhibited by simultaneous treatment with dimethyl sulphoxide (DMSO 0·25–1·0 g kg−1, i.p.). DMSO was also active against bromobenzene- and thioacetamide-induced hepatotoxicity, but failed to protect mice against carbon tetrachloride-induced liver damage. Hepatic glutathione depletion in mice amounting to 94% after paracetamol (0·5 g kg−1, orally) and to 60% after bromobenzene (0·25 ml kg−1, orally) was dose-dependently reduced by the simultaneous administration of DMSO (0·25–1·0 g kg−1, i.p.). This indicates less conjugation of the toxic metabolites of paracetamol and bromobenzene to liver glutathione (G-SH) in the presence of DMSO.
Effectiveness of pyridostigmine in reversing neuromuscular blockade produced by soman
Authors: Dirnhuber P , Green D M
Published: April 2011

The effects of pyridostigmine pretreatment on the neuromuscular blockade produced by soman in anaesthetized, atropinized animals have been studied on the soleus and anterior tibialis muscle (rhesus monkeys, cats and rabbits) and the gastrocnemius muscle (guinea-pigs and rats). Pyridostigmine pretreatment produced a complete recovery of neuromuscular function following blockade by soman; the rate of recovery was similar in all the species, suggesting a common mechanism of action. In the absence of pyridostigmine or if pyridostigmine was delayed until after blockade by soman, there was no recovery of neuromuscular function. Detailed studies in the guinea-pig showed that the recovery of neuromuscular function was related to the dose of soman and to the degree of carbamoylation of blood cholinesterase at the time of nerve agent challenge, i.e. to the dose of pyridostigmine and the time interval between the administration of pyridostigmine and soman. It is suggested that the effectiveness of pyridostigmine pretreatment is due to the carbamoylation of a portion of the tissue acetylcholinesterase, which protects it against irreversible inhibition by soman: after poisoning spontaneous decarbamoylation produces sufficient free acetylcholinesterase to restore normal function.
The relationship between cholinesterase inhibition in the chick biventer cervicis muscle and its sensitivity to exogenous acetylcholine
Authors: Green A L , Lord J A H , Marshall I G
Published: April 2011

The effect of physostigmine has been studied on cholinesterase in homogenates of chick biventer cervicis muscles and on the contractile responses of the intact muscles to acetylcholine and carbachol. The concentration of physostigmine required to produce the maximum increase in sensitivity to acetylcholine almost completely inhibited the cholinesterase in muscle homogenates. This concentration of physostigmine had no effect on muscle contractures elicited by carbachol. By taking account of the combined effects of acetylcholine diffusion and enzymic hydrolysis, a quantitative theoretical relationship has been derived between the level of cholinesterase activity in cylindrical muscles and the fractional occupancy of the acetylcholine receptors in these muscles in the presence of different concentrations of exogenous acetylcholine. This theory attributes the thousand-fold increase in sensitivity to exogenous acetylcholine produced by anticholinesterases in chick biventer cervicis muscles largely to an alteration in acetylcholine concentration gradient within the muscle and accounts satisfactorily for the shift in the dose-response curve for acetylcholine which occurs after treatment of the muscles with various concentrations of physostigmine.
Pharmacological study of chicken airway smooth muscle
Authors: Chand N , Eyre P
Published: April 2011

Isolated chicken bronchus contracts to carbachol, PGF2α, histamine, 5-HT, bradykinin and phenylephrine. The bronchial strips from the horse plasma sensitized domestic fowl contracted to specific sensitizing antigen in vitro (Schultz-Dale anaphylactic reaction) and were 5 to 10 fold more reactive to PGF2α, histamine and 5-HT compared with the bronchi from normal chickens. Second antigen challenge was inactive or produced a weak response (desensitization). Allowing the bronchi to rest for 1 h resulted in partial recovery of anaphylactic response. Bronchi which had partially contracted submaximally to carbachol, antigen or PGF2α, relaxed to isoprenaline, adrenaline and PGE1 and E2.
The interaction of preservatives with polyhydroxyethylmethacrylate (polyHEMA)
Authors: Richardson N E , Davies D J G , Meakin B J , Norton D A
Published: April 2011

The interaction of the four most commonly used preservatives in contact lens solutions (chlorbutol, thiomersal, chlorhexidine gluconate and benzalkonium chloride) with polyhydroxyethylmethacrylate (polyHEMA), has been examined. Benzalkonium chloride and chlorhexidine gluconate show typical high affinity type isotherms. The interaction of benzalkonium chloride with polyHEMA from aqueous solution was reversible whereas that of chlorhexidine was only reversible in the presence of electrolyte or surfactant. Chlorbutol showed a typical reversible linear isotherm. Thiomersal does not interact with polyHEMA above pH 5·0. The extent of chlorhexidine—polyHEMA interactions is increased by the presence of formulatory adjuvants such as electrolyte and hydrophilic polymers. PolyHEMA lenses that apparently have been equilibrated with chlorhexidine gluconate will, on the addition of fresh preservative solution, bind further quantities of chlorhexidine above that which would be predicted from the sorption isotherm.
Bioavailability of griseofulvin from a novel capsule formulation
Authors: Fell J T , Calvert R T , Riley-Bentham P
Published: April 2011

The in vivo availability of griseofulvin from a novel formulation has been compared with the micronized powder. The formulation technique involves the conversion of the hydrophobic surface of the drug to a hydrophilic one by treatment with a film forming polymer. This enhances the wettability of the power, and increases its dissolution rate. The results of the in vivo study show the formulation technique has increased the rate and extent of bioavailability of griseofulvin when compared with the non-treated powder.
Direct effect of a nomifensine derivative on dopamine receptors
Authors: Poat Judith A , Woodruff G N , Watling K J
Published: April 2011

A study was made of the effects of nomifensine, 4′-hydroxynomifensine and 3′,4′-dihydroxynomifensine on dopamine receptors in rat striatum and nucleus accumbens, using the dopamine-sensitive adenylate cyclase assay. Nomifensine and its 4′-hydroxy metabolite were both inactive as dopaminergic agonists. 3′,4′-dihydroxynomifensine was, however, a potent agonist, being approximately 2 to 4 times less active than dopamine. The effects of dopamine and of 3′,4′-dihydroxynomifensine were blocked by Fluphenazine. It is concluded that the dopaminergic activity of 3′,4′-dihydroxynomifensine is dependent upon the presence of the two hydroxyl groups.