bluuebunny/crossref_metadata_2025 huggingface dataset:
Further biochemical characterization of [3H]dihydroazapetine binding to α-adrenoceptor — related proteins from the rat vas deferens
Authors: Ruffolo Robert R , Turowski Bethany S , Patil P N
Published: April 2011

The binding of [3H]dihydroazapetine, a reversible blocker of the α-adrenoceptor, has been characterized in a membrane preparation from the rat vas deferens. Binding is rapid, reversible and shows evidence of saturation. Postganglionic sympathetic denervation of the tissue does not decrease binding to the subcellular fraction. Drugs known to act on the α-adrenoceptor are specific inhibitors of [3H]dihydroazapetine binding while those acting on other receptors are without effect. Scatchard plot analysis suggests that two specific binding components are present, one of which has a similar dissociation constant for [3H]dihydro-azapetine to that determined pharmacologically. [3H]Dihydroazapetine binding is lowest in the physiological pH range and tends to decrease with increasing temperature in the range of 25 to 60°. Calcium, magnesium, sodium and potassium inhibit binding of [3H]dihydroazapetine with the divalent ions being approximately 100 times more potent. Studies with group selective reagents indicate that a disulphide bridge, and sulphydryl and carbonyl groups, are at or near the binding site and are necessary for binding. The site is protein possibly with involvement of phospholipids. Specific binding of [3H]dihydroazapetine is inhibited by low concentrations of local anaesthetics suggesting that the binding site of the antagonist may be related to the ‘calcium mobilization’ site of the α-adrenoceptor.
The influence of methysergide on 5-hydroxytryptamine-induced changes in regional distribution of blood flow
Authors: Forsyth Ralph P , Saxena Pramod R
Published: April 2011

Systemic and regional haemodynamic variables were measured at the baseline and after saline or 5-HT infusions (5 μg kg−1 min−1, i.v.) or methysergide injections (0–5 mg kg−1, i.V.). Cardiac output and its complete distribution were measured by the radioactive microsphere (15 μm diam.) technique. Although 5-HT did not change the systemic variables, methysergide caused a moderate increase in systolic and mean blood pressure and heart rate. 5-HT caused a substantial increase in gastric and a moderate increase in cerebral and myocardial blood flow at the expense of that to the lungs (arteriovenous shunt + bronchial flows), kidneys and skin. While methysergide was able to reduce the vascular responses to 5-HT in stomach, skin, kidneys, heart, lungs and brain, the drug itself, like 5-HT, decreased the number of microspheres reaching the lungs. Since a large number of 15 μm microspheres can escape through the arteriovenous anastomoses to lodge in the lungs it seems likely that both 5-HT and methysergide can reduce the ‘non-nutrient’ flow through these anastomoses.
The use of 13C-nmr spectroscopy for the detection and identification of metabolites of carbon-13 labelled amitriptyline
Authors: Hawkins D R , Midgley I
Published: April 2011

The antidepressant drug amitriptyline and two of its metabolites, nortriptyline and desmethylnortriptyline, each containing two 13C atoms, have been used to determine the sensitivity and selectivity of 13C-nmr spectroscopy for the detection of unchanged amitriptyline and N-desmethyl metabolites in the urine of animals dosed orally with the labelled drug. The resonance signals from the 13C atoms detected in the 13C-nmr spectrum of the entire extract from a control 12 h rat urine sample to which 1 mg of each labelled compound had been added were easily detected, using an instrument accumulation time of 1 h. The 13C-nmr spectrum of an extract of hydrolysed urine from a dog that had received an oral dose of [13Q]amitriptyline (30 mg) exhibited signals that could be assigned to metabolites resulting from N-dealkylation and N-oxidation, as well as those bearing the intact amitriptyline side-chain. These assignments were confirmed by analysis of the same extract by g.c.-ms and h.p.l.c.
Acidic in vivo metabolites of cannabinol isolated from rat faeces
Authors: Yisak Wolde-Ab , Widman Martanne , Agurell Stig
Published: April 2011

Six acidic metabolites were isolated from rat faeces and identified by gas chromatography-mass spectrometry and proton magnetic resonance. Cannabinol-7-oic acid was the most abundant acidic metabolite isolated. Others present in decreasing order of prominence were 1″-hydroxy-, 4”-hydroxy-, 3″-hydroxycannabinol-7-oic acid, cannabinol-3”-one-7-oic acid and 2″-hydroxycannabinol-7-oic acid.
Comparison between spontaneously beating atria from control and streptozocin-diabetic rats
Authors: Foy J M , Lucas P D
Published: April 2011

Isolated spontaneously beating atria from streptozocin diabetic rats were compared with those from controls. Diabetic atria were found to have reduced rates, increased forces of contraction and reduced sensitivity to the inotropic effects of noradrenaline, isoprenaline, tyramine and calcium. Positive chronotropic responses to tyramine were also reduced but those to noradrenaline and isoprenaline were increased suggesting that tyramine releasable stores of noradrenaline were reduced. Elevation of glucose concentration in the medium from 5·6 to 27 min resulted in a decrease of inotropic sensitivity to the agents used in both control and diabetic rat atria. Resting contractile force of control rat atria was reduced by the inclusion of either 22 niM 2-deoxyglucose, 10−3 i.u. insulin ml−1 or 5 mM acetate in the medium. The rate was also reduced by medium containing 2-deoxyglucose but increased by insulin. 2-Deoxyglucose also reduced inotropic but increased chronotropic sensitivity to isoprenaline. Possible mechanisms responsible for the changes observed are discussed.
Time-dependent deformation of some direct compression excipients
Authors: Rees J E , Rue P J
Published: April 2011

Three techniques were used to compare the time-dependent deformation of microfine cellulose (Elcema G250), anhydrous lactose, dicalcium phosphate dihydrate (Emcompress), modified starch (Sta-Rx 1500) and sodium chloride. (1) In stress-relaxation experiments using a reciprocating tablet machine, none of the materials behaved as a Maxwell body in contrast to recent published work (David & Augsburger, 1977). Possible reasons for this disagreement are discussed. (2) Heckel plots showed that increasing the time for which a material was under compression (contact times of 0·17 and 10 s) had no effect on dicalcium phosphate compacts but increased the consolidation of other materials in the rank order sodium chloride < lactose < cellulose < starch. (3) Deformation tests on preformed compacts were carried out in diametral compression by loading compacts to 75% of their breaking force at four different strain rates between 0·05 and 6·5 mm min−1. The deformation of Sta-Rx compacts was time-dependent. Sodium chloride compacts exhibited brittle behaviour in the diametral compression test and in the 10 s contact time experiment. This was apparently due to work-hardening, following the extensive plastic deformation of crystals during compaction as indicated by the stress relaxation results.
Phospholipase inactivation induced by an amino-piperazine derivative: a study at the lipid — water interface
Authors: Defrise-Quertain F , Chatelain P , Ruysschaert J M
Published: April 2011

1-Amino-4-octylpiperazine, AP 22, an antiviral agent causes lipid accumulation in nervous tissue cultures. A physicochemical membrane model was used to demonstrate the formation of a lipid-AP 22 complex hindering phospholipase A2 action. A well defined amphiphilic balance seems essential to explain the mode of action of the drug. The hydrophilic group prevents enzyme-substrate complex formation whereas the hydrophobic group allows the penetration in the lipid layer and determines the stability of the drug-lipid complex. This stability of the drug-lipid association has a direct influence on phospholipase A2 activity but does not affect phospholipase C activity. No inactivation of phospholipase A2 due to a drug-enzyme interaction could be detected.
The indirect sympathomimetic activity of etilefrine — a comparison with tyramine and ephedrine using [3H]noradrenaline
Authors: Frost B R , Halloran T N , Frewin D B , Gerke D C , Downey J A
Published: April 2011

The indirect sympathomimetic activity of etilefrine has been examined using the ventral caudal artery of the rat. This vessel has a rich sympathetic innervation and lends itself to studies on [3H]noradrenaline efflux from these sites. Etilefrine possessed significant indirect activity on the artery and this action, although less than that of tyramine, was equivalent to that caused by ephedrine. Pretreatment of the vessels with a mixture of iproniazid, doca, cocaine and U0521 (3′,4′-dihydroxy-2-methyl propiophenone) significantly enhanced[3H]-noradrenaline efflux from the artery.
The absorption of aliphatic carbamates from the rat colon
Authors: Wood S G , Upshall D G , Bridges J W
Published: April 2011

The colonic absorption of a series of aliphatic carbamates has been studied using an in situ preparation in the rat. The absorption process appeared to be passive and no metabolism by the colon membrane was detected. A linear correlation between the logarithms of the absorption rate constants and apparent partition coefficients was found. The absorption rates were not affected by concurrent water flux.
The effect of some formulation and process variables on the surface roughness of film-coated tablets
Authors: Rowe R C
Published: April 2011

The effect of some formulation and process variables on the surface appearance of film-coated tablets has been examined by measuring the arithmetic mean roughness, Ra, values across the faces of tablets before and after they were coated with hydroxypropyl methyl-cellulose. For all tablet cores except those that were very porous, film coating resulted in an increasing surface roughness; for very porous cores a decrease was found. Tablets with rough surfaces were produced by coating with low molecular weight grades of the polymer; increaseing the polymer molecular weight resulted in a smoother finish with a minimum roughness at intermediate molecular weight grades. Increasing the polymer concentration above 2% w/v caused an increase in roughness as did increasing film thickness to 140 μm. There was a minimum in roughness at film thicknesses of 20 μm. The addition of pigment in low concentrations (0–25% v/v) caused a marginal increase in surface roughness but at concentrations above the critical pigment volume concentration, the surfaces were very rough. The results illustrate the potential of the method in the optimization of film formulations and process conditions during product development.
Lithium-6 stable isotope determination by atomic absorption spectroscopy and its application to pharmacokinetic studies in man
Authors: Birch N J , Robinson Delia , Inie R A , Hullin R P
Published: April 2011

No useful radioisotope of lithium exists to assist in. the study of its biochemical pharmacology. A simple method has been developed for the determination of the stable isotope 6Li by atomic absorption spectroscopy (AAS). The technique is applicable in any laboratory equipped with simple AAS apparatus. Analysis of total lithium content (E) by flame emission spectroscopy is followed by separate determination (A6 and A7) of atomic absorption by the sample of the light emitted by separate hollow cathode lamps manufactured from the isotopes 6Li and 7Li. The standard curve of absorption ratio (A6/A7) against isotopic ratio (6Li/7Li) at any concentration (E) is an exponential which may be solved using a simple programmable calculator. Application of this method to the study of the pharmacokinetics of 6Li adminstered to 4 normal volunteers previously loaded with 7Li suggests that the rate of appearance of lithium in blood is unaffected by the previous state of lithium loading.
Sustained release of sulphadiazine
Authors: Wise Donald L , McCormick Gerald J , Willet Gloria P , Anderson Lynne C , Howes John F
Published: April 2011

An implantable system was developed which released sulphadiazine in mice over an extended period of time efficacious against infective challenges by Plasmodium berghei. The most successful preparation was a copolymer of L(+)-lactic acid + (±)-lactic acid (90 and 10% by weight, respectively) with a molecular weight of 150 000, with which sulphadiazine was mixed at 33.3% of the total weight, in a formulation as beads of 1.5 mm diameter. This preparation released sulphadiazine at a nearly constant rate over three months as measured by the appearance in urine of mice of radioactivity from [35S] sulphadiazine in transplanted material. When implanted in mice, the beads gave effective protection against repetitive (weekly) infective challenges with P. berghei by implanted beads at dosages equivalent to 57 mg kg−1 sulphadiazine and greater over 21 weeks.
Dopamine antagonistic effects of a series of analogues of oxiperomide and spiroxatrine measured behaviourally in the rodent
Authors: Costall Brenda , Naylor Robert J
Published: April 2011

The activity spectra of oxiperomide, spiroxatrine and analogues were determined in two experimental models of abnormal peri-oral movements (induced by intrastriatal dopamine and subcutaneously administered 2-(NN-dipropyl)amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (NN-diPr-5,6-diOHATN) in the guinea-pig), and in a stereotypy test (induced by subcutaneous apomorphine in the guinea-pig); the ability of the test compounds to induce catalepsy or catatonia in the rat was also determined. The parent compounds oxiperomide and spiroxatrine possessed optimal activity in all tests, although responses to the series of compounds allowed clear differentiation between an ability to antagonize the peri-oral movements (dopamine- or NN-di Pr-5,6-diOHATN induced) and an ability to antagonize apomorphine stereotypy. However, all compounds that antagonized the abnormal peri-oral movements also caused catalepsy/catatonia. The results are considered in terms of the selection of suitable agent(s) for the treatment of peri-oral dyskinesias.
Potentiation of neostigmine and pyridostigmine by 4-aminopyridine in the rat
Authors: Miller Ronald D , Dennissen Peter A F , van der Pol Francien , Agoston Sandor , Booij Leo H D J , Crul Jan F
Published: April 2011

The interaction between 4-aminopyridine and neostigmine or pyridostigmine was studied in vivo in the rat sciatic nerve-anterior tibialis preparation using the constant infusion of pancuronium technique. The ED50 (dose of drug which produced a 50% antagonism) of neostigmine, pyridostigmine and 4-aminopyridine were 18, 49 and 440 μg kg−1 respectively. The addition of 100 μg kg−1 of 4-aminopyridine, which produced no antagonism by itself, decreased the neostigmine ED50 to 7·4 μg kg−1. The addition of 200 μg kg−1 of 4-aminopyridine, which produced a 30% antagonism by itself, decreased the ED50 of pyridostigmine to 11 μg kg−1. We conclude that both neostigmine and pyridostigmine interact with 4-amino-pyrine synergistically.
The effects of a hydroxyl group on some chemical and biological properties of n-pentyl ammonium salts
Authors: Barlow R B
Published: April 2011

The effects of a hydroxyl group on the activity and affinity of compounds related to n-pentyltrimethylammonium have been studied on the guinea-pig ileum, frog rectus, acetylcholinesterase and on partitioning (Rm) and size (φov, Vm). The hydroxyl group lowered affinity in all tests, confirming the importance of hydrophobic forces in binding to receptors. Activity on the ileum was lowered appreciably but on the rectus only slightly. The effects on Rm did not indicate any interactions between hydroxyl, onium group and water but the apparent size of the hydroxyl group (Δφov) depends on the nature of the onium group.
The effect of the photodecomposition of chlorpromazine on lecithin monolayers
Authors: Nejmeh Maha , Pilpel N
Published: April 2011

Chlorpromazine hydrochloride (cpz) is decomposed when irradiated with ultraviolet light, forming H+, hydrochloric acid, chlorpromazine sulphoxide and 2-hydroxypromazine. The order of the reaction (as measured by the expansion that is produced in a lecithin/cpz monolayer) varies between zero and about 3/4. The results have been used to explain some of the adverse side effects that are observed when patients are treated with cpz.
Gastric ulceration and the concentration of salicylate in plasma in rats after administration of 14C-labelled aspirin and its synthetic triglyceride, 1,3-dipalmitoyl-2(2′-acetoxy-[14C]carboxylbenzoyl) glycerol
Authors: Kumar R , Billimoria J D
Published: April 2011

Triglycerides containing aspirin in place of one or more fatty acid residues of the molecule have been synthesized. Metabolism of the compound with the labelled (14C) drug residue introduced specifically into the 2-position of the triglyceride is reported. Plasma salicylate concentrations with this synthetic glyceride were determined and compared with those obtained with commercially available aspirin labelled with the 14C-isotope. Both compounds gave a therapeutic concentration of salicylate in the plasma after ingestion. The 1,3-di-fatty acyl-2-aspirin glyceride was absorbed through the intestine as 2-aspirin monoglyceride, some 20% of which was transported through the thoracic-duct chyle and about 30% through the portal system. Whereas pronounced ulceration of the rat stomach occurred with free aspirin, the above fatty acyl glyceride of aspirin produced no ulceration.
Assessment of the neuroleptic potential of some novel benzamide, butyrophenone, phenothiazine and indole derivatives
Authors: Costall B , Funderburk W H , Leonard C A , Naylor R J
Published: April 2011

A series of experimental models were used to determine the activity spectra of potential neuroleptic agents on extrapyramidal and/or mesolimbic dopamine systems: catalepsy induction by the drug alone or in the presence of the acetylcholine-like agent, RS86 [spiro-(N'-methylpiperidyl-4′)-N-ethyl succinamide hydrogen fumarate], or α-methyl-p-tyrosine (α-MT), stereotypy antagonism (amphetamine) and hyperactivity antagonism (intra-accumbens and intrastriatal dopamine). Antiemetic potential was also considered. Whilst classical neuroleptics were active in all test situations, other neuroleptics including benzamide, phenothiazine, butyrophenone and indole derivatives exhibited novel activity spectra: clozapine failed to interact with α-MT, metoclopramide failed to antagonize a mesolimbic hyperactivity or interact with the acetylcholine-like agent. Other benzamide derivatives, clebopride, AHR6092, sultopride and tiapride also failed to interact with RS86, but whilst clebopride was active in all other test situations, AHR6092 was inactive in all but the antiemetic test, sultopride was only weakly cataleptogenic and tiapride only antagonized stereotypy and hyperactivity from the striatum. AHR6839, AHR6134, AHR6645, AHR6505B and AHR1709 were generally inactive in the catalepsy tests but exerted dopamine antagonistic potential in other test procedures. The antagonistic ability of AHR1709 was only revealed in the tests where dopamine function was specifically raised in the nucleus accumbens and caudate-putamen by intracerebral dopamine injections. Data are discussed in terms of a dissociation of drug effects on different cerebral dopamine systems.
The release of a model low-dose drug (riboflavine) from hard gelatin capsule formulations
Authors: Stewart A G , Grant D J W , Newton J M
Published: April 2011

The in vitro release of a model low dose drug, riboflavine, from hard gelatin capsules, formulated with a range of diluents, in the absence and presence of magnesium stearate (0.5, 1.0 and 2.0% w/w), has been assessed by a dissolution technique. Comparison of the values of the time for 50% of the drug content of the capsule to appear in solution T50, by analysis of variance, indicated that the type of diluent significantly influenced the drug release. Irrespective of the magnesium stearate content, the diluents could be ranked in the following order of effectiveness: Primojel > sodium bicarbonate > Avicel ≃ Dri-flo starch ≃ lactose > Emcompress ≃ kaolin > starch. Correction of the T50 values for possible adsorption of riboflavine onto the water insoluble diluents, using experimentally determined adsorption isotherms, altered the relative order of effectiveness of the diluents to Primojel > sodium bicarbonate > kaolin ≃ lactose > Avicel ≃ Dri-flo starch > Emcompress > starch. Comparison of the urinary excretion of riboflavine, after administration of capsule formulations containing lactose, Emcompress or kaolin as the diluent, to volunteers, suggests that the dissolution results not corrected for adsorption provide a better indication of the in vivo performance of the formulations.
A method to estimate binding constants at variable protein concentrations
Authors: Romer Jurg , Bickel Marcel H
Published: April 2011

The association constants of the binding of chlorpromazine and imipramine to serum albumin at low saturation of the protein were determined by a new experimental approach with the protein concentration rather than the ligand concentration being varied. This approach is suitable for estimating binding constants in systems with one class of binding sites. In addition, the method is proposed to complement conventional binding studies of systems with two classes of binding constant with higher accuracy.
An in vitro method simulating drug release from viscous eye drops in rabbit and man
Authors: Melis-Decerf C , van Ooteghem M
Published: April 2011

A method has been developed using a diffusion cell in an attempt to determine the drug release from viscous solutions under conditions simulating the blinking movements in the rabbit and human eye. Diffusion coefficients were determined at rest and at different velocities. For the solutions at rest, corresponding with the conditions at the surface of the rabbit cornea, the diffusion velocity decreases with increasing viscosity. When the solution is moved at a velocity corresponding to that of lachrymal fluid at the surface of the human eye, the influence of viscosity may be neglected.
A comparison of the cardiovascular effects of centrally administered clonidine and adrenaline in the anaesthetized rat
Authors: Borkowski Kazimierz R , Finch Lionel
Published: April 2011

Intracerebroventricular (i.c.v.) injections of clonidine and adrenaline-induced hypotension and bradycardia in urethane anaesthetized spontaneous hypertensive rats. The hypotension induced by clonidine (3 μg i.c.v.) was antagonized by pretreatment with the α-antagonists piperoxan, which also antagonized clonidine-induced bradycardia, and yohimbine. The hypotension and bradycardia induced by adrenaline (10 μg i.c.v.) were unaffected by α-antagonist pretreatment, while β-antagonist pretreatment with (-(-propranolol or metoprolol was effective against adrenaline but not clonidine-induced hypotension and bradycardia. Pretreatments with the histamine H2-receptor antagonists metiamide and cimetidine antagonized clonidine but not adrenaline-induced hypotension. These data indicate that different central mechanisms are involved in mediating the hypotension and bradycardia induced by centrally administered clonidine and adrenaline and do not, therefore, support the hypothesis that the hypotensive effects of clonidine (i.c.v.) are mediated by central adrenaline receptor activation in urethane-anaesthetized spontaneous hypertensive rats.
Long-lasting inhibition of angiotensin response in rats by depot administration of octanoyl-[Leu8]-angiotensin II
Authors: Abdulkader Regina C , Silva Helio B , Marcondes Marcello , Vasconcelos Eleonidas A , Paiva Antonio C M
Published: April 2011

Depot administration of a lipophilic angiotensin II (AII) antagonist was tested for obtaining prolonged inhibition of the pressor response to AII in rats. Intramuscular injections of 1.5 or 5.0 mg of octanoyl-[Leu8]AII (oct-LAII), in oil solution produced the same degree of AII inhibition either 6 h or 24 h after the injection. The inhibition was comparable to that expected from the continuous intravenous infusion of oct-LAII at the rate of 1.2 μg kg−1 min−1. The prolonged effect of intramuscular injections of oct-LAII in oil solution may be useful for chronic studies of physiopathological states involving the renin-angiotensin-aldosterone system.
Plasma corticosterone responses to stress following chronic oral administration of diazepam in the rat
Authors: Barlow S M , Knight A F , Sullivan F M
Published: April 2011

The effect of daily, oral administration of diazepam on plasma corticosterone responses to stressors of varying intensity was investigated. In rats exposed to the mild stress of noise, diazepam, 10 mg kg−1 but not 1.0 or 0.1 mg kg−1, reduced plasma corticosterone concentrations by 30% in comparison with controls. However, in rats exposed to the more severe stressors, foot-shock or immobilization, none of these doses of diazepam reduced plasma corticosterone responses. In unstressed rats, diazepam 10 mg kg−1 raised plasma corticosterone concentrations. It is suggested that plasma corticosterone concentrations are not a reliable indicator of the tranquillizing effect of diazepam during stress.
p-Chloroamphetamine-induced hyperthermia pharmacologically distinct from fenfluramine-induced hyperthermia
Authors: Quock Raymond M , Weick Barton G
Published: April 2011

The influence of various drug pretreatments upon the responses of rabbits to the putative indirect 5-hydroxytryptamincrgic agonists p-chloroamphetamine (PCA) and fenfluramine were examined. In naive rabbits PCA evoked hyperthermia, behavioural excitation and prominent forepaw clonic activity, while fenfluramine produced only hyperthermia and behavioural stimulation. The hyperthermic and behavioural responses of both agents were reduced by the 5-hydroxytryptamine (5-HT) uptake inhibitor, fluoxetine, potentiated by the monoamine oxidase inhibitor, pheniprazine, and unaltered by the dopaminergic antagonist, haloperidol. Pretreatment with the 5-hydroxytryptaminergic receptor blockers cinanserin, cyproheptadine or D-2-bromolysergic acid diethylamide markedly attenuated the effects of fenfluramine but only slightly influenced the responses to PCA. Depeletion of central 5-HT stores with p-chlorophenylalanine also affected responses to fenfluramine more than responses to PCA. The tryptaminergic receptor blocker methergoline abolished both PCA-induced hyperthermia and forepaw clonus-but not behavioural stimulation—while the effects of fenfluramine were only partly reduced. We interpret these data to mean that PCA- and fenfluramine-induced drug effects have different underlying mechanisms, the PCA responses relying possibly upon tryptamine while the fenfluramine responses are 5-hydroxytryptaminergic.
The application of cryobiology to the microbiological assay of nystatin
Authors: Cosgrove R F , Beezer A E , Miles R J
Published: April 2011

Improvements in the reproducibility of nystatin agar diffusion assays have been achieved by the use of liquid nitrogen stored inocula and deep frozen standard stock solutions. The overall percentage variability of the assay has been reduced from over 5% with daily prepared standards and inocula to around 1% with a frozen inocula and to 0.6% with a combination of frozen inocula and standards. The implications of these improvements in the standardization of nystatin assays, and microbiological assays generally are discussed.
Modification of cortical neuron responses to acetylcholine by viloxazine
Authors: Jones R S G , Roberts M H T
Published: April 2011

Viloxazine, an antidepressant with no peripheral antiacetylcholine activity, was capable of reducing responses of single cortical neurons to acetylcholine. Acetylcholine responses could also be potentiated by viloxazine. Both potentiation and reduction by viloxazine were often seen in the same study, reduction of responses invariably preceding potentiation. These results suggest that viloxazine may have selective effects on central cholinergic receptors. Responses of cortical neurons to monoamines could also be potentiated by viloxazine although it has little effect on monoamine uptake. These results are compatible with the idea that potentiation of monoamine responses may occur by a postsynaptic mechanism.
N-o-Methoxyphenylpiperazine: a simple blocker of dopaminergic receptors in the brain
Authors: Minard Frederick N , Cain John C , Grant Dennis S , Dren Anthony T
Published: April 2011

N-o-Methoxyphenylpiperazine (MPP) is a moderately effective in vivo blocker of dopaminergic receptors. Its ability to increase the concentration of rat brain homovanillic acid (HVA) and the resulting time course for HVA were similar to the actions of clozapine. The increased concentration of HVA did not result from decreased outflow from brain because HVA also rapidly decreased after a subsequent injection of pargyline. MPP blocked the circling behaviour caused by apomorphine in mice with a unilateral striatal lesion, and MPP and apomorphine reciprocally blocked the occurrence of stereotypy and increased HVA in rats. Diazepam partially prevented the MPP-induced elevation of HVA. Thus, both biochemical and pharmacological evidence indicate the dopaminergic blocking action of MPP.
Percutaneous absorption: in vivo experiments
Authors: Albery W John , Hadgraft Jonathan
Published: April 2011

The percutaneous absorption of esters of nicotinic acid has been studied in vivo in man. The time for erythema to be produced has been measured both when the ester is applied continuously and in ‘pulse’ experiments when the ester is removed before the erythema develops. The results show that the erythema is produced long before steady state diffusion across the epidermis is established and the penetration of methyl nicotinate is characterized by D/l2 = 2.3 × 10−4 s−1 where D is the diffusion coefficient and l the thickness of the barrier. Results using glycerol water mixtures in the external phase show that the route of penetration for methyl nicotinate is through the interstitial channels and not through the keratinized cells. Data for absorption from various creams and ointments (Barrett et al 1964) show that the route is independent of the nature of the external phase. Steady state data for the absorption of salicylic acid and carbinoxamine through the abdominal skin of guinea-pigs (Arita et al 1970) show that the route of penetration does not change as the experiment proceeds. Data for the absorption of other substances (Michaels et al 1975) also fit the interstitial route.
Kidney function and lithium concentrations of rats given an injection of lithium orotate or lithium carbonate
Authors: Smith Donald F , Schou Mogens
Published: April 2011

A recent study by Kling et al (1978) noted the finding of higher lithium concentrations in serum and brain of rats after an intraperitoneal injection (2 mmol lithium kg−1) of lithium orotate as a slurry than of lithium carbonate in solution. The authors suggested that lithium orotate might offer advantages in the treatment of patients. We repeated the experiments of Kling et al but in addition examined the kidney function of the rats. Glomerular filtration rate and urine flow were markedly lower in rats given lithium orotate than in rats given lithium carbonate, sodium chloride or a sham injection. The renal lithium clearance was significantly lower, the kidney weight and the lithium concentrations in serum, kidney and heart significantly higher after injection of lithium orotate than after injection of lithium carbonate. The higher lithium concentrations could be accounted for by the lower kidney function. It seems inadvisable to use lithium orotate for the treatment of patients.
Pentobarbitone and skeletal muscle contractions: on the interaction with the effect elicited by the β-adrenoceptor agonist, terbutaline
Authors: Holmberg Eva , Waldeck Bertil
Published: April 2011

The soleus, a slow-contracting muscle, and the extensor digitorum longus (EDL), a fast-contracting muscle from guinea-pig were prepared for isometric recording in vitro. Sub-tetanic contractions were evoked by transmural field-stimulation. Pentobarbitone increased the force of contraction in both muscles. In the soleus it shifted the stimulation frequency-response curve to the left. Terbutaline caused a decrease in the force of subtetanic contractions of the soleus, an effect which was dependent on the stimulation frequency. In the presence of pentobarbitone, the stimulation frequency had to be lowered by about 2 Hz in order to maintain the optimum response to terbutaline. The EDL responded to terbutaline with an increased force of contraction. In this case the stimulation frequency was less critical and the effects were the same in the presence and in the absence of pentobarbitone. Experiments with α-chloralose yielded results similar to those obtained with pentobarbitone.
A comparative study of the microbiological assays currently available for nystatin raw material
Authors: Cosgrove R F , Beezer A E , Miles R J
Published: April 2011

The classical agar diffusion and turbidimetric methods of assay for nystatin are compared with the more recently documented assays for this antibiotic which depend upon physicochemical measurement of the response of micro-organisms. Liquid nitrogen stored inocula were used throughout. It is concluded that the newer methods of assay are as reproducible and reliable as the agar diffusion and turbidimetric methods and that they are generally more sensitive. The choice between the assay methods compared can thus be based on speed, cost and sample through-put.
Relationships between poloxamer structure and the solubilization of some para-substituted acetanilides
Authors: Collett J H , Tobin Elizabeth A
Published: April 2011

Saturation solubilities of several para-substituted acetanilides have been measured at 37 °C in aqueous solutions of structurally related polyoxyethylene-polyoxypropylene block copolymers-poloxamers L62, L63, L64, P65 and F68. These poloxamers differ only in the amount of ethylene oxide in the hydrophil. Solubilities increased with increasing poloxamer concentration. As the oxyethylene chain length of the poloxamer increased, then the solubilizing capacity per equivalent of oxyethylene decreased. The moles of acetanilide derivative solubilized per mole of poloxamer increased with poloxamer oxyethylene content in the case of the less hydrophobic acetanilides but was invariant in the more hydrophobic ones. The solubilizing capacities have been discussed in terms of the inter-relationships between the hydrophobic nature of the solubilizate and solubilizer and the site of solubilization on the poloxamer molecule.
The effect of simultaneous administration of 3,4-dihydroxyphenylpyruvic acid and L-dopa on the bioavailability of L-dopa in rat and mouse
Authors: Hietala P , Lindén Inge-Britt , Gronfors Nina
Published: April 2011

In the rat, administration of 3-(3,4-dihydroxy)-l-phenylalanine (l-dopa) simultaneously with the corresponding α-keto acid, 3,4-dihydroxyphenylpyruvic acid (DHPPA), gives significantly higher concentrations of l-dopa in the serum and of dopamine and homovanillic acid in the brain than the same dose of l-dopa alone. Correspondingly, DHPPA potentiates the effect of l-dopa on the locomotor activity in reserpine-treated mice. DHPPA is postulated to increase the absorption of intact l-dopa from the gut by preventing the transamination reaction between l-dopa and the physiological α-keto acids.
Powder mixing in direct compression formulation by ordered and random processes
Authors: Johnson M C R
Published: April 2011

The mixing processes taking place in a two component system involving a cohesive drug, tetracycline and a direct compression vehicle, spray dried lactose (SDL), have been studied by chemical analysis of powder samples and fluorescence microscopy. At a drug concentration level of 0.25% w/w, both random and ordered mixing is taking place. Mixture quality is better (Cv = 1 %) using a fine grade of crystalline lactose (CL) than with SDL (Cv = 4%). Using fractionated material, it was found that SDL between 106 and 300 μm gave Cv values up to 12%, whereas with SDL below 106 μm values of 2% were obtained. The poor quality of the SDL mixtures is attributed to ordered unit segregation.
Uptake of 5-hydroxytryptamine in blood platelets and its inhibition by drugs: role of plasma membrane and granular storage
Authors: Laubscher Andreas , Pletscher Alfred
Published: April 2011

The initial uptake of 3H-5-hydroxytryptamine (3H-5-HT) showed linearity for short time intervals in normal and reserpinized blood platelets of guinea-pigs, but was lower in reserpinized platelets. The Km values for the 3H-5-HT uptake were virtually identical in normal and reserpinized platelets, whereas Vmax was lower in the latter. Imipramine and chlorpromazine caused the same percentage inhibition of 3H-5-HT uptake in normal and reserpinized platelets; the reserpine-like compound Ro 4–1284 inhibited the uptake of 3H-5-HT in the normal, but not markedly in the reserpinized platelets. Haloperidol, prenylamine and Ro 4–9040 were more potent inhibitors in normal than in reserpinized platelets. It is concluded that (a) the Km of the initial uptake of 5-HT by platelets is probably determined by the mechanism at the plasma membrane, whereas Vmax may be codetermined by the intracellular storage capacity, (b) platelets are models for differentiating the site of action (plasma membrane or storage organelles) of drugs interfering with 5-HT uptake, and (c) neuroleptics- and reserpine-like compounds may either act selectively on the plasma membrane or on the intracellular storage organelles, or affect both of these subcellular sites.
The reversal by pyridostigmine of neuromuscular block produced by soman
Authors: French Mary C , Wetherell Janet R , White P D T
Published: April 2011

The effect of pyridostigmine on neuromuscular block produced by soman was studied in the isolated phrenic nerve-diaphragm preparation. In the rat, soman produced an irreversible reduction in tetanic tension and functional acetylcholinesterase (AChE) activity. Pretreatment with pyridostigmine before exposure of the diaphragm to soman, followed by removal of the anticholinesterase from the organ bath, produced a return of tetanic tension and an increase of 5% in functional AChE activity. Similar results were obtained in the guinea-pig. The changes in synaptic AChE activity were verified pharmacologically by showing a decrease in the blocking activity of acetylcholine in preparations pretreated with pyridostigmine in comparison to those given soman alone following removal of the anticholinesterase. The blocking dose of carbachol did not change in these two groups indicating that desensitization was not a component of the protective action. A comparison was also made of the results obtained by measuring inhibition of AChE in situ with those obtained from muscle homogenates. The implications of these results are discussed.
The protection of primates against soman poisoning by pretreatment with pyridostigmine
Authors: Dirnhuber P , French M C , Green D M , Leadbeater L , Stratton J A
Published: April 2011

The effectiveness of pyridostigmine pretreatment against soman poisoning has been determined in rhesus monkeys and marmosets receiving atropine therapy. Pretreatment with the maximum sign-free dose (200 μg kg−1, i.v.) raised the subcutaneous LD50 of soman by a factor of 28 in rhesus monkeys and 15 in marmosets. Theprotection afforded by a quarter of the sign-free dose of pyridostigmine was not significantly less. These levels of protection are higher than any reported in non-primate species.
Comparative metabolism of codeine in man, rat, dog, guinea-pig and rabbit: identification of four new metabolites
Authors: Cone E J , Darwin W D , Gorodetzky C W
Published: April 2011

The metabolism and excretion of codeine and its metabolites in untreated urine of man, rat, dog, guinea-pig and rabbit have been examined. Metabolites were identified by gas chromatography mass spectrometry operated in the chemical ionization mode (methane). Concentrations of codeine and metabolites were measured by selected ion monitoring. Both codeine and norcodeine were detected in the urine of all species but a new metabolite, hydrocodone, was found only in the urine from man, guinea-pig and dog. Additional metabolites (presumably resulting from the metabolism of hydrocodone) were also detected in man and guinea-pig. Overall recoveries of drug and metabolites from untreated urine were low for all species.
N-Chloroacetyl 5-methoxytryptamine (isamide): a selective antagonist of 5-hydroxytryptamine in the rat uterus
Authors: Huidobro-Toro J Pablo , Huidobro F , Ruiz Manuel
Published: April 2011

Isamide, the N-chloroacetyl derivative of 5-methoxytryptamine, produced a dose-dependent competitive blockade of uterine contractions in vitro induced by 5-HT. The pA2 value for the 5-HT-isamide interaction was 4.42. The blockade was short-lasting and reversible; after recovery, a dose-dependent increase in the uterine sensitivity to 5-HT was found. The blockade proved to be selective to the 5-HT receptor. The simultaneous application of 5-HT plus isamide partially prevented the 5-HT-induced auto blockade phenomenon. In addition, isamide did not affect the contractile responses of the uterus to oxytocin or bradykinin or the contractile effects of the rat vas deferens to adrenaline.
Specific membrane-binding of angiotensin II—the role of degradative enzymes
Authors: Moore A F , Povinelli M A
Published: April 2011

The possible role of degradative enzymes was examined in the specific binding of angiotensin II (AII) to cell membranes. Red blood cell membranes did not bind AII specifically under any of the ambient conditions studied, indicating a lack of AII receptors and no role for the degradative enzymes in specific binding. Rabbit aorta smooth muscle cell membranes bound AII specifically, and this binding had similar characteristics to those previously described for this preparation. It is concluded that specific binding of AII to cell membranes does not involve degradative enzymes, and probably represents binding to the biologically active receptor.
Rapid paper chromatographic separation of [14C] angiotensin II from some metabolites: application to organ distribution
Authors: Wagner Lorin A , Blosser William G , Buckley J P
Published: April 2011

A rapid, inexpensive method for the separation of 5-1-isoleucyl[14C] angiotensin II (A-II) from its various metabolites has been devised. A-II was extracted from tissues with absolute methanol (recovery 96%) and paper chromatographed in a butanol-acetic acid-water (18:2:5) medium for two ascents at 60° C. The resulting RF for A-II of 0.45 was then compared with the RF values of three A-II metabolites produced by enzymatic degradation of the 14C-A-II and [14C]isoleucine. Trypsin degradation produced the [14C]hexapeptide metabolite, chymotryptic degradation produced the [14C]tetrapeptide metabolite and carboxypeptidase A degradation produced the [14C]heptapeptide. Increases in temperature produced a continuous increase in RF values for all the substances examined but the resolution decreased above 60° C. Similarly, increases in the temperature caused the appearance of secondary peaks with some but not all peptides. The tryptic digest (hexapeptide) and the chymotryptic digest (tetrapeptide) are apparently acid- and heat-stable under the experimental conditions. All of the peptides examined failed to produce secondary peaks when heated at neutral pH. The method was used to study the tissue distribution of 14C-A-II after intravenous injection.
Synthesis, properties and biological activity of tritiated N-benzylamidino-3,5-diamino-6-chloro-pyrazine carboxamide — a new ligand for epithelial sodium channels
Authors: Cuthbert A W , Edwardson J M
Published: April 2011

A method is described for the synthesis and purification of tritiated N-benzylamidino-3,5-diamino-6-chloro-pyrazine carboxamide (benzamil). The tritium was inserted at the meta position of the benzyl ring, from which it apparently does not exchange with solvent hydrogen. When stored in ethanol at −4°C the radioligand remains stable for at least 15 months. The pharmacology of benzamil is very similar to that of amiloride in terms of its effects on sodium transporting epithelia except that it has a higher affinity. The affinity of benzamil for sodium channels in amphibian epithelia in the absence of sodium is approximately 109 M−1. The new ligand can be used to label sodium channels in epithelia, and may be useful in channel isolation procedures.
A nuclear magnetic relaxation study of bound water in solutions of disodium cromoglycate
Authors: Attiga S A , Eley D D , Hey M J
Published: April 2011

The amount of water bound to disodium cromoglycate (DSCG) in frozen aqueous solutions was determined from the amplitude of the n.m.r. free induction decay. The hydration number was found to be 15 molecules H2O/molecule DSCG of which 6 H2O molecules were less strongly bound than the rest. Proton T1 and T2 relaxation times in non-frozen solutions implied a value of 10−8 s for the correlation time of the bound water at 291 K. This is consistent with the mobility of DSCG molecules in a smectic mesophase.
Sources of variation during collaborative evaluation of in vitro dissolution tests for two solid preparations
Authors: Cartwright A C
Published: April 2011

Collaborative in vitro dissolution tests on a sample of commercial tolbutamide tablets and a sample of oxytetracycline capsules were carried out in eight laboratories. The two preparations tested showed differences between the products in release characteristics, particularly in the disintegration phase. This may have caused the difference in the pattern of variance in the two trials. In the case of tolbutamide tablets the value of the repeatability standard deviation was small, and therefore the major contribution to the variance was in the difference between laboratories. With oxytetracycline capsules the major contribution to the variance lies in the random errors common to all laboratories (i.e. the within-laboratory variance). One major source of inter-laboratory variance was identified as the level of vibration at the side of the dissolution flask. Another source of variation was found to be due to using a stated extinction coefficient instead of comparing the absorbances of the samples to those of a solution of a reference substance.
Analysis of the contractile effect of 5-hydroxytryptamine on the isolated posterior communicating artery of the cat
Authors: Marín J , Salaices M , Marco E J , Gãmez B , Lluch S
Published: April 2011

5-Hydroxytryptamine (5-HT) induced dose-dependent increases in tension on the isolated posterior communicating artery (PCA) of the cat were significantly antagonized by lysergic acid diethylamide (LSD, 6 times 10−9 m). In the presence of phentolamine (10−6 m) the contraction induced by the two lowest doses of 5-HT was significantly reduced. Pretreatment of the animals with reserpine (3 mg kg−1, i.p., total dose) did not modify the dose-response curve to 5-HT except for the lowest dose. Removal of both superior cervical sympathetic ganglia 15 days before the experiment brought about a significant increase in the vasoconstriction induced by 5-HT at all the doses compared with the control. Cocaine (10−6m) induced a significant shift to the left of the dose-response curve to 5-HT but the maximum response was the same as in the control. The augmented response to 5-HT after denervation was partially antagonized by LSD (6 times 10−9 m) but not by phentolamine (10−6 m). These results show that the vasoconstriction elicited by 5-HT in the PCA of the cat is mainly due to direct stimulation of tryptaminergic receptors. The participation of an indirect adrenergic component in the contractile effects of 5-HT seems to be negligible.