bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaction of glutethimide and phenobarbitone with ethanol in man
Authors: MOULD G P , CURRY S H , BINNS T B
Published: April 2011

Interactions of ethanol with glutethimide and phenobarbitone in man were examined by means of psychomotor tests and measurement of ethanol and glutethimide in body fluids. Blood ethanol was about 11% higher overall when glutethimide and ethanol were given than in controls given ethanol alone, and 30% higher at 105 and 135 min. When phenobarbitone and ethanol were given there was a slight but significant reduction in blood ethanol. In the presence of ethanol there was a fall in plasma and urinary glutethimide. Changes in blood ethanol were reflected by changes in reaction time tests. Changes in plasma glutethimide were reflected by changes in tracking efficiency and finger tapping speed. These studies illustrate the need to assess drug concentrations in other interaction studies with ethanol and depressant drugs.
Effects of solubilization on drug diffusion
Authors: BLOOR J R , MORRISON J C
Published: April 2011

The diffusion of ephedrine, sulphathiazole, chloramphenicol, paracetamol, isoniazid and amphetamine in solutions of Tween 40, Tween 80 and cetomacrogol 1000 have been studied. With the exception of isoniazid, the observed diffusion coefficients, corrected for resistance to flow, depend upon the surfactant used and both the drug and surfactant concentration. The effect of drug solubilization upon the diffusion coefficient is also discussed.
Homologues of benzilylcholine mustard
Authors: YOUNG J M , HILEY ROBIN , BURGEN A S V
Published: April 2011

Seven homologues of the alkylating muscarinic antagonist benzilylcholine mustard (BCM) have been prepared. The rate of reaction of the aziridinium ion derivatives with water is largely independent of the structure, whereas the rate of reaction with the muscarinic receptor drops markedly when the N-alkyl group is larger than n-propyl. PrBCM is practically equiactive with BCM. Recovery from block caused by PrBCM was first-order with a half-time of 32 h at 37°.
Inhibition of dopadecarboxylase in the rat by a series of benzyloxyamines
Authors: LAZARE R , WATSON P A
Published: April 2011

A series of eleven benzyloxyamines has been evaluated for in vitro and in vivo inhibition of dopa decarboxylase. The effect of these inhibitors on the rise in [14C]amines in the brain after [14C]dopa has also been assessed. Of these compounds, 3,4-dihydroxybenzyloxyamine appears to be a potent selective peripheral inhibitor of dopa decarboxylase. Its activity is similar to that of Ro 4–4602 [N1-(dl-seryl)-N2-(2,3,4-trihydroxybenzyl) hydrazine].
Abolition of the morphine effect on body temperature in midbrain raphe lesioned rats
Authors: SAMANIN R , KON S , GARATTINI S
Published: April 2011

The hyperthermia and the hypothermia elicited by 5 mg/kg, i.p. or 30 mg/kg i.p. of morphine in rats are abolished by a previous lesion of the midbrain raphe resulting in a lowering of forebrain 5-HT and 5-hydroxyindolacetic acid. Lesions lateral to the midbrain raphe which do not modify brain 5-HT are without effect on body temperature changes induced by morphine. Animals lesioned in the midbrain raphe are still able to respond with a hyperthermia or with a hypothermia when they are treated respectively with 2,4-dinitrophenol or phentolamine.
The effect of fourteen day treatment with diuretics on mouse blood sugar and glucose tolerance
Authors: FOY J M , FURMAN B L
Published: April 2011

Treatment of mice for 14 days with ethacrynic acid or frusemide (100 mg/kg daily orally) increased the fasting blood sugar and liver glycogen. Oral glucose tolerance was altered so that blood sugar concentrations in drug-treated groups were significantly above control values. The failure of the drugs to affect intravenous glucose tolerance and sensitivity to insulin or to tolbutamide suggested that the decrease in the oral glucose tolerance was attributable to some effect of the drug treatments on the rate of absorption of glucose from the gastrointestinal tract. Treatment with hydrochlorothiazide (100 mg/kg daily orally) exerted no effect on blood sugar, liver glycogen or glucose tolerance.
The relation between the subcellular distribution of [3H]reserpine and its proposed site of action
Authors: WAGNER LORIN A , STITZEL ROBERT E
Published: April 2011

The amount of [3H]reserpine retained after injection is greater in the heart, a tissue with a high density of adrenergic innervation than in femoral muscle. Subcellular distribution studies emphasized that 15 and 60 min after injection of [3H]reserpine it could not be shown to be uniquely associated with the noradrenaline-containing granules. The possibility existed that the large amount of reserpine bound to cellular lipids at these times might mask a more specific binding. A reduction in the dose and a lengthening of the time between drug administration and tissue measurement to 18 h revealed a small amount of [3H]reserpine to be bound more firmly to the microsomal or amine granule-containing fraction. Prior saturation of tissue binding sites by treatment with large amounts of unlabelled reserpine or tetrabenazine decreased the retention of subsequently injected [3H]reserpine. This decreased tissue retention resulted in an increase in the formation of [3H]trimethoxybenzoic acid.

A model is proposed relating tissue distribution and binding to reserpine's mechanism of action.
The quantitative determination of fluocinolone acetonide and acetonide acetate in formulated products by high pressure liquid chromatography
Authors: BAILEY F , BRITTAIN P N
Published: April 2011

A chromatographic procedure for the determination of fluocinolone acetonide and acetate is described. The method employs high speed liquid chromatography through a Permaphase ODS column with an aqueous methanol eluant phase. The application of the method to the determination of fluocinolone acetonide and acetate in cream, and ointment formulations, is described.
Effect of frusemide on the reactivity of rat portal vein
Authors: BLAIR-WEST J R , MCKINLEY M J , MCKENZIE J S
Published: April 2011

Short lengths of rat portal vein were suspended in Krebs bicarbonate solution. Contractile responses to noradrenaline and angiotensin II and the parameters of spontaneous contractions were determined before and after addition of frusemide at 10–6 and 10–4 g/ml. Frusemide at 10–6 g/ml slightly suppressed the amplitude of spontaneous contractions and slightly decreased the responses to noradrenaline and angiotensin II. At 10–4 g/ml the drug had a much greater inhibitory effect on endogenous and exogenous stimulation. The concentrations used appear to be similar to those achieved during effective diuretic and hypotensive treatment. It is postulated that frusemide may have a direct inhibitory action on the reactivity of vascular smooth muscle mrticularlv in the capacitance vessels.
On the localization of the hypotensive effect of L-dopa
Authors: HENNING M , RUBENSON A , TROLIN G
Published: April 2011

Mean arterial blood pressure was recorded in anaesthetized rats before and after a mid-collicular transection of the brain (decerebration). Basal blood pressure was not changed by the decerebration. Injection of l-dopa (200 mg/kg, i.p.) after peripheral dopa decarboxylase inhibition by l-α-hydrazino-α-methyl-β-(3,4-dihydroxyphenyl) propionic acid (MK 486, 100 mg/kg, i.p.) resulted in a significant reduction of arterial pressure to the same level in both control (sham- operated) and decerebrated rats after 30 min. In other experiments, anaesthetized rats were spinalized at C7-Th1. Basal blood pressure became significantly lower than in control and decerebrated rats and l-dopa after MK 486 in the same doses did not affect blood pressure. Biochemical determinations of noradrenaline and dopamine showed that administration of l-dopa after MK 486 to decerebrated rats in the same doses as in the blood pressure experiments resulted in a pronounced increase of dopamine in both parts of the brain.
On the inducing activity of eucalyptol
Authors: JORI A , DI SALLE E , PESCADOR R
Published: April 2011

Eucalyptol increases the microsomal activity of rat liver after a single dose given subcutaneously. Further doses do not enhance the effect. Eucalyptol does not affect the concentration of cytochrome P450 in liver microsomes. In this it differs from pheno- barbitone. Both drugs increase the biliary flow but only pheno- barbitone enhances the excretion of conjugated bilirubin after an intravenous load of bilirubin. The results suggest that the induction of liver microsomal enzymes elicited by eucalyptol differs from that elicited by phenobarbitone.
Determination of thermodynamics of halogen groups in solutions of drug molecules
Authors: Davis S S
Published: April 2011

The contribution of the halogen groups (F, Cl, Br, I) to solute activity and partition coefficients has been investigated using literature data. The activity coefficient for an aromatic solute at infinite dilution is increased as the size of the halogen group increases. Partition coefficients are affected similarly but there is variation among group values for a given halogen. This is related to group position and the partition solvent. Preferred group values for partition have been selected and for different solvent systems mean preferred values can be calculated for two general solvent classifications; polar and non-polar. There is excellent correlation between group values and the size of the halogen function as given by surface area. The group values for non-polar solvents are related to those of the polar solvents through the Hammett electronic substituent constant. The use of the group values in structure-activity relations is discussed with reference to the thermodynamic model of Higuchi and Davis.
The influence of solution viscosity on the dissolution rate of soluble salts, and the measurement of an “effective” viscosity
Authors: Florence A T , Elworthy P H , Rahman A
Published: April 2011

The rate of solution of KCl and NaCl from compressed discs has been determined under controlled conditions, in water at 25° and in solutions of varying concentrations of polyvinylpyrrolidone (molecular weight 360 000), polyoxyethylene glycol 6000 and cetomacrogol 1000. Dissolution rate constants decrease with increasing bulk solution viscosity, as expected, but no one equation relating rate constant and bulk viscosity fits the results for the systems studied. Calculation of an effective viscosity from the diffusion coefficients of the salts in water and the diffusion coefficients of the salt in the polymer solutions enables an empirical correlation of the results to be made. The relation of the effective viscosity to the microscopic viscosity is discussed in an Appendix.
Dextromethorphan-monoamine oxidase inhibitor interaction in rabbits
Authors: Sinclair John G
Published: April 2011

Severe toxic reactions may occur clinically when imipramine, pethidine or dextromethorphan is administered to a patient being treated with a monoamine oxidase inhibitor (MAOI). Previous reports indicate that imipramine or pethidine produces symptoms characterized by motor restlessness, tremor, extreme hyperpyrexia and death when administered to phenelzine-pretreated rabbits. The present study shows that dextromethorphan (5 mg kg−1) produces identical symptoms in rabbits pretreated with phenelzine sulphate (30 mg kg−1) or nialamide HCl (50 mg kg−1) 42 and 18 h before temperature recording. The dextromethorphan-MAOI interaction appears to be due to a 5-hydroxytryptamine potentiation. In the unanaesthetized cat nictitating membrane preparation, dextromethorphan (5 mg kg−1) markedly enhanced the response of noradrenaline and 5-HT but antagonized the effects of tyramine. This suggests that dextromethorphan blocks the uptake of these amines in the adrenergic nerve endings.
The 5-hydroxytryptamine content of rabbit hearts and its release during in vitro perfusion
Authors: Fozard J R , Mwaluko G M P
Published: April 2011

Rabbit hearts were perfused in vitro at constant pressure by the Langendorff technique. After 30 min perfusion, hearts from untreated animals contained significantly more 5-HT than those from animals pretreated with heparin. The cardiac 5-HT content of the non-heparinized group decreased during a further 55 min perfusion and the amount lost from the hearts was equal to that recovered from the perfusion fluid. In contrast, the 5-HT content of hearts from heparinized animals did not change significantly during this period, and no 5-HT could be detected in the perfusates. Investigation of the distribution of 5-HT within the hearts from heparinized animals disclosed a significantly greater concentration of 5-HT in the right atrium than in the rest of the heart. It is concluded that the small, perfusion-resistant store of 5-HT within hearts from heparinized rabbits represents the true endogenous 5-HT content in this species, but that much higher values may be obtained unless care is taken to exclude a contribution from blood platelets.
Evidence for catecholamine involvement in the suppression of locomotor activity due to hypoxia
Authors: Brown Roger , Engel Jörgen
Published: April 2011

Locomotor activity of mice under 12 or 21% oxygen in nitrogen was measured. Under 12% oxygen there was a decrease in locomotor activity which was not reversed by administration of amphetamine; however, administration of a sub-threshold dose of l-dopa in combination with a peripheral decarboxylase inhibitor before the amphetamine restored the locomotor stimulant action of the drug under hypoxia. In contrast to amphetamine, the increase in locomotor activity after the administration of a combination of noradrenaline and dopamine receptor stimulating agents, Clonidine plus apomorphine respectively, was not inhibited by hypoxic conditions. Data suggest an involvement of central catecholamine neurotransmission in the disruption of locomotor activity due to hypoxia.
Conopharyngine pseudoindoxyl, a new alkaloid from Tabernamontana pachysiphon Stapf, var cumminsii (Stapf.) H. Huber
Authors: Crooks P A , Robinson B
Published: April 2011

A chlorform extract of the residue, remaining after extraction of the bases obtained from the leaves of T. pachysiphon var cumminsii* with ether, has been shown to contain the alkaloids conopharyngine, 20-hydroxyconopharyngine and conopharyngine pseudo-indoxyl, and two alkaloids of as yet unknown structure.
The effect of particulate dispersing agents on the antifoaming properties of dimethicone 1000 in antiflatulent products
Authors: Carless J E , Stenlake J B , Williams W D
Published: April 2011

The effect of finely divided silica on the antifoaming properties of polydimethylsiloxanes (dimethicone 1000) when formulated in a typical antiflatulent tablet has been examined. A dynamic froth test has been used to show that removal of extractable dimethicone by ether extraction of the tablet powder markedly reduces the antifoaming properties of the powder, despite retention of a small percentage of the polydimethylsiloxane dispersed on the surface of the silica and aluminium hydroxide gel content of the tablet. A series of static froth tests similarly demonstrate that tablet formulations from which silica is omitted also possess significant antifoaming properties.
The effect of free silica on the mucosal protective and antiflatulent properties of polydimethylsiloxane
Authors: Birtley R D N , Burton J S , Kellett D N , Oswald B J , Pennington J C
Published: April 2011

The mucosal protective and antiflatulent properties of polydimethylsiloxane (PMS) alone, or containing free silica have been examined in rats. Both PMS and PMS + 6% silica significantly protected rat gastric mucosa from the irritant effects of aspirin but there was no significant difference between the protective effect of each agent. The antiflatulent property of PMS, as determined by X-ray measurements of foam production in the rat stomach, was significantly enhanced by the addition of free silica.
The binding of conformationally restricted antihistamines to histamine receptors
Authors: Ison R R , Franks Fiona M , Soh K S
Published: April 2011

Some 1,1-diary 1–3-aminoprop-1-enes and 1,2-diaryl-4-amino-but-1-and −2-enes, including isomers of triprolidine and pyrrobutamine, have been prepared, their geometrical configurations established by pmr spectroscopy, and their affinities for histamine receptors measured on the guinea-pig ileum. These isomers differed considerably in their affinities and a particularly large difference was observed with the isomers of triprolidine (1170:1). This is because the binding of 3-aminoprop-1-enes is enhanced when α-pyridyl and aminomethyl groups are trans to one another or when p-tolyl and aminomethyl groups are cis, whereas activity is reduced when these groups are in opposite configurations. There is also a considerable difference between the geometrical isomers of pyrrobutamine (ca 200:1) but the most active compounds all have the same configuration whether 3-aminoprop-1-enes or 4-aminobut-2-enes. For high activity it appears necessary to have a trans Ar.C: CH.CH2.NC4H8 arrangement with the aromatic nucleus (α-pyridyl or phenyl) coplanar with the double bond, together with an aromatic function such as p-tolyl, benzyl or p-chlorobenzyl in a position cis to the aminomethyl group. All these compounds have restricted conformations so that the series serves as a useful model for the stereochemical requirements of the antihistamine receptor.
The pharmacology of azidomorphine and azidocodeine
Authors: Knoll J , Furst Susanna , Kelemen K
Published: April 2011

From a series of newly synthesized morphine derivatives 6-deoxy-6-azidodihydroisomorphine (azidomorphine) and 6-deoxy-6-azidodihydroisocodeine (azidocodeine) were selected for detailed pharmacological study. In the hot plate test in rats, azidomorphine proved to be about 300 times and azidocodeine about 13 times more potent than morphine. Azidomorphine given over ten weeks was significantly less toxic in the rat than morphine or fentanyl. A total dose 40 times that of the analgesic ED50 dose of morphine (200 mg kg−1) produced the highest grade physical dependence in mice as measured by naloxone-precipitated jumping. However, even a total dose of 2800 times the analgesic ED50 dose of azidomorphine (70 mg kg−1) was less effective in producing physical dependence. Treatment on every second day with increasing doses of morphine led to the development of high grade tolerance and chronic physical dependence in rats and monkeys (Rhesus macacus). Severe abstinence syndrome was precipitated after the administration of nalorphine in rats pretreated for 24 days with rapidly increasing doses of morphine and grave symptoms of abstinence were elicited in pretreated monkeys on withdrawal of morphine on the 55th, 175th and 300th days of treatment. In parallel experiments neither the development of tolerance nor that of physical dependence was demonstrable in rats and monkeys pretreated with increasing equi-analgesic doses of azidomorphine.
Antibronchoconstrictor activity of two new phosphodiesterase inhibitors, a triazolopyrazine (ICI 58 301) and a triazolopyrimidine (ICI 63 197)
Authors: Davies G E
Published: April 2011

A triazolopyrazine (ICI 58 301) and a triazolopyrimidine (ICI 63 197), both potent inhibitors of 3′5′-cyclic adenosine monophosphate phosphodiesterase, protected conscious guinea-pigs against an otherwise lethal bronchospasm caused by inhalation of histamine. Both compounds were active when given by mouth and the activity was both rapid in onset and persistent. Bronchospasm caused by histamine or acetylcholine in guinea-pig isolated lungs was reduced when the lungs were perfused with dilute solutions of the compounds and the bronchodilator activity of catecholamines was potentiated. In anaesthetized animals the compounds were relatively more active against severe bronchospasm than against milder stimuli. The antibronchoconstrictor effects on conscious guinea-pigs were blocked by propranolol but not by practolol even in much larger doses. Propranolol did not, however, block the effect on the isolated lung. It appears possible that the antibronchoconstrictor activity is a manifestation of the inhibition of phosphodiesterase.
Further observations on the experimental antidysrhythmic activity of indoramin hydrochloride
Authors: Rashid S , Alps B J
Published: April 2011

Indoramin showed potent activity in reversing severe myocardial conduction disorders and ventricular fibrillation induced by hypothermia, and protected against the precipitation of electrically-induced ventricular fibrillation at low doses in pentobarbitone-anaesthetized cats. It would appear that the α-adrenoceptor blocking and local anaesthetic membrane stabilizing properties of indoramin are responsible for the mechanisms by which these dysrhythmias are reversed as they are with those induced by ouabain and adrenaline, previously described.
A quantitative approach to the in vitro availability of drugs from some non-ionic surfactant solutions
Authors: Collett J H , Withington R
Published: April 2011

Equations that can be used in calculating the theoretical dialysis rates of drugs from surfactant solutions have been derived. Theoretical dialysis rates for the dialysis of salicylic acid from polysorbate solutions at a range of pH levels are compared with those determined experimentally. At low pH levels there is good agreement between theoretical and experimental values. With increasing pH at each surfactant concentration the values diverge. A possible reason for this divergence is considered.
The packing properties of moist bulk solids
Authors: Eaves T , Jones T M
Published: April 2011

The specific volumes of three bulk solids at moisture contents up to 50% w/w (dry basis) under various consolidating stresses have been shown to be dependent on the nature of the bulk solid. The values obtained can be related to the intraparticulate porosity and inherent cohesiveness of the dry materials. The influence of moisture on the packing properties and tensile strength of the three bulk solids is discussed in terms of the granulation process.
Decreased conversion of tyrosine to catecholamines in the brain of rats treated with p-chlorophenylalanine
Authors: Tagliamonte A , Tagliamonte P , Corsini G U , Mereu G P , Gessa G L
Published: April 2011

Repeated treatment with p-chlorophenylalanine (100 mg kg−1) daily for 5 days impairs the transport of amino-acids from plasma into the brain and decreases the rate of conversion of [3H]tyrosine to [3H] catecholamines in the rat brain. The possible mechanisms involved are discussed.
Comparative convulsant activity of various penicillins after intracerebral injection in mice
Authors: Gerald Michael C , Massey Joanne , Spadaro Daniel C
Published: April 2011

The convulsant effects of penicillin derivatives (penicillin G, Phenoxymethylpenicillin, penicillin O, ampicillin, methicillin) and cephaloridine have been evaluated after being given intracerebrally to mice. Penicillin G was most neurotoxic; ampicillin and Phenoxymethylpenicillin were one-fifth as toxic. Incubation with penicillinase markedly reduced or eliminated the convulsant effects of penicillin G, Phenoxymethylpenicillin and ampicillin; this enzyme incubation did not alter the severity of seizures elicited by methicillin and cephaloridine. Diphenylhydantoin and phenobarbitone did not reduce penicillin G-induced seizures. A non-convulsant dose of leptazol potentiated the convulsions produced by the penicillins and cephaloridine. Injection volume, pH and the concentration of sodium and potassium did not produce behavioural changes within the ranges studied.
Continuous shear, viscoelastic and spreading properties of a new topical vehicle, FAPG base
Authors: Barry B W
Published: April 2011

The rheology of a new topical vehicle FAPG base was investigated over the temperature ranges of 25–37°. Continuous shear rheograms obtained with a Ferranti-Shirley cone and plate viscometer were hysteresis loops with spur points; loop areas, yield values and apparent viscosities decreased with increase in temperature and an activation energy for viscous flow of 10.4 kcal mol−1 (43.5 kJ mol−1) was derived. In creep (concentric cylinder geometry) the base was viscoelastic with a low limit of linearity with respect to strain. Creep compliance curves showed an initial elastic response, a region of retarded elasticity and a viscous region; compliances increased and viscosities decreased with temperature rise. Patient acceptance of skin spreadability of the base was assessed using a master curve concept; the spreading properties were close to the preferred values for maximum patient acceptance. It is concluded that FAPG base deserves further study as a vehicle for dermatological use.
Mass spectrometry in the analysis of steroid drugs and their metabolites: electron-impact-induced fragmentation of ring D
Authors: Middleditch B S , Vouros Paul , Brooks C J W
Published: April 2011

Certain steroid drugs, their metabolites, and related model compounds which possess a 17-hydroxy group can be converted to trimethylsilyl ethers which give characteristic ions of type [128 + R]+in their mass spectra, where R is the mass of the other 17-substituent. Extensive deuterium labelling studies are carried out to verify the modes of formation of these and related ions which are of diagnostic value in analytical work.
The estimation of acetylsalicylic acid and salicylate in biological fluids by gas-liquid chromatography
Authors: Thomas Barry H , Solomonraj G , Coldwell Blake B
Published: April 2011

A gas-liquid chromatographic method is described for the simultaneous separation and determination of acetylsalicylic acid (ASA) and salicylic acid (SA) in biological fluids. The salicylates are completely extracted from deproteinized plasma or urine at pH 2 with ether containing p-toluic acid as the internal standard. The silylated derivatives are formed using bis(trimethylsilyl) trifluoroacetamide and separated at 150° on preconditioned 100–120 mesh Gas-Chrom Q coated with 5% OV17 packed into a 6 ft, 1/4 inch o.d. glass column in a gas chromatograph with a flame ionization detector and integrator. Detector response is linear over the range from 0–2 mg ml−1 for SA and from 0–100 μg ml−1 for ASA. The time required for the analysis of SA alone or with ASA is about 80 min, the analysis of ASA alone requires about 20 min. The precision of the method is 1 % or better for drug concentrations above 10 μg ml−1. The limits of detectability for SA and ASA are 1 and 2 μg ml, respectively.
A circular dichroic investigation of the binding of fenoprofen, 2(3-phenoxyphenyl)-propionic acid, to human serum albumin
Authors: Perrin J H
Published: April 2011

The extrinsic Cotton effects found on the binding of fenoprofen and some of its analogues to human serum albumin have been investigated. The fenoprofen appears to bind hydrophobically to the albumin via the phenyl rings and after dipole interactions of the carbonyl group and the ether oxygen. This binding is non-stereospecific.
Further studies on the adrenergic neuron blocking activity of some β-adrenoceptor antagonists and guanethidine
Authors: Mylecharane E J , Raper C
Published: April 2011

The effects of low (0.2) and high (20 μg ml−1) concentrations of (±)- and (+)-propranolol, (±)-, (+)- and (-)-sotalol and guanethidine were tested for their ability to reduce responses to sympathetic stimulation in the isolated vas deferens preparation from the guinea-pig. At 0.2 μf ml−1 all drugs produced a slowly developing reduction in the responses to sympathetic stimulation while responses to noradrenaline were largely unchanged. The blockade, which was similar in extent in all six compounds, was reversed by (+)-amphetamine but not by washing. With high concentrations of and (±)-propranolol and guanethidine, the block was rapid in onset and rate and responses to noradrenaline were potentiated. The block was reversed by washing and unaffected by (+)-***amphetamine. Sotalol and its isomers, which possess little non-specific depressant activity, had qualitatively similar actions at 0.2 and 20 μg ml−1. At the latter concentration responses to noradrenaline were potentiated. The results suggest that low concentrations of the β-adrenoceptor antagonists produce a blockade which is typical of guanethidine-like drugs. At high concentrations non-specific depressant (local anaesthetic) actions of propranolol and its isomers are largely responsible for the blockade. A similar mechanism may also operate when high concentrations of guanethidine are used.
The pharmacokinetics of phentermine and chlorphentermine in chronically treated rats
Authors: Lüllmann Heinz , Rossen Elisabeth , Seiler Klaus-Ulrich
Published: April 2011

Young rats were treated with [3H]labelled phentermine or chlorphentermine for varying periods (1 day to 8 weeks). The plasma tissue and concentrations of the drugs were determined. The distribution of phentermine reflected a partition, the tissue: blood ratios remaining constant for the entire period. In contrast, chlorphentermine was increasingly accumulated the longer the treatment lasted, as indicated by rising tissue: blood ratios. Chlorphentermine proved to be tightly bound to tissue components. The highest tissue: blood ratio (160 after 8 weeks) was found in lungs and the highest increase in the accumulation rate (10 fold in 8 weeks) was for the adrenals. These results, together with biochemical and ultra-structural findings, suggest that the highly amphiphilic chlorphentermine induces an impairment of phospholipid metabolism resembling lipidosis.
The inhibition of histamine formation in vivo
Authors: Mole K H , Shepherd D M
Published: April 2011

Histamine formation was measured by the [14C]histamine content of the stomach following injection of [14C]histidine into rats. Carbonyl reagents (e.g. oxyamines) which inactivate pyridoxal phosphate, the co-enzyme of histidine decarboxylase, were the most effective inhibitors of histamine formation in vivo. Although the oximes prepared from imidazol-4(5)-ylmethoxyamine and pyridoxal or pyridoxal phosphate cannot inactivate the co-enzyme, they proved sufficiently potent to merit further study as inhibitors of histamine formation in vivo.
Lesions in the septal nuclei of the rat raise mean systemic arterial pressure and prevent the development of sound-withdrawal hypertension
Authors: Marwood J F , Gan E K , Lockett Mary F
Published: April 2011

Midline lesions in the hippocampal commisure involving the bed nucleus (I) in the forebrains of rats, and lesions which destroyed the medial septal nuclei (III), caused mean systemic arterial pressure to rise by 30–40 mm Hg in female rats of an inbred hypertensive Wistar strain. Lesions involving the anteromedial portions of both lateral septal nuclei (II) raised mean arterial pressure by 10–20 mm Hg. After pentolinium, mean arterial pressure remained raised, by approximately 20 mm Hg, in the 7th postoperative week after lesions I, II and III. The mean systemic arterial pressures of intact and shamlesioned rats rose by 30–40 mm Hg when exposed to reduction of sound level from 65–85 to 35–45 db for 5–6 weeks: this treatment did not influence the mean arterial pressures of rats with lesions I, II or III. The pressor effects of (-)-noradrenaline (0ṁ25 μg), tyramine (25 μg), angiotensin (10 ng) and vasopressin (0ṁ2 mU) did not differ in ganglion blocked sham-lesioned and lesioned animals. Organ/body weight ratios did not increase in the lesioned animals; overall, both the pituitary and adrenal weights were just significantly (P > 0ṁ05) reduced. Lesions II and III caused a significant reduction in kidney weight and lesion II a significant rise in the index of thyroid activity.
The evaluation of the α-adrenoceptor blocking action of indoramin, phentolamine and thymoxamine on the rat and guinea-pig isolated mesenteric vasculature and aortic spiral preparations
Authors: Collis M G , Alps B J
Published: April 2011

The perfused mesenteric vasculature of the rat is a specific, sensitive and stable preparation for the rapid determination of α-adrenoceptor blocking pA2 values. Both types of pA2 determination—the direct determination (Schild, 1947) and the Arunlakshana & Schild (1959) analysis—can be made on this tissue. Indoramin, phentolamine and thymoxamine were evaluated and gave respectively α-block pA2 values of 8ṁ05, 7ṁ84 and 6ṁ47. The pA2 values made on the rat perfused mesentery were compared with those obtained on the rat aorta (indoramin 7ṁ68, phentolamine 8ṁ29, thymoxamine 6ṁ50), the guinea-pig aorta (indoramin 7ṁ38, phentolamine 7ṁ64, thymoxamine 6ṁ93) and the perfused mesenteric bed of the guinea-pig (indoramin 8ṁ48, phentolamine 7ṁ51, thymoxamine 6ṁ97). Statistical analyses of Kb (dissociation constant) values suggest that indoramin has an additional blocking action on resistance vessels, which is not possessed by phentolamine or thymoxamine.
The α-adrenoceptor blocking effect of indoramin on human isolated smooth muscle
Authors: Variava Dinaz H , Turner Paul
Published: April 2011

The pharmacological effects of indoramin, a new hypotensive drug, were studied on human isolated smooth muscle preparations. Indoramin was shown to have a potent α-adrenoceptor blocking activity on specimens of colon, ileum and vein. The blockade fulfilled the established criteria for competitive antagonism of noradrenaline. The mean pA2 values were 6ṁ57 for the circular muscle of the colon, 6ṁ91 for longitudinal muscle of the colon, 6ṁ64 for longitudinal muscle of the ileum and 6ṁ58 for saphenous vein. Indoramin (10−3m) did not reduce acetylcholine-induced contractions of the longitudinal muscle of the colon and ileum.
Influence of electrolytes on the hydration of methylcellulose in solution
Authors: Marriott P H , John E G
Published: April 2011

Light-scattering techniques were used to obtain weight-average molecular weights for three grades of methylcellulose in water. On addition of electrolyte to the polymer solutions the molecular weight was not found to alter but the root-mean-square end-to-end length decreased. This contrasts with the results of Neely (1963). The exponent α of the Mark-Houwink viscosity equation was also found to decrease in the presence of electrolyte. Two stages of polymer dehydration are suggested for non-ionic cellulose ether derivatives.
The formulation and sterilization of a surgical lubricant gel based on carboxypolymethylene
Authors: Adams Isobel , Davis Stanley S
Published: April 2011

A lubricant gel of optimal consistency containing a local anaesthetic (lignocaine) has been formulated which can be sterilized by gamma irradiation. A rheological specification was obtained by examination of some currently used preparations. The variation in their consistency was large but all exhibited pseudoplastic flow with a yield value. Gels based on tragacanth, the methylcelluloses and the Carbopols were suitable as lubricants before sterilization and after autoclaving, but on gamma irradiation the gel structure was destroyed. Ethanol (5–10%) protected the Carbopol formulations. Irradiation of lignocaine solutions caused some cloudiness and a small drop in pH. Ethanol and metabisulphite acted as protective agents. A final formulation was developed consisting of a Carbopol gel (1%) neutralized by lignocaine base (2%) and the biological availability of the local anaesthetic was assessed using an in vitro method.
Inhibition of human platelet 5-hydroxytryptamine uptake by ß-phenethylamine derivatives
Authors: Richter Anna , Smith S E
Published: April 2011

Forty-eight derivatives of ß-phenethylamine have been studied as inhibitors of 5-hydroxytryptamine uptake by human blood platelets in vitro. Inhibitory potency was found to be increased by para-substitution with electronegative groups, by α-methylation in the D-configuration and by addition of N-alkyl groups, and to be reduced by saturation of the ring, by ortho-methoxylation, meta- or ß-hydroxylation and by hydrazine formation. It is suggested that optimal affinity involves folding of the molecule to fit a cleft-like carrier site. The structural requirements for activity show features of similarity to those of tryptamine and tricyclic antidepressant derivatives and some resemblance with requirements for inhibition of the adrenergic uptake1 mechanism of the heart. No obvious correlation exists between the activity of these drugs as inhibitors of platelet 5-HT uptake and their ability to exert effects thought to involve central tryptaminergic mechanisms.
Effect of acute and chronic treatment with practolol on cardiovascular responses in the pithed rat
Authors: Lewis M J
Published: April 2011

Chronic administration of practolol to the pithed rat produced a reduction in the pressor responses to electrical stimulation of the spinal cord and potentiation of pressor responses to high doses of (—)-noradrenaline compared to control animals. Acute administration of practolol caused an increase in the pressor responses to both electrical stimulation and high doses of noradrenaline. Heart rate responses to both forms of stimulation were less than control values after both acute and chronic dosage with practolol. It is possible that practolol reduces the release of noradrenaline at the sympathetic nerve ending after chronic administration.
A molecular orbital study of tissue selectivity in ß-adrenoceptor blocking agents
Authors: Germer Henry A
Published: April 2011

A molecular orbital study has been made on a group of eight ß-adrenoceptor blocking agents using CNDO/2 type calculations. Of the group, two are relatively selective for cardiac receptors, two for vascular receptors and four are non-selective. Comparison of the net charges on the ß-hydroxyl group oxygens and onium group nitrogens, as well as the O-N distances, reveals small differences. In the traditional view of adrenoceptor agent molecular geometry, the onium group and the aromatic part of the molecule are near the trans-configuration for the low energy conformation of all eight molecules. However, when the relation of a primary side chain feature, such as the O-N axis, and the plane of the aromatic ring is examined, noticeable steric differences between the various agents are evident.
Aggregation of antihistamines in aqueous solution: micellar properties of some diphenylmethane derivatives
Authors: Attwood D , Udeala O K
Published: April 2011

The micellar properties of the antihistamine drugs, diphenhydramine hydrochloride, bromodiphenhydramine hydrochloride, chlorcyclizine hydrochloride and diphenylpyraline hydrochloride, have been studied in aqueous solution. The zeta potentials of the micelles were calculated from their electrophoretic mobilities as determined by a dye-tracer technique. Estimates of the degree of ionization of the micelles using a combination of conductivity and electrophoresis data were in reasonable agreement with values previously determined by light scattering. The extent of micellar hydration has been calculated from viscosity data. The hydrophobic and electrical contributions to the free energy of micellization have been calculated and related to the chemical structure.
Neuromuscular and other blocking actions of a new series of mono and bisquaternary aza steroids
Authors: Gandiha A , Marshall I G , Paul Dharam , Singh Harkishan
Published: April 2011

The effects of a newly-synthesized series of mono and bisquaternary aza steroids have been investigated in the anaesthetized cat. All the compounds have been tested for neuromuscular blocking, ganglion blocking and vagolytic activity. The monoquaternary compounds of the series were weak neuromuscular blocking agents, their main action being to produce ganglion blockade and a fall in blood pressure. Both the bisquaternary compounds of the series primarily exhibited neuromuscular blocking activity of short duration and rapid onset. 4-Methyl-17 β-dimethylamino-4-aza-5α-androstane dimethiodide (HS-467) was approximately equipotent with tubocurarine as a neuromuscular blocking agent, whereas 17a-methyl-3β-pyrrolidino-17a-aza-D-homo-5-androstene dimethiodide (HS-310, chandonium iodide) was 4–5 times more active. Both compounds exhibited extremely weak ganglion blocking activity. Structure-activity relations are discussed, and it is concluded that in this series two quaternary heads are necessary for optimal neuromuscular blocking activity. The possibility that in the bisquaternary compounds interonium distance, or stereochemical conformation may be the main factor in determining specific neuromuscular blocking activity is discussed.
The effects of a human plasma fraction on carrageenan-induced paw oedema in the rat
Authors: Ford-Hutchinson A W , Elliott P N C , Bolam J P , Smith M J H
Published: April 2011

A fraction isolated from normal human plasma inhibits the swelling of carrageenan-induced paw oedema in the rat when given as a single intravenous injection at time intervals up to 24 h before and up to 3 h after the administration of the carrageenan. Repeated doses of the fraction cause a delay in the development of the paw oedema.
Powder mixing in the tableting of fenfluramine hydrochloride; evaluation of a mixer
Authors: Cook P , Hersey J A
Published: April 2011

A vertical cone mixer has been used to mix a single active component, fenfluramine hydrochloride, with a number of diluents used for production batch-scale tablet preparation. The mixing operation was followed by the analysis of fenfluramine hydrochloride in a number of samples equivalent to the final tablet size. The results may be suitably analysed by treating the diluent materials as a single component in a binary mixture.
Application of orthogonal functions to spectrophotometric analysis. The combined polynomial method
Authors: Wahbi A M , Ebel S
Published: April 2011

A general method is outlined for the linear combination of orthogonal polynomials belonging to one group of points to eliminate interferences in spectrophotometric analysis. The method is particularly useful when it is difficult to find a set of wavelengths over which the coefficient of the irrelevant absorption is negligibly small relative to the assay coefficient. The method is illustrated by the determination of salicylamide in the presence of chloroquine.
“First-pass” metabolism of paracetamol in rat liver
Authors: Cohen Gerald M , Bakke Olav M , Davies Donald S
Published: April 2011

Paracetamol was administered intraperitoneally or intravenously to male rats. Its ‘availability’ in the systemic circulation after intraperitoneal administration was only 34% of that after intravenous administration. This suggested a high “first-pass” metabolism of intraperitoneally administered drug, which was confirmed using the rat isolated perfused liver. The hepatic extraction ratio for paracetamol decreased with increasing concentrations of the drug in the perfusion fluid, suggesting that gastric emptying rate, by controlling the concentration of drug in the portal vein, could influence the amount of “first-pass” metabolism.
Detection, isolation and characterization of normorphine and norcodeine as morphine metabolites in man
Authors: Boerner Udo , Roe Robert L , Becker Charles E
Published: April 2011

Normorphine and norcodeine were identified by two-dimensional thin-layer chromatography (t.l.c.) as human urinary morphine metabolites from 24 h urine samples of three patients who had received 190–210 mg morphine sulphate intravenously and from one patient who had chronically received 220 mg morphine sulphate orally per day. Both metabolites were isolated by preparative t.l.c. Comparison of the isolated norcodeine and normorphine with their respective authentic compounds, prepared by chemical synthesis, showed identical melting points, mass fractionation patterns, and chemical ionization spectra, confirming t.l.c. identification.
Histamine, 5-hydroxytryptamine, kinins and the anti-inflammatory activity of human plasma fraction in carrageenan-induced paw oedema in the rat
Authors: Bolam J P , Elliott P N C , Ford-Hutchinson A W , Smith M J H
Published: April 2011

In the carrageenan-induced paw oedema reaction in the rat, the swelling and accumulation of [131I]albumin showed a similar time course over 4 h. Both aspects of the oedema were inhibited by a fraction prepared from human plasma. Treatment of the animals with substances which either deplete the levels or antagonize the actions of either histamine, 5-hydroxytryptamine or kinins showed that these mediators are concerned in the development of rat paw oedema after the injection of either carrageenan or yeast but not with the anti-inflammatory action of the plasma fraction.
Structural effects in drug distribution: whole animal pharmacokinetics
Authors: Notari Robert E , Burkman A M , van Tyle W Kent
Published: April 2011

Computer-generated data simulating the results of assays of homogenized whole animals as a function of time following rapid intravenous injection have been employed to calculate various pharmacokinetic constants in both one and two compartment open models. The results have been compared to those obtained with data representing analysis of blood samples at identical time intervals. Data for whole animal analysis are equally reliable in calculating the first-order constants for distribution and elimination when applied to the appropriate cases. However, the range of utility is smaller when the whole animal method is used. The whole animal approach does offer some unique advantages over the classical plasma data method and these are discussed. The range of utility and the method for calculating pharmacokinetic rate constants from whole animal data are clearly defined.
Structural effects in drug distribution: comparative pharmacokinetics of apomorphine analogues
Authors: Burkman A M , Notari Robert E , van Tyle W Kent
Published: April 2011

A two compartment open model, modified to include brain as a third compartment, was found to describe the pharmacokinetics of three aporphines in mice. Data include whole animal analysis, brain analysis and evaluation of stereotypical gnawing behaviour. The relative potencies of the derivatives, based upon brain content, were found to be apomorphine = 1, norapomorphine = 0·06 and N-n-propylnorapomorphine = 0·39. The potency of the N-n-propyl analogue is less than that previously reported on an intraperitoneal (i.p.) dosage basis (1·14). The ability to distribute into the brain, based on the entire time course for drug in that compartment, appears to be N-n-propylnorapomorphine >apomorphine >norapomorphine. The values for t 1/2 in mice are 29 min for the N-n-propyl derivative, 20 min for norapomorphine and 47 min for apomorphine which was previously reported to be 8·5 min based upon the inappropriate assumption of a one compartment model. The successful pharmacokinetic analysis was combined with the evaluation of structural effects on drug distribution and its resultant influence on pharmacokinetic response for the three closely related derivatives to demonstrate the applicability of the previously described whole animal pharmacokinetic treatment (Notari, Burkman & Van Tyle, 1974).
A general method of determining the first order input rate constant of a drug that is directly absorbed into the central compartment
Authors: Vaughan D P , Mallard D J H , Mitchard M
Published: April 2011

A simple equation by which the first order rate constant for the absorption of a drug into the central compartment of any linear mammillary pharmacokinetic model can be calculated is presented. No specific knowledge of the distribution or elimination characteristics of the drug is required.
The influence of phospholipids on the transport of antibacterial agents across non-aqueous barriers, and the methods used to quantitate the rate processes
Authors: Padfield John M , Kellaway I W
Published: April 2011

Penicillin G and ampicillin are known to bind with phospholipids, which may influence antibiotic transport across the bacterial cell wall. This influence has been investigated in vitro in a three-phase cell containing 1-octanol as the non-aqueous barrier. The data have been analysed by an iterative technique using digital computation, in order to quantitate the rate processes. The results indicate that binding of the antibiotics with phospholipids occurs at the oil-water interface which influences the further transport of the antibiotics through the non-aqueous phase. The possible biological significance is discussed.