bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of theophylline and caffeine on thermoregulatory functions of rats at different ambient temperatures
Authors: Lin M T , Chandra A , Liu G G
Published: April 2011

Both systemic and central administration of theophylline and caffeine produced a dose-dependent rise in rectal temperature at ambient temperatures of 8, 22 and 30°C. The hyperthermia in response to either xanthine was brought about by an increase in metabolic heat production. In addition, their administration produced behavioral excitation, cutaneous vasodilation (as estimated by an increase in the foot and tail skin temperatures) and diuresis. There was no change in respiratory evaporative heat loss. Probably, the hyperthermia induced by the two drugs was due to behavioral excitation leading to an increased metabolism at the ambient temperatures studied. Furthermore, either destruction of central catecholaminergic nerve fibres (with 6-hydroxydopamine) or blockade of α-adrenergic and dopaminergic (with phentolamine and haloperidol) receptors antagonized the xanthine-induced hyperthermia. The data suggest that these xanthines elicit a central activation of both adrenergic and dopaminergic receptors via release of endogenous catecholamines that leads to behavioral excitation and hyperthermia in rats.
Solubility in amide-water cosolvent systems: a thermodynamic view
Authors: Lindstrom Richard E , Lee Chi Ho
Published: April 2011

The solubility of methyl p-hydroxybenzoate was determined in a series of amide-water cosolvents in the temperature range 25–40 °C. Thermodynamic values for the transfer of the ester between the cosolvent system were calculated using a method which permits a focus on the effects of amide alkylation. The results are interpreted in terms of hydrophobic bonding principles which suggest that the alkyl groups on the amide detract from amide-water interaction and enhance amide-ester interaction.
Identification of in vivo liver metabolites of Δ1 -tetrahydrocannabinol, cannabidiol, and cannabinol produced by the guinea-pig
Authors: Harvey D J , Martin B R , Paton W D M
Published: April 2011

The metabolites of Δ1 -trahydrocannabinol (Δ1 -THC), cannabidiol (CBD), and cannabinol (CBN) produced in vivo by the guinea-pig have been studied by combined gas-liquid chromatography-mass spectrometry. 45 metabolites of Δ1 -THC were identified of which 12 have not been reported before. Several other metabolites were detected but not identified. The major metabolic routes involved allylic and aliphatic hydroxylations, oxidations to ketones and acids, oxidative degradation of the side-chain presumably by the β-oxidation pathway, and formation of glucuronide conjugates. Di- and tri-substituted metabolites were abundant. The metabolism differed considerably from that observed in mouse and rat in that 1″- and 6β-hydroxylation and oxidative degradation of the side-chain were major metabolic pathways. 1″-Hydroxy-Δ1 -THC was found as a pair of diasteroisomers. Similar metabolic pathways were observed with CBD; twenty metabolites were identified of which two were new. Only 6 metabolites of CBN were identified. These were mainly mono-substituted in the same positions as were observed with Δ1 -THC and CBD.
Cardiovascular withdrawal effects of clonidine and tiamenidine on abrupt cessation of oral treatment in conscious cats
Authors: Finch L , Hicks P E
Published: April 2011

In conscious renal hypertensive cats prepared with permanent indwelling arterial catheters oral administration of clonidine (0·05 mg × 3 daily) clonidine (0·0125 mg × 3 daily), or tiamenidine (0·25 mg × 3 daily) induced hypotension and bradycardia during 6 days of treatment, although these responses were not well sustained. A pronounced tachycardia was demonstrated in all cats, 16–20 h after cessation of treatment with the higher dose of clonidine, however, only two cats in this group showed increased blood pressures above pre-dose levels at this time; these ‘withdrawal’ effects were absent 44 h after the final dose. No evidence of tachycardia, or blood pressure overshoot was seen up to 44 h after cessation of the low clonidine treatment regime, providing evidence for a dose-withdrawal effect relationship. Significant tachycardia was demonstrated in all cats 15–19 h after cessation of treatment with tiamenidine with no evidence of blood pressure elevation; the tachycardia was absent 48 h after the final dose. In four of these same cats clonidine (0·1 mg × 2 daily), in a long-acting, sustained release formulation (LA clonidine), elicited prolonged falls in blood pressure and heart rate over a 10 day period. No evidence of withdrawal effects were obtained 14–48 h after cessation of this treatment.
Metabolite involvement in bromocriptine-induced circling behaviour in rodents
Authors: Reavill C , Jenner P , Marsden C D
Published: April 2011

Bromocriptine and apomorphine produced identical circling responses in rodents with medial forebrain bundle lesions. Rotation induced by bromocriptine, but not by apomorphine, was inhibited by prior treatment with reserpine or α-methyl-p-tyrosine suggesting a requirement for intact presynaptic events. Bromocriptine-induced circling also was inhibited by the catecholamine re-uptake blockers nomifensine and desmethylimipramine, supporting the role of presynaptic mechanisms. Bromocriptine-induced circling, but not apomorphine circling, was reduced by pre-treatment with SKF 525A, an inhibitor of monooxygenase enzymes, suggesting metabolite involvement in the turning response. This compound prolonged hexobarbitone sleeping times and zoxazolamine paralysis times in mice. These indices of drug metabolizing activity also were prolonged by pre-treatment with desmethylimipramine while nomifensine prolonged only hexobarbitone sleeping times and α-methyl -p tyrosine had no effect on either index. The data suggest that a metabolite of bromocriptine may be of importance in causing circling and that uptake of bromocriptine (or a metabolite) into presynaptic catecholamine terminals may be necessary.
Inhibition of intestinal water and electrolyte absorption by senna derivatives in rats
Authors: Leng-Peschlow Elke
Published: April 2011

Three intestinal segments were simultaneously perfused with Tyrode solution in the anaesthetized rat using a perfusion rate of 12 ml h−1. Dried purified senna extract containing 60% Ca-sennosides A + B (I) administered with the perfusion fluid had no or only minimal effects on intestinal absorption. Large doses (4 g litre−1) slightly reduced net Na, CI and H2O absorption predominantly in the colon and the ileum; the jejunum was unaffected. Dried purified senna extract containing 18% oxidized Ca-sennosides (II) reduced net Na, Cl and H2O absorption in all three intestinal segments, the effects increasing from the jejunum to the colon. Large doses (4 g litre−1) induced net Na and H2O secretion. II being administered with the colon perfusion fluid affected H2O and electrolyte absorption in the colon and to a lesser degree, in the ileum. Pure rhein (III, 0·28 g litre−1) had similar effects to II. Pure sennosides A + B (IV, 2 g litre−1) had no effect on intestinal absorption. These results confirm that changes in the absorptive behaviour of the gut mucosa are, at least partly, responsible for the laxative action of anthraquinone drugs and that this effect is mainly dependent on the presence of oxidized derivatives. There is evidence that the drug's effect is not locally restricted to the colon as is seen from the ileal response after intracolonic administration. Side-effects like griping which are sometimes observed after senna treatment seem to originate from motility changes rather than from changes in absorption.
Effects of glycine, β-alanine and diazepam upon morphine-tolerant-dependent mice
Authors: Contreras E , Tamayo L
Published: April 2011

The effects in mice of glycine, β-alanine and diazepam on the analgesic response to morphine, on the intensity of tolerance and on the physical dependence on the analgesic have been examined. The two amino acids increased the analgesic response to morphine in a doserelated manner. However, both compounds were ineffective in the analgesic test (hot plate) when administered without morphine. Diazepam was ineffective in the analgesic test and it did not alter morphine analgesia, except when administered in a high dose which decreased and analgesic response. Glycine, either in single or repeated doses, did not modify tolerance to morphine, whereas β-alanine induced a dose-related partial antagonism, which promptly reached a plateau. Diazepam induced a small decrease in the intensity of tolerance to the analgesic. The abstinence syndrome to morphine, induced by naloxone administration to primed mice, was reduced by single doses of glycine or β-alanine. Diazepam behaved as a weak inhibitor of the abstinence syndrome when administered at a high dose. The potentiation of morphine analgesia and the antagonism of the abstinence syndrome induced by the amino acids may be related to their hyperpolarizing action in the c.n. system. The effects of β-alanine on morphine tolerance cannot be explained by the same mechanism.
Effects of 3,4-dihydroxyphenylpyruvic acid and L-glutamic acid on some pharmacokinetic parameters of L-dopa in the rat
Authors: Lindén Inge-Britt
Published: April 2011

In the rat, various oral doses of 3,4-dihydroxyphenylpyruvic acid (DHPPA) administered simultaneously with L-dopa were shown to elevate the serum L-dopa and cerebral dopamine concentrations dose-dependently. With increasing DHPPA: L-dopa ratio the L-dopasparing effect became greater. Although oral and intravenous doses of DHPPA showed that it was readily converted to L-dopa in the serum, only small amounts of dopamine (DA) were detected in the brain. The high 3-O-methyldopa concentrations, measured in the serum after DHPPA administration, might be responsible for the failure of the L-dopa formed to pass the blood-brain barrier. Concomitant administration of L-dopa and glutamic acid gave significantly higher L-dopa values in the serum and DA and homovanillic acid values in the brain than did the same dose of L-dopa alone. This indicates that the transamination of L-dopa can also be effected by coadministration of L-dopa and an amino group donor in vivo.
The effect of proteolytic enzymes on the disposition of tetracycline
Authors: Edwards G , Calvert R T
Published: April 2011

The acute administration of a mixture of trypsin and chymotrypsin did not significantly affect the rate or extent of disappearance of tetracycline from the rat gut in situ, nor did chronic administration of enteric coated tablets containing trypsin and chymotrypsin to rats significantly influence the rate or extent of absorption of tetracycline compared with rats receiving enteric coated placebo tablets. Similarly, chronic enzyme administration did not effect either the systemic clearance, half life or apparent volume of distribution of intravenously administered tetracycline compared with rats receiving placebo tablets.
Are the pA2 values of selective β-adrenoceptor antagonists valid when obtained on guinea-pig tracheal preparations contracted with carbachol?
Authors: O'Donnell Stella R , Wanstall Janet C
Published: April 2011

On carbachol-contracted tracheal preparations from guinea-pigs, the slope of the Schild plot for propranolol (isoprenaline as agonist) was 1·0. The slope of the plots for atenolol β1selective) and butoxamine (β2-selective) were less than 1·0, whether isoprenaline or fenoterol was agonist. This was in contrast to previous reports on intrinsic tone tracheal preparations. It was established that the low slopes for atenolol and butoxamine on carbachol-contracted preparations were not related to aspects of the experimental procedures. Low slopes on carbachol-contracted preparations tended to occur when the antagonist used was selective and, although the reason for this is not clear, it may be related to the presence of both ft- and β2-adrenoceptors in this tissue. Therefore, it is suggested that pA2 values obtained for selective β-adrenoceptor antagonists on guinea-pig tracheal preparations contracted with carbachol may not be strictly valid, and that antagonists should be studied on intrinsic tone tracheal preparations when pA2 values are to be compared with pA2 values from other tissues to quantify the selectivity of the antagonist.
Central cardiovascular and biochemical effects of baclofen in the conscious rat
Authors: Persson Bengt , Henning Matts
Published: April 2011

Baclofen (β-p-chlorophenyl-GABA, 1–25-10 mg kg-1 i.p.) elicited dose-dependent increases in blood pressure and heart rate in conscious rats. Similar responses were observed after intracisternal or intracerebroventricular injections of baclofen 0·125-1 μg kg−1. Baclofen i.p. was largely ineffective after spinal transection at C7, Pretreatment with phenoxybenzamine, bethanidine or hexamethonium antagonized the cardiovascular effects of i.p. baclofen. These actions were significantly attenuated after catecholamine depletion and synthesis inhibition by means of α-methyl-m-tyrosine and α-methyl-p-tyrosine. The responses to baclofen were not affected by bilateral adrenal demedullation but abolished by pentobarbitone anaesthesia. Hence, the cardiovascular effects of baclofen are probably evoked from central nervous structures and mediated via the sympathetic nervous system. In doses corresponding to those used in the circulatory studies i.p. baclofen increased endogenous concentrations of brain DA and decreased DA utilization but only slightly affected brain NA concentrations and utilization.
Zero order drug delivery from double-layered porous films: release rate profiles from ethyl cellulose, hydroxypropyl cellulose and polyethylene glycol mixtures
Authors: Donbrow M , Samuelov Y
Published: April 2011

Laminated double-layered films comprising a drug-containing and drug-free layer were prepared using tripelennamine, barbitone, salicylic acid and caffeine dispersed in hydroxypropylcellulose (HPC) attached to ethyl cellulose (EC) films containing various proportions of polyethylene glycol (PEG) or HPC to enhance permeability. Drug release in vitro followed zero-order kinetics, rate constants being dependent on the thickness of the drug-free membrane, which was rate-controlling. Thickness-corrected zero order constants were independent of drug-loading, which did, however, control the duration of release. Permeability coefficient measurements on the same rate-controlling films used as single barrier membranes enabled the effective drug concentration (Co) at the interface between the laminated membranes to be estimated; Co was independent of drug loading and was of the order expected from the aqueous solubilities of the drugs. Release rates were enhanced by addition of hydrophilic polymer to the rate-controlling membranes, either linearly with fraction of additive for PEG to 0·6 or HPC to 0·4, or logarithmically for HPC from 0·4 to 0·8. Enhancement coefficients, which were different for each system, reflected the different mechanisms of hydrophilic polymer action. PEG was leached out rapidly, pores being formed in the matrix. In contrast, HPC was largely retained, so that the enhancement was less. The logarithmic enhancement stemmed from formation of swollen hydrated channels, which, unlike the low HPC fractions or the PEG systems, allowed entry of buffer ions, so that only in these channel systems were the release rates altered by change of the external pH.
Effects of 5-hydroxytryptamine, fluoxetine and chlorimipramine on reflex bradycardia in rats
Authors: Lin M T , Tsay B L , Fan Y C
Published: April 2011

In the urethane-anaesthetized rat, increasing 5-hydroxytryptaminergic receptor activity or functional 5-HT in brain with either the specific inhibitors of 5-HT reuptake (e.g. fluoxetine and chlorimipramine) or the 5-HT itself greatly reduced the reflex bradycardia induced by the systemically administered adrenaline. The data indicate that activation of central 5-HT-ergic receptors tends to inhibit reflex bradycardia.
Aspirin binding and the effect of albumin on spontaneous and enzyme-catalysed hydrolysis
Authors: Aarons Leon , Clifton Patricia , Fleming George , Rowland Malcolm
Published: April 2011

A method of measuring the binding of aspirin to albumin without the interference of hydrolysis was developed. At concentrations of 10 mg litre−1, aspirin is about 85% bound to bovine serum albumin (4 g%), whereas its hydrolysis product, salicylic acid, is 95% bound. Salicylic acid was shown to displace aspirin from albumin binding sites. Both salicylic acid and aspirin bind more strongly to bovine serum albumin than to human serum albumin at protein concentrations of 4 g%. Protein binding protected aspirin against spontaneous hydrolysis although protein-bound aspirin still hydrolysed at a finite rate. In contrast, albumin enhanced the enzyme-catalysed hydrolysis of aspirin. By using a simple model, the rate constants for the individual processes contributing to the overall hydrolysis rate constant in the presence of albumin and esterase are calculated.
In vitro metabolic effects of gliclazide and glibenclamide in the rat
Authors: Musbah M O , Furman B L
Published: April 2011

The actions of gliclazide and glibenclamide on glucose uptake and glycogen deposition by rat hemidiaphragm and glucose utilization by rat epididymal adipose tissue have been examined in vitro. Neither drug exerted an insulin-like action on muscle or adipose tissue with respect to glucose uptake, glycogen deposition or glucose utilization. Neither gliclazide nor glibenclamide augmented the stimulating action of insulin on glucose uptake or glycogen deposition in the rat hemidiaphragm. In a high concentration (1 μgg ml−1), but not in lower concentrations, glibenclamide enhanced the action of insulin in stimulating glucose utilization by rat epididymal adipose tissue. Gliclazide was without any significant effect. Twenty eight day oral treatment with gliclazide did not increase basal or insulin-stimulated glucose uptake or glycogen deposition in rat hemidiaphragm muscle or glucose utilization by epididymal adipose tissue. It is concluded that in normal rats sulphonylureas do not exert important insulin-like actions or insulin potentiating effects.
Effects of two glucose absorption inhibitors: phenformin and 43–522 on hepatic gluconeogenesis
Authors: Ho R S , Kelly L A
Published: April 2011

The glucose absorption inhibitors, Phenformin and 3-phenylpropylaminoguanide HCl (SaH 43–522) have different effects on hepatic gluconeogenesis. Unlike phenformin, 43–522 in vivo does not inhibit hepatic gluconeogenesis; inhibition occurred only when 43–522 was added directly to a liver perfusion system. This suggests that when 43–522 is administered in vivo it is metabolized to an agent that does not inhibit hepatic gluconeogenesis whereas phenformin is not metabolized, and does inhibit gluconeogenesis. This is an advantage of 43–522 since it thereby specifically inhibits intestinal glucose absorption without a potential hypoglycaemic effect due to the suppression of gluconeogenesis.
The effect of viloxazine on drug-induced inhibition of food intake in the rat
Authors: Pleece S A , Kirby Marilyn J , Redfern P H
Published: April 2011

In male Wistar rats trained to eat their normal daily dietary requirement in a restricted 2 h period, dose-dependent decreases in food consumption were produced by fenfluramine, tiflorex, mazindol and amphetamine. The antidepressant drug viloxazine (Vivalan) alone did not alter food intake significantly, nor did the drug prevent the inhibitory effects of either mazindol or amphetamine. However, complete prevention of the inhibitory effect of fenfluramine was achieved with 7·5 mg kg−1 viloxazine, while 40 mg kg−1 viloxazine similarly prevented the anorectic action of tiflorex. An interaction involving 5-hydroxytryptaminergic mechanisms is suggested, and since viloxazine given after fenfluramine or tiflorex produced no reversal of the inhibition of food intake, it is suggested that viloxazine prevents access of the anorectic agents to their site of action. The clinical significance of these interactions is discussed.
The differential effects of morphine, oxotremorine and antipsychotic drugs on DOPAC concentrations in rat brain
Authors: Stanley Michael , Wilk Sherwin
Published: April 2011

The effects of morphine and oxotremorine on concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in the rat striatum and tuberculum olfactorium (TO) have been compared with the effects of the antipsychotic drugs haloperidol, chlorpromazine and clozapine. All the drugs elevated DOPAC concentrations in both brain regions. While the dose-response curves for the antipsychotic drugs were parallel, had steep slopes and similar maxima, the curves for morphine and oxotremorine were irregularly shaped but the curve for morphine in the TO had some similarity to that of the antipsychotic drugs. From these findings, it is concluded that the dose-dependent increase in striatal DOPAC effected by antipsychotic drugs can be used to differentiate them from other drugs known to elevate dopamine metabolites.
Molecular connectivity and gas chromatographic retention parameters
Authors: Millership J S , Woolfson A D
Published: April 2011

The relation between gas chromatographic retention parameters and molecular connectivity has been investigated for several series of compounds including hydrocarbons, compounds containing oxygen functional groups (esters, aldehydes, ketones, alcohols and ethers) and drug molecules. With the oxygenated compounds good correlation was observed with the first order valence connectivity index, whilst for the other groups multiparameter equations were required for satisfactory correlation. The effect of column to column variation within a series was also investigated.
Effects of olfactory bulbectomy and peripherallyinduced anosmia on thermoregulation in the rat: susceptibility to antidepressant type drugs
Authors: Forster Christine , Parkes Janet , Cox B
Published: April 2011

Olfactory bulb ablation in the rat produces an acquisition deficit in a step-down passive avoidance test, hyper-reactivity to environmental stimuli, elevated plasma-11-hydroxycorticosterone, and a deficit in the thermoregulatory response to low ambient temperatures, which is not evident at normal ambient temperatures. Like the other features of the bulbectomy syndrome, this thermoregulatory deficit is not related to anosmia per se, since rats made peripherally anosmic with intranasal ZnSO4 (5%) do not show a thermoregulatory deficit at low ambient temperatures. The abnormal response to cold could be prevented by chronic daily administration of amitriptyline (10mg kg−1), mianserin (10mg kg−1), and the 5-HT uptake inhibitor, Org 6582 (10 mg kg−1) for 7 days. The possibility that the thermoregulatory deficit has the same biochemical basis as the behavioural changes is discussed and a 5-HT involvement in the syndrome is considered.
Drug distribution as a function of binding competition. Experiments with the distribution dialysis technique
Authors: Bickel Marcel H , Gerny Rolf
Published: April 2011

In the distribution dialysis technique each of the two dialysis chambers contains a binding system, and a drug is allowed to distribute between them. This technique was tested by using various intracellular and extracellular binder preparations over wide concentration ranges, and model drugs selected for their known binding properties. The drugs were then tested at therapeutic concentrations in standardized systems of liver homogenate (0·5 g ml−1) and whole blood (0·02 ml ml 1) The resulting intracellular/extracellular concentration ratios were characteristic for the binding properties of the various drugs. Thus, for imipramine, a drug with strong tissue and weaker plasma binding properties, the concentration ratios were 25 for the system homogenate/buffer, 0·8 for buffer/blood, and 15 for the competitive system homogenate/blood. In experiments with homogenates from various tissues (liver, lung, kidney, intestine, brain) and blood in the standard system, the following approximate ratios were obtained: 1 for antipyrine, 2 for phenylbutazone, 14 for imipramine (but only 8 with muscle, skin and adipose tissue). These results reflect both the individual binding to intracellular and extracellular components and the tissue/blood concentration ratios in vivo. It is suggested that distribution dialysis is an in vitro method for characterizing the distribution of drugs. It is also concluded that drug distribution is largely determined by a binding competition between tissue and blood sites.
Participation of adrenal medulla in 6-aminonicotinamide-induced hyperglycaemia in the rat
Authors: Kaul C L , Talwalker P K , Grewal R S
Published: April 2011

In fasted rats 6-aminonicotinamide (6-AN) produced delayed hyperglycaemia, the peak effect being seen by 7 h. Fasting plasma insulin concentrations were not significantly altered but liver glycogen concentrations were decreased following treatment with 6-AN. Adrenalectomy, demedullation and pretreatment with reserpine, phentolamine, nicotinamide and nicotinic acid completely blocked the hyperglycaemic response whereas guanethidine and propranolol or oxprenolol were ineffective. Catecholamine concentrations in the adrenal venous plasma were markedly increased by treatment with 6-AN, the peak effect being seen by 5 h. It is concluded that adrenal medullary release, which is slow in onset, is mainly responsible for the development of sustained hyperglycaemia in the rat.
Regional differences in the responses to prostanoids of circular muscle from guinea-pig isolated intestine
Authors: Sanger Gareth J , Bennett Alan
Published: April 2011

The effects of prostaglandins (PGs) D2, E2, F2α, an epoxymethano analogue of PGH2 (U-46619), prostacyclin (PGI2), 6-keto-PGFlα and thromboxane (Tx) B2 were tested on spirally-cut strips of guinea-pig isolated ileum or colon. In the ileum no prostanoid exerted a marked effect on the resting tissue, but PGD2, PGE2 or PGI2 1 μg ml−1 inhibited submaximal contraction to KC1. U-46619 1 μg ml−1 either inhibited or increased contractions to KC1, but PGF2α, 6-keto-PGF1α or TxB2 1 μg ml−1 had no significant effect. PGE2 relaxed colonic strips whereas the other prostanoids caused contraction, except for TxB2 which had no effect. The PG antagonist SC-19220 blocked colonic contractions to the prostanoids, and a residual inhibitory effect of PGD2, U-46619 or PGI2 was demonstrated by the reduction of submaximal contractions to acetylcholine. Our results suggest that prostanoid receptors mediating inhibitory responses of circular muscle predominate in the ileum, whereas in the colon both excitatory and inhibitory prostanoid receptors occur.
The antifibrillatory potency of aprindine, mexiletine, tocainide and lignocaine compared on Langendorff-perfused hearts of rabbits and guinea-pigs
Authors: Almotrefi Abdulrahman A , Baker J B E
Published: April 2011

The effectiveness of three new antiarrhythmic drugs, aprindine, mexiletine and tocainide in elevating ventricular fibrillation threshold measured in the Langendorff-perfused rabbit heart and in protecting against ouabain-induced arrhythmias in the Langendorff-perfused guinea- pig heart has been compared with that of lignocaine. All these drugs have produced a significant rise in the threshold but quantitatively mexiletine was about equal to, tocainide five times less and aprindine thirty-eight times more potent than lignocaine in this effect. Aprindine differed from the other three drugs in that it had a slow onset of action and its effect was not entirely removed upon reperfusion with the drug-free solution. Only aprindine and mexiletine provided complete protection against ouabain-induced ventricular fibrillation while 3 of 6 and 4 of 6 hearts fibrillated in the presence of lignocaine or tocainide respectively.
In vitro actions of NN-dimethyl-2-aminoindane and related compounds
Authors: Little Hilary J , Rees J M H
Published: April 2011

The actions of 2-aminoindane, 2-amino-1,2,3,4-tetrahydronaphthalene and amphetamine and their N-methyl and NN-dimethyl derivatives on the guinea-pig ileum were compared. All, except the tertiary 2-aminoindane, inhibited the responses to electrical stimulation and it is suggested that this is not fully explained by their sympathomimetic properties. NN- Dimethyl-2-aminoindane increased these responses and caused contractions of the unstimulated ileum due to a nicotine-like action. The indane series was more effective in producing contractions of the ileum than the other compounds. The three tertiary derivatives antagonized competitively the actions of histamine on the ileum and those of 5-hydroxytryptamine on the rat uterus.
Influence of the sterilization method and of magnesium oxide on the tissue responses in the rat to modified starch glove powders
Authors: Pelling D , Butterworth K R
Published: April 2011

The tissue response to samples of a surgical glove powder was assessed from counts of the adhesions and granulomas found 7 and 14 days after introduction into the peritoneal cavity of rats, and by a histological study of affected tissues. Negative control groups treated with no powder and positive controls treated with talc were included. Various sample treatments were implemented to examine the effect of the sterilization method on the tissue response and the influence of magnesium oxide, normally added as a dispersing agent. The glove powder produced less reaction when steam-sterilized than when γ-irradiated and the presence of magnesium oxide at 2% concentration made no detectable difference.
Quantitative structure-activity relationships: the Van't Hoff heats of transfer of resorcinol monoethers from water to n-octanol
Authors: Beezer Anthony E , Hunter William H , Storey David E
Published: April 2011

The partition coefficients of resorcinol and some resorcinol monoalkyl-ethers from water to n-octanol have been measured as a function of temperature. These data are used to evaluate ΔG, ΔH and ΔS for the solute transfer process. The data suggest direct calorimetric measurement of these parameters should be performed. Correlation with calori-metrically determined ‘biological response’ will permit a more detailed and precise commentary upon the quantitative structure-activity relationships for these compounds.
The assay of pseudoephedrine hydrochloride in tablets and liquid formulations by two phase acid-base titration
Authors: Jones R , Marnham G
Published: April 2011

A novel titration method for the assay of pseudoephedrine hydrochloride in formulations is presented. Pseudoephedrine base is extracted into chloroform and titrated with acid in a two phase system. The method is specific for the drug in tablet and syrup formulations. The precision and speed of assay are comparable with existing spectrometric and titration methods for amine drugs.
Age-dependent differences in the effect of phenprocoumon on the vitamin K1-epoxide cycle in rats
Authors: Trenk Dietmar , Beermann Dieter , Oesch Franz , Jähnchen Eberhard
Published: April 2011

The anticoagulant activity and the pharmacokinetics of phenprocoumon as well as the effect of phenprocoumon on the vitamin K1-epoxide cycle in younger (12 weeks) and older (36 weeks) male inbred Lewis rats has been examined in a study of the mechanism responsible for the increase in the responsiveness to oral anticoagulant drugs (OAD's) with increasing age. After a single i.v.-dose of phenprocoumon (0†355 mg kg−1 the anticoagulant effect obtained was greater in older than in younger rats. There were no differences between younger and older rats in the rate of elimination, volume of distribution and in the free fraction and free concentration values of phenprocoumon in plasma and liver. After i.v.- injection of 64·3 μg kg−1 [3 H]vitamin K1 and different doses of phenprocoumon (0·02 to 3 mg kg−1) the [3 H]vitamin K1 concentration in the liver decreased and the [3 H] vitamin K1-2, 3-epoxide concentration increased dependent on the dose and the liver concentration of phenprocoumon. These changes were more pronounced in the older than in the younger rats. Concentration-response curves gave similar EC50-values for both age-groups but a 1·6-fold higher maximal response (expressed as vitamin K1-epoxide/vitamin K1 ratios) in the older rats. Since OAD's exert their anticoagulant effect most probably by inhibiting an enzyme (vitamin K1-epoxide reductase) which regenerates vitamin K1 from the epoxide metabolite and since the vitamin K1-epoxide/vitamin K1 ratios in the liver may reflect the degree of inhibition of the epoxide reductase by OAD's, our results may indicate that the inhibitory effect of phenprocoumon on this enzyme is more pronounced in older than in younger rats. This could explain the age-dependent differences in the anticoagulant activity.
On the importance of agonist concentration-gradients within isolated tissues. Increased maximal responses of rat vasa deferentia to (–)-noradrenaline after blockade of neuronal uptake
Authors: Kenakin Terry P
Published: April 2011

It is assumed often that blockade of agonist uptake processes in isolated tissues results only in shifts to the left of the concentration-response curves to the agonist with no concomitant increase in the maximal response. This may not be true in tissues where diffusion is not fast enough to permit penetration of the agonist to a sufficient number of muscle cells for production of tissue maximal response. Under these circumstances an agonist-concentration gradient is created within the tissue which, when altered, could lead to an increase in the maximal response to the agonist. The increased maximal responses of rat vasa deferentia to (–)-noradrenaline after blockade of neuronal uptake by either cocaine or desmethylimi-pramine have been analysed in terms of a concentration-gradient hypothesis. The data are compared with a theoretical calculation based on a model of restricted diffusion of enzymesubstrates into structured tissues. Both the experimental data and theoretical calculations suggest that an altered concentration-gradient of (–)-noradrenaline within the muscle layers of rat vasa deferentia is responsible for the increased maximal response. The effects of such gradients are discussed in terms of quantitation of drug-receptor phenomena and as a caveat to ascribing increases in maximal responses to post-synaptic effects of uptake inhibitors.
Factors affecting the release and excretion of dopamine in the rat
Authors: Akpaffiong M J , Redfern P H , Woodward B
Published: April 2011

The effects of inorganic salts and of diuretic agents on the excretion of dopamine (DA) were examined in the rat. Both types of treatment evoked significant increases in urinary DA excretion, urine volume and urinary sodium excretion. In the salt-treated animals a significant correlation was observed between DA excretion and urine volume, whereas after diuretic treatment there was better correlation between DA and urinary sodium excretion. The salt- treated animals showed a high correlation between administered chloride and DA excretion. Subcutaneous administration of DA produced a significant diuresis and an increase in sodium excretion. The mechanisms responsible for these responses are discussed with reference to the possibility that DA has a physiological role in the kidney.
Analysis of factors affecting the mean sizes of granules produced from ternary mixtures of powders
Authors: JAIYEOBA K T , SPRING M S
Published: April 2011

Multiple linear regression analysis has been used to relate the mean sizes of granules prepared from ternary mixtures of powders to such physical properties as particle size, solubility and wettability and to processing variables such as the amount of binder and the proportions of the different components. The major influences on granule size were the amount of binder and the affinity of the third component for the binder liquids.
Some solute-solvent complexes involving testosterone and testosterone propionate
Authors: JAMES K C , MEHDIZADEH M
Published: April 2011

Solute-solvent interactions have been studied by observing the influences of carbon tetrachloride, carbon disulphide, ethyl oleate, isopropyl myristate and octanol on the solubilities of testosterone and testosterone propionate in an inert solvent (cyclohexane). Complexation with testosterone was detected, but there was no evidence of complexation between testosterone propionate and these solvents. The solvent-induced infrared shifts were due to non-specific solvent effects. The existence of solute-solvent complexes between the two solutes and chloroform, previously detected by infrared absorption, was confirmed. The solubility technique, which has previously only been used with solid complexing agents, is adaptable to liquid complexing agents, but has limitations.
Evaluation and comparison of colorimetric, radiometric and high performance liquid chromatographic assays for aminopyrine-N-demethylation by rat liver microsomes
Authors: BAST A , NOORDHOEK J
Published: April 2011

Aminopyrine (DMAP) is metabolized by two successive N-demethylations to monomethyl-4-aminoantipyrine (MMAP) and 4-aminoantipyrine (AAP). Separation and quantification of DMAP and its metabolites in microsomal incubation mixtures by h.p.l.c. showed that other reactions also occur. In the radiometric method where [Me2-14C] DMAP is used as substrate, [14C]formaldehyde is formed during the N-demethylation. However since commercial [14C]DMAP, is not completely double labelled, and both MMAP and AAP are formed, it is impossible to calculate the formaldehyde formation accurately from the specific activity of [14C]DMAP. Moreover, it was shown that DMAP, AAP and particularly MMAP may all develop considerable colour intensity with the Nash reagent, which is used to determine formaldehyde. Despite this difficulty, DMAP may still be used as a model substrate in vitro, with the Nash assay being used to determine formaldehyde if low substrate concentrations and a short incubation time are used. Thus the interference of DMAP or its metabolites with the Nash assay is negligible. As the same Km and Vmax values were obtained from both the radiometric and the relatively precise colorimetric assay it is suggested that there is little wrong with either method, at least under our experimental conditions. The h.p.l.c. method however, underestimates formaldehyde formation, probably because metabolites other than MMAP and AAP are formed. The latter method however may be used to analyse the aminopyrine metabolism in more detail.
Evaluation of a prototype micro-electronic autoclave cycle integrator
Authors: KIRK B , HAMBLETON R
Published: April 2011

Instability and non-uniformity of spore preparations and the non-conformity of chemical indicators to the temperature coefficients of spore inactivation are problems associated with current methods of autoclave cycle monitoring. A prototype micro-electronic instrument, which largely overcomes these problems, is described. It monitors autoclave cycles in terms of the integral F0 and Nabla functions. Its thermometric and integrating accuracy is demonstrated. A discussion of the problems associated with the use of sensitive electronic instruments in the autoclave room environment reveals the need for independent monitoring areas when such devices are used. Inactivation constants were determined for spores of the organism Bacillus stearothermophilus, NCTC 10 003 and were described using D115 (12.0 min) and Z (9.0 °C) values and the first order reaction Arrhenius constants A (1041, 2 min−1) and Ea (74.4 kcal mol−1, 311 kJ mol−1). These have been compared with recently published values. The standardization of F0 and Nabla is discussed with reference to the setting of minimum values related to product bioburden and maximum values related to an acceptable degree of product degradation.
The mechanism of interaction between chlorhexidine digluconate and poly(2-hydroxyethyl methacrylate)
Authors: PLAUT B S , DAVIES D J G , MEAKIN B J , RICHARDSON N E
Published: April 2011

The extent of the interaction between chlorhexidine digluconate and poly(2-hydroxyethyl methacrylate), (PHEMA), is independent of temperature between 22–50 °C which is consistent with an ion-ion interaction mechanism. Different contact lens materials exhibit different affinities for chlorhexidine digluconate, the extent of uptake correlating in rank order with the number of free carboxylic acid sites in the polymers. Esterification of the carboxyl groups with diazomethane, resulted in a reduction in the affinity of the treated polymers for chlorhexidine to a near basal level. The uptake of chlorhexidine in soaking solution experiments involving lenses made from PHEMA and the more ionic material, poly(2-hydroxyethyl methacrylate - co-isobutyl methacrylate - co - methacrylic acid), was consistent with their carboxylate content. However, the fraction of bound disinfectant released was lower from the terpolymer, suggesting there are differences in bonding strengths between chlorhexidine and different contact lens hydrogels.
Two metabolites of sulphinpyrazone and their identification and determination by mass spectrometry
Authors: JAKOBSEN P , PEDERSEN A KIRSTEIN
Published: April 2011

Sulphinpyrazone is an antiplatelet agent in vivo and in vitro. Two active metabolites, a sulphide (S) and a hydroxylated sulphide (S-OH) have been identified in rabbit and human plasma and a selective and sensitive g.c.-m.s.-method for quantitative determination of the sulphide and hydroxylated sulphide in plasma and urine has been evolved which allows concentrations down to 5 ng ml−1 for the sulphide and 30 ng ml−1 for the hydroxylated sulphide to be detected. The time course of the metabolite concentrations in plasma corresponds to the biological findings, suggesting that the metabolites contribute significantly to the in vivo effects of the drug.
A metabolic and pharmacokinetic comparison of theophylline and aminophylline (theophylline ethylenediamine)
Authors: MONKS T J , SMITH R L , CALDWELL J
Published: April 2011

The metabolism and pharmacokinetics of intravenously administered theophylline and aminophylline (theophylline ethylenediamine) have been studied in 3 volunteers, using 14C-labelled theophylline. Both compounds were metabolized extensively and 1, 3-dimethyl-uric acid, 1-methyluric acid, 3-methylxanthine and two unknown minor metabolites were excreted in the urine, in addition to theophylline. The elimination of theophylline, 1, 3-dimethyluric acid, 1-methyluric acid and the unknown metabolites followed first-order kinetics, but that of 3-methylxanthine followed Michaelis-Menten kinetics. When given as aminophylline, theophylline was metabolized more rapidly and extensively than when given alone. The recovery of 14C in the urine was significantly higher after aminophylline than after theophylline. Abstention from intake of dietary methylxanthines for 7 days resulted in more rapid and extensive metabolism of aminophylline compared with results from the same subjects on their usual diets. The results indicate that, from a metabolic and pharmacokinetic viewpoint, aminophylline and theophylline are not equivalent.
Effect of pH on the micellar properties of amphiphilic drugs in aqueous solution
Authors: ATTWOOD D , NATARAJAN R
Published: April 2011

The influence of pH on the micellar properties of several amphiphilic drugs under conditions of constant ionic strength has been investigated. No significant effect of pH on the critical micelle concentration or micellar size of chlorpromazine hydrochloride was noted over a pH range well below the pKa. The micellar properties of opipramol, thiopropazate, flupenthixol, clopenthixol, and trifluoperazine, which contain a piperazine moiety showed considerable pH dependence. The concentration dependence of the pKa in these micellar systems was taken into consideration in the selection of pH values representative of complete protonation of either one or both of the piperazine N atoms. A lower aggregation number and higher critical micelle concentration was observed at a low pH corresponding to complete protonation of both charge centres. Mepyramine maleate exhibited a non-micellar mode of association at pH 5·5 which could be described by a stepwise association model in which association constants, KN, increased sequentially with aggregation number, N, according to the relationship, KN = K(N − 1)/N where K = 31·3 dm3 mol−1. No significant association could be detected at pH 2 when the pyridine ring N was fully protonated.
Effects of structural variations of non-ionic surfactants on micellar properties and solubilization: surfactants containing very long hydrocarbon chains
Authors: ARNARSON THORDIS , ELWORTHY P H
Published: April 2011

Polyoxyethylene mono-ethers of dotriacontanol (C32E41) and 4, 9-dimethyltritriacontanol (C35E40) have been synthesized. The micellar weights in water at 298K were 4·82 × 105 and 5·90 × 105, the aggregation numbers 212 and 260, and the levels of hydration 290 and 283 mol water mol−1 surfactant, respectively. The solubilization of azobenzene, cortisone acetate, griseofulvin, sulphadiazine, phenylbutazone, betamethasone, tolbutamide, and menaphthone was studied in 2% solutions of the above surfactants. The presence of large micelles did not result in increased solubilization; C32E41 and C35E40 had a lower solubilizing capacity than that of cetomacrogol.
A theoretical conformational study of substituted o-anisamides as models of a class of dopamine antagonists
Authors: PANNATIER A , ANKER L , TESTA B , CARRUPT P A
Published: April 2011

The quantum mechanical PCILO method has been used to investigate the conformational behaviour of N-(2-aminoethyl)- and N-(2-dimethylaminoethyl)-o-anisamide, two model molecules of substituted benzamides. The molecules are shown to have only limited conformational freedom due to the presence of two intramolecular hydrogen bonds acting as conformational locks. The molecules in their preferred conformation are characterized by a distance between the centre of the aromatic ring and the nitrogen atom of almost 6 Å, i.e. almost 1 Å longer than in the fully extended dopamine conformers. Some implications at the receptor level of this topographical dissimilarity are discussed.
Actions of dopamine and apomorphine on the vasoconstrictor responses of perfused mesenteric arteries of mouse, rat and rabbit
Authors: ANWAR N , MASON D F J
Published: April 2011

Dopamine (10−7-10−6 m) and apomorphine (5 × 10−7 − 5 × 10−6 m) inhibited the vasoconstrictor responses of the perfused mesenteric artery preparations of rat, rabbit and mouse to adrenergic nerve stimulation but did not affect responses to added noradrenaline. The inhibitory effects of both dopamine and apomorphine were prevented by haloperidol (3 × 10−7 m) but not by yohimbine (3 × 10−8 m) in rat and rabbit mesenteric artery preparations. In contrast, yohimbine (3 × 10−8 m), but not haloperidol, antagonized the inhibitory effect of dopamine and apomorphine in mouse mesenteric artery preparations. In higher concentrations, dopamine (10−6 − 10−4 m) produced a direct vascoconstrictor effect, which involved post-junctional α-adrenoceptors in all three species. However, in preparations contracted with 10−7 m 5-hydroxytryptamine and in the presence of phentolamine (3 × 10−7 m) and propranolol (10−6 m), dopamine (10−6 − 10−4 m) produced a direct relaxant effect in rabbit mesenteric artery preparations but not in those of rat and mouse. It is suggested that inhibition of neurogenic vasoconstrictor responses, by dopamine and apomorphine, may be mediated through a specific prejunctional inhibitory dopamine receptor in the mesenteric artery of rat and rabbit whereas in the mouse they involve activation of α-adrenoceptors.