bluuebunny/crossref_metadata_2025 huggingface dataset:
Propranolol uptake with high capacity by rat perfused lung
Authors: Iwamoto Kikuo , Watanabe Jun , Yonekawa Hina
Published: April 2011

Lung isolated from 7-week-old rats was perfused with pH 7.4 Krebs-Ringer bicarbonate buffer solution (35 mL) containing 1 to 100 μg mL−1 of propranolol and 3% BSA at the recirculation rate of 8 mL min−1. Almost parallel bi-exponential drug concentration-time curves were obtained at the initial load lower than 10 μg mL−1, whereas relatively slow, mono-exponential decline was found after perfusion at 100 μg mL−1. Pharmacokinetic analysis for the perfusate propranolol concentration-time curves when loaded at 1 to 10 μg mL−1 yielded almost comparable values for the pulmonary perfusion clearance (0.387 ± 0.092 to 0.486 ± 0.095 mL min−1 g−1). In contrast, this parameter was significantly reduced at 100 μg mL−1 (0.113 ± 0.042 mL min−1 g−1). The present findings suggest a trend towards saturation kinetics in the in-vitro pulmonary clearance of propranolol.
Multiple Compression and Plasto-elastic Behaviour of Paracetamol and Microcrystalline Cellulose Mixtures
Authors: Yu H C M , Rubinstein M H , Jackson I M , Elsabbagh H M
Published: April 2011

Radial tensile strength, friability, ER/PC (elastic recovery/plastic compression) ratio and energy ratio analyses were evaluated for various mixtures of paracetamol and microcrystalline cellulose (Avicel). A good correlation occurred between the energy ratio and the other variables. Linear relationships were found between log tensile strength and percentage energy ratio and also between radial tensile strength and stress relaxation energy. Capping occurred when the percentage energy ratio was greater than 15% and the ER/PC ratio greater than 1.5. To produce tablets with acceptable tensile strength and friability, the percentage energy ratio for Avicel/paracetamol should be greater than 10%. The optimal mixture of the two powders, as far as the tensile strength, friability and absence of capping were concerned, was found to be 50% w/w Avicel, 50% w/w paracetamol.
Effects of a Perfluorochemical Blood Substitute on Diazepam Binding by Human Albumin
Authors: Graben R D , Parsons D L
Published: April 2011

The binding of 0.4 μg mL−1 diazepam and 0.75 mol diazepam mol−1 of albumin by a perfluorochemical (PFC) emulsion, Fluosol-DA, 20%, by human serum albumin (HSA), and by their mixtures, has been examined at ambient temperature. The concentration of free diazepam was determined by standard centrifugation followed by supernatant ultrafiltration. Non-specific loss of diazepam occurred to the ultrafiltration device. This loss was independent of drug concentration and a correction factor was employed to calculate the true free diazepam concentration. Diazepam was extensively bound by the PFC emulsion. The percent free diazepam increased as the emulsion concentration decreased, while the binding of diazepam appeared to be independent of drug concentration. Diazepam did not partition into the pure PFC liquids, indicating that emulsion-bound diazepam is only associated with the emulsifiers of the droplets. Diazepam was extensively bound by HSA and the percent free diazepam increased as drug concentration increased or as HSA concentration decreased. The PFC emulsion significantly displaced HSA bound diazepam in all mixtures examined. Studies with the individual and combined components of the emulsion indicated that this displacement is largely attributed to the oleic acid component and, to a much smaller degree, the Pluronic F-68 component of the emulsion.
Binding of Drugs to Human Skin: Influencing Factors and the Role of Tissue Lipids
Authors: Walter K , Kurz H
Published: April 2011

For a series of ten drugs with different physicochemical properties, binding to human skin (epidermis and corium) was determined. Epidermis was obtained by suction blistering, and corium was sliced with a microtome (0.2 mm). Binding experiments were performed in dialysis chambers, containing labelled drug solutions. All drugs investigated were bound to epidermis and corium. With one exception, epidermal drug binding was significantly higher than corial binding. Nevertheless, a good correlation between binding of drugs to both skin fractions could be found. In a range from 10−7 to 10−3 mol L−1 binding of drugs to both skin fractions is linear and not saturable. A good correlation was found between binding and lipophilicity of drugs, determined as the partition coefficients between an organic phase (octanol or heptane) and phosphate buffer of pH 7.0. The results show that binding to epidermis and corium is not saturable and depends on lipophilicity of drugs, indicating unspecific binding. Further binding experiments were performed with lipid-depleted tissue. Since drug binding to lipid-depleted samples and control samples differ only to a moderate extent, it is suggested, that tissue lipids play a marginal role on drug binding. Hence, drugs are bound to human skin by other components like proteins.
Vasoactive Intestinal Polypeptide as Possible Mediator of Relaxation in the Rat Gastric Fundus
Authors: de Beurme F A , Lefebvre R A
Published: April 2011

Relaxations were induced in longitudinal muscle strips of the rat gastric fundus by stimulation of non-adrenergic non-cholinergic (NANC) neurons and by administration of vasoactive intestinal polypeptide (VIP) or isoprenaline. The effect of antiserum against vasoactive intestinal polypeptide (VIP antiserum) and of control serum on these relaxations was investigated. Incubation with VIP antiserum (dilution 1/50) for 1 h almost completely prevented the relaxation by VIP. It partially prevented the relaxation evoked by electrical stimulation while the relaxation induced by isoprenaline was not influenced. Control serum decreased the VIP- and stimulation-induced relaxations much less than did VIP antiserum. In addition, the effect of the putative VIP antagonist (4Cl-D-Phe6, Leu17) VIP was studied on the relaxations induced by NANC neuron stimulation and by VIP. The VIP antagonist (3.10−5 M, incubation time 10 min) had a relaxatory effect itself but had no influence on either VIP- or stimulation-induced relaxations. The results with VIP antiserum confirm the involvement of VIP in the inhibitory NANC neurotransmission of the rat gastric fundus.
External control of drug release: controlled release of insulin from a hydrophilic polymer implant by ultrasound irradiation in diabetic rats
Authors: Miyazaki Shozo , Yokouchi Chizuko , Takada Masahiko
Published: April 2011

The development of a polymeric system capable of delivering insulin in-vivo at increased rates on demand by an external ultrasound irradiation is reported. Implants composed of EVA1 copolymer and insulin were placed subcutaneously in diabetic rats. When the diabetic rats receiving implants containing insulin were exposed to an ultrasound irradiation, a sharp drop in the blood glucose levels was observed after the irradiation, indicating a rapid rate of release of insulin in the implanted site.
Inhibition of histamine N-methyltransferase activity in guinea-pig pulmonary alveolar macrophages by nicotine
Authors: Gairola C , Godin C S , Houdi A A , Crooks P A
Published: April 2011

Both S-(−)- and R-(+)-nicotine enantiomers are inhibitors of histamine Nτ-methylation activity in guinea-pig pulmonary alveolar macrophage cultures, exhibiting IC50 values of 7 and 8 μM, respectively. S-(−)-Nicotine is not biotransformed under the conditions of the experiment, however, R-(+)-nicotine undergoes significant N-methylation to produce N-methylnicotinium ion. S-(−)-Nicotine appears to inhibit the N-methylation of its optical antipode by the alveolar nicotine N-methyltransferase. The results indicate that a contributing factor in the toxicology of cigarette smoke inhalation may be due to the inhibition of pulmonary metabolism of histamine by nicotine.
A rapid and sensitive high-performance liquid chromatographic method for the determination of diclofenac sodium in serum and its use in pharmacokinetic studies
Authors: El-Sayed Yousry M , Abdel-Hameed Mohamed E , Suleiman Mohammad S , Najib Naji M
Published: April 2011

A rapid, and sensitive high-performance liquid chromatographic method has been developed for the determination of diclofenac sodium in serum using flufenamic acid as the internal standard. Serum protein was precipitated with acetonitrile. The drugs were eluted from a 5 μm C-8 reversed-phase column at ambient temperature with a mobile phase consisting of acetonitrile-water (50:50% v/v) adjusted to pH 3.3 with glacial acetic acid, at a flow rate of 2 mL min−1 with UV detection at 280 nm. Each analysis required no longer than 10 min. Quantitation was achieved by the measurement of the peak-height ratio and the relative and absolute recoveries varied from 90 to 98%. Detection limits for diclofenac sodium in serum is 25 ng mL−1. Intraday coefficients of variation (CV) ranged from 2.47 to 4.61 % and interday CVs from 3.52 to 7% at three different concentrations. Preliminary stability tests showed that diclofenac sodium is stable for at least 2 weeks in serum after freezing. The method is applied for the determination of the pharmacokinetic parameters of diclofenac after administration of two formulations (enteric-coated tablet and slow-release tablet), to a healthy male volunteer.
Digitonin-solubilized histamine H1-receptors bind to polyethylenimine-treated glass-fibre filters
Authors: Treherne J M , Young J M
Published: April 2011

The binding of [3H]mepyramine to histamine H1-receptors solublized from guinea-pig cerebellum by 1% digitonin could be assayed by adsorption of the receptor-bound [3H]ligand to glass-fibre filters pretreated with 0.3% polyethylenimine (PEI). Nonspecific binding was higher than in parallel experiments in which the bound and free [3H]ligand was separated by gel-filtration on Sephadex G-25 columns, but the parameters characterizing the inhibition curves were otherwise similar. The PEI-treated filter method could also be used to assay [3H]-(+)-N-methyl-4-methyl-diphenhydramine ([3H]QMDP) binding to solubilized H1-receptors, but the level of non-specific binding was higher and was only satisfactorily defined by icotidine or temelastine. A particular utility of the PEI-treated filter assay will be in measurements of the kinetics of H1-receptor-ligand interactions.
Effects of Tapioca Obtained From Cassava (Manihot utilissima) on the Disintegration and Dissolution Rates of Paracetamol Tablets
Authors: Esezobo S , Zubair S , Pilpel N
Published: April 2011

The properties of tapioca obtained from cassava (Manihot utilissima) have been evaluated. Its binding effect in tablets of paracetamol on the disintegration and dissolution rates was compared with tablets prepared with polyvinylpyrrolidone and gelatin. The nature and amount of the binders were found to alter the disintegration and dissolution rates of the tablets by reducing their wettability as measured by the adhesion tension of water. A linear relationship has been found to exist between the adhesion of water on the tablets and their disintegration and dissolution rates.
Mediators of the Plasma Extravasation Response to Silver Nitrate in the Rat Skin, Subplantar Region and Ankle Joint
Authors: Fyfe Margaret C , Chahl Loris A
Published: April 2011

Plasma extravasation responses to silver nitrate (AgNO3), histamine, 5-hydroxytryptamine (5-HT), bradykinin and prostaglandin E1 (PGE1) in the abdominal skin, hindpaw ankle joint and subplantar region of rats have been investigated using the Evans blue dye leakage technique. All substances tested produced plasma extravasation and combination of low doses (5 × 10−10mol) of either histamine or bradykinin with PGE, (5 × 10−10mol) exhibited potentiation of responses of all regions. Responses to AgNO3 (1 × 10−6mol) were significantly reduced by the H1 receptor antagonist, mepyramine, only in the abdominal skin, but the H2 receptor antagonist metiamide reduced the responses at subplantar and ankle joint regions. Indomethacin significantly reduced the AgNO3 responses at the ankle joint only, but aprotinin reduced it at the other two regions. In rats pretreated with a combination of all antagonists the residual plasma extravasation response to AgNO3 was very small, indicating that the response could be almost totally accounted for by the combined actions of mast cell amines, kinins and prostanoids. The finding that prostanoids played a major role in the plasma extravasation response of the rat ankle joint to AgNO3 indicated that this model would be useful for the screening of non-steroidal anti-inflammatory drugs.
The effect of some tricyclic antidepressants on the inhibition of mouse brain monoamine oxidase in-vivo by phenelzine
Authors: Green A L , O'Grady J E , Vass M
Published: April 2011

Four tricyclic antidepressants, amitriptyline, imipramine, desipramine and iprindole have been shown to partially protect mouse brain monoamine oxidase in-vivo from the irreversible enzyme inhibition produced by subsequent injection of phenelzine. Levels of protection were similar when the enzyme was assayed with selective substrates (5-hydroxytryptamine and phenethylamine) for both the A and B forms of the enzyme. Although other explanations cannot at this stage be ruled out, these observations are consistent with the tricyclic antidepressants acting as reversible inhibitors of brain monoamine oxidase in-vivo.
Hypothermia induces supersensitivity of mouse vas deferens to adrenergic agonists: evidence for postjunctional α2-adrenoceptors
Authors: Goncalves J , Proenca J , Albuquerque A A , Paiva M Q
Published: April 2011

Hypothermia-induced potentiation of α-adrenoceptormediated responses of the mouse vas deferens to noradrenaline is mainly caused by inhibition of the sites of loss. However, even after blockade of the sites of loss for noradrenaline or when using methoxamine (which is not a substrate for uptake or metabolism) hypothermia still causes a significant increase in responsiveness. This remaining supersensitivity was shown to be an increased receptor affinity. Furthermore, hypothermia revealed contractile responses to low concentrations of UK 14304 (an α2-agonist).
Characterization of Albumin-Alginic Acid Complex Coacervation
Authors: Singh O N , Burgess D J
Published: April 2011

Complex coacervation of albumin and alginic acid has been investigated to characterize this process, and to prepare a microencapsulation system suitable for the encapsulation of live cells, protein and polypeptide drugs. The optimum conditions of pH, ionic strength and total polyion concentration were in accordance with predictions based on the method of Burgess & Carless (1984). Albumin/alginic acid complex coacervation appears to fit the Vies-Aranyi model for complex coacervation. Coacervation was limited compared with other polypeptide/polysaccharide systems such as gelatin and acacia, with albumin/ alginic acid complex precipitates rather than complex coacervates forming under certain conditions. In particular coacervation was limited to concentrations below 0·5% w/v. At concentrations between 0·35 and 0·5% w/v both complex coacervation and precipitation occurred, and at concentrations above 0·5% w/v only precipitation was detected. The albumin/alginic acid complex coacervate is very viscous and this together with the limited conditions governing the occurrence of coacervation makes this system unsuitable for the preparation of microcapsules.
Locomotor Behaviour of Selective Dopamine Agonists in Mice: Is Endogenous Dopamine the Only Catecholamine Involved?
Authors: Pichler Ludwig , Pifl Christian
Published: April 2011

The purpose of the study was to determine the effect alone and in combination of the selective dopamine (DA) agonists SKF 38393 (D1-) and B-HT 920 (D2-) on the locomotor activity of reserpine pretreated mice (5 mg kg−1 i.p.). After 4 h, reserpine-B-HT 920 (up to 20 mg kg−1 s.c.) did not induce locomotor activity whereas SKF 38393 was markedly effective at high doses (≥ 30 mg kg−1 s.c). In contrast, at 24 h, reserpine-B-HT 920 (0·2–6 mg kg−1 s.c.) elicited considerable locomotor activity and SKF 38393 (1–100 mg kg−1 s.c.) was effective at lower doses when compared with the corresponding 4 h reserpine experiments. When, however, these animals additionally received α-methyl-p-tyrosine (αMPT; 300 mg kg−1 i.p., at 4 h before the DA agonists) neither B-HT 920 (0·2–20 mg kg−1 s.c.) nor SKF 38393 (1–100 mg kg−1 s.c.) had an effect of their own. When B-HT 920 was tested in the presence of a fixed-dose of SKF 38393 (10 or 3 mg kg−1 s.c., combination experiments) B-HT 920 (0·6–20 mg kg−1 s.c.) induced considerable locomotor activity at 4 h post reserpine. At 24 h post reserpine the dose-response curve of B-HT 920 (0·06–20 mg kg−1 s.c.) was shifted to the left and the maximum effect was greatly increased. When additional αMPT was given, the dose response curve was the same but the maximum effect was markedly reduced. When SKF 38393 was tested in the presence of a fixed-dose of B-HT 920 (2 mg kg−1 s.c.; combination experiments) this resulted in a dose response curve in the range of 0·3–10 mg kg−1 s.c. at 4 h post reserpine. At 24 h post reserpine the curve shifted to the left by approximately a factor of 30 (0·1–3 mg kg−1 s.c.) and the maximum effect was markedly increased. Additional αMPT shifted the curve to the right by a factor of approximately 30 without a substantial change in the maximum effect. It is concluded that simultaneous stimulation of D1- and D2- receptors is necessary to elicit locomotor activity in mice. From dose response analysis of experiments with additional αMPT it is furthermore concluded that endogenous noradrenaline may play an additional modulatory role.
A note on the use of salicylate saliva concentration in clinical pharmacokinetic studies
Authors: Khan Azhar Z , Aarons Leon
Published: April 2011

A sequential approach is presented to the problem of determining the minimum number of blood samples needed to calculate the plasma to saliva concentration ratio to a required precision. The method was applied to salicylate concentrations obtained from six rheumatoid arthritis patients. In order to achieve a 10 per cent coefficient of variation in the plasma to saliva salicylic acid concentration ratio, on average 9 samples were required for total plasma concentration and 8 samples for unbound concentration. In some cases it was not possible to achieve the required precision with the given number of samples. Correlation of salicylic acid concentrations in saliva with total and unbound plasma concentration were equally as good. The limitations of saliva data in clinical pharmacokinetic studies are discussed.
Absence of pharmacokinetic interaction between ofloxacin and fenbufen in rats
Authors: Katagiri Yoshihiro , Naora Kohji , Ichikawa Nobuhiro , Hayashibara Masakazu , Iwamoto Kikuo
Published: April 2011

The possible pharmacokinetic interaction between a new quinolone and fenbufen was investigated by comparing the plasma concentration-time profiles and serum protein binding of ofloxacin, fenbufen and its active metabolite, felbinac, in rats. The rats were administered intravenous doses of ofloxacin (5 mg kg−1), fenbufen (10 mg kg−1) alone or concomitantly. The plasma elimination half-lives were about 55 min in both groups. A slight elevation of plasma concentration of ofloxacin and a small decrease of its total body clearance were observed after its coadministration with fenbufen. The extent of ofloxacin binding to rat serum tended to be slightly reduced by fenbufen which coexisted at relatively high concentrations. Plasma concentration-time curves, pharmacokinetic parameters and serum protein binding of fenbufen and felbinac were not affected by the coadministration with ofloxacin. These results suggest that any substantive pharmacokinetic interaction may be unlikely after the concomitant administration of ofloxacin and fenbufen.
Visceral Leishmaniasis: Drug Carrier System Characteristics and the Ability to Clear Parasites from the Liver, Spleen and Bone Marrow in Leishmania donovani Infected BALB/c Mice
Authors: Carter K C , Dolan T F , Alexander J , Baillie A J , Mccolgan C
Published: April 2011

The efficacy of various sodium stibogluconate formulations against Leishmania donovani has been investigated using a BALB/c mouse model of visceral leishmaniasis. Only one therapy, multiple dosing with drug loaded sonicated vesicles, liposomes or niosomes, was found to be effective against parasites in the liver, spleen and bone marrow. Other treatments significantly reduced parasite liver burdens but either failed to effect spleen and bone marrow parasites, or were effective but toxic. Prophylactic treatment with sodium stibogluconate preparations, six days before infection, reduced parasite multiplication in the liver (free, niosomal and liposomal drug) and the spleen (sonicated, drug loaded niosomes only), but had no suppressive effect on bone marrow parasite burdens compared with controls. These results indicate that in-vivo sodium stibogluconate persists in some compartments at parasiticidal concentrations and that failure to reach this concentration at some sites of infection such as bone marrow, is the cause of treatment failure and relapse.
The Enhanced Daily Excretion of Urinary Methylamine in Rats Treated with Semicarbazide or Hydralazine May Be Related to the Inhibition of Semicarbazide-sensitive Amine Oxidase Activities
Authors: Lyles G A , Mcdougall S A
Published: April 2011

The effects of amine oxidase inhibitors upon the daily urinary excretion of monomethylamine (MMA), dimethylamine (DMA), trimethylamine (TMA) and ammonia in the rat have been examined. Administration of hydralazine (5 mg kg−1) or semicarbazide (100 mg kg−1); drugs which irreversibly inhibit semicarbazide-sensitive amine oxidases (SSAO) but not monoamine oxidase (MAO), enhanced MMA excretion by around three- to six-fold above pretreatment levels, whereas no effect of pargyline (25 mg kg−1), a selective irreversible inhibitor of MAO was found. No apparent changes in DMA or TMA excretion in response to drug-treatment were observed. Ammonia excretion also was generally unchanged except for an apparent marked increase (approximately four-fold) over the 24 h following semicarbazide, a result which might be explained if ammonia is a degradation product of semicarbazide metabolism in the rat. With recent evidence that MMA is a substrate in-vitro for SSAO activities, results here may indicate that SSAO or related enzymes are involved in endogenous MMA turnover.
Definition of the In-vivo Binding of [3H]Spiperone in Rat Brain Using Substituted Benzamide Drugs
Authors: Chivers J K , Reavill C , Jenner P , Marsden C D
Published: April 2011

The ability of some substituted benzamide drugs to define in-vivo the binding of [3H]spiperone to brain dopamine receptors in rats was assessed using behaviourally effective doses in comparison with haloperidol. As judged using haloperidol, [3H]spiperone identified dopamine receptors in the substantia nigra, striatum, tuberculum olfactorium and. hypothalamus, but not in frontal cortex or nucleus accumbens. The substituted benzamide compounds alizapride, metoclopramide, clebopride and YM 09151-2 prevented the accumulation of [3H]spiperone in the substantia nigra, striatum, tuberculum olfactorium and hypothalamus. However, YM 09151-2 also caused displacement of [3H]spiperone accumulation in the nucleus accumbens and frontal cortex. (±)-Sulpiride, (±)-sultopride, amisulpiride and prosulpride all prevented the accumulation of [3H]spiperone in the hypothalamus but were ineffective in one or more of the other regions containing dopamine receptors defined by [3H]spiperone. The isomers of sulpiride and sultopride stereoselectively defined the accumulation of [3H]spiperone in dopamine containing brain regions. The (-)-isomers of both drugs prevented the accumulation of [3H]spiperone in the substantia nigra, striatum, tuberculum olfactorium and hypothalamus. In contrast, (+)-sulpiride and (+)-sultopride were ineffective. Selected substituted benzamide drugs can be used to define the interaction of ligands with dopamine receptors in-vivo. These substances may be useful in PET studies in man. The isomers of some substituted benzamine drugs may be used to define dopamine receptors in-vivo by enantiomeric selectivity.
Effects of Anti-inflammatory Drugs on Interleukin 1-induced Cartilage Proteoglycan Resorption In-vitro: Inhibition by Aurothiophosphines but no Influence from Perturbed Eicosanoid Metabolism
Authors: Rainsford K D
Published: April 2011

A range of anti-inflammatory drugs having varying effects on eicosanoid metabolism and other actions was studied for their potential to inhibit α-interleukin 1 (IL-1)-induced cartilage proteoglycan resorption in-vitro. No significant effects on resorption were observed with inhibitors of cyclo-oxygenase, lipoxygenase or mixed inhibitors of both these enzymes, and no influence on IL-1 effects was observed with added eicosanoids. Among the clinically used disease modifying anti-arthritic agents, only auranofin and the immunoregulatory agent, tilomisole, were found effective in inhibiting resorption. Some auranofin analogues having chloride or nitrate leaving groups that inhibit DNA polymerase-α were found to be potent inhibitors of IL-1 induced resorption.
The influence of structure on the accumulation of caffeine induced by methyl xanthine derivatives
Authors: Segura Jordi , Roberts David J , Tarrus Emili
Published: April 2011

In rats given caffeine (25 mg kg−1 p.o.) and 1,3,8-trisubstituted xanthine (1,3,8-TSX) derivatives (10 mg kg−1 p.o.) the accumulation of the former in plasma was 300% higher than that in control animals given caffeine alone. The effect on caffeine accumulation appears to be independant of the nature of the N3 substituent and its absence in rats given 1,3-disubstituted xanthines (1,3-DSX) instead of 1,3,8-TSX suggests that the presence of the C8-methyl group in the latter compounds is responsible for the accumulation phenomenon. The results of our previous work imply that these observations in this rat model can be extrapolated to man.
Interaction between the cardiovascular effects of Clonidine and the κ-opioid agonist U-50,488H in the anterior hypothalamic area of the rat brain
Authors: Verberne Anthony J M , Louis William J
Published: April 2011

In thiobutabarbitone-anaesthetized rats, microinjection of Clonidine (1–40 nmol) into the anterior hypothalamic area (AHy) produced dose-dependent reductions in mean arterial blood pressure and heart rate. Microinjection of the κ-opioid agonist U-50,488H (3 and 10 nmol) did not modify these parameters. Simultaneous co-administration of Clonidine (4 nmol) and U-50,488H (10 nmol) into the AHy resulted in significant potentiation of the clonidine-induced hypotension and marked attenuation of the bradycardia. A lower dose of U-50,488H (3 nmol) coadministered with Clonidine (4 nmol) did not influence the cardiovascular responses to Clonidine. These findings suggest that AHy neurons involved in the cardiovascular responses to Clonidine may be modulated by κ-opioid receptor stimulation.
Solid State Adsorption of Antibiotics onto Sorbitol
Authors: Nikolakakis I , Newton J M
Published: April 2011

The ability of two types of sorbitol, instant and crystalline, to hold antibiotics permanently after mixing has been assessed by an air sieving technique. Sorbitol instant was found to have a greater adsorption capacity and binding strength than crystalline sorbitol. The six antibiotics studied were found to fall roughly into two groups of different adsorption capacities: (1) pivampicillin, cephalexin monohydrate and erythromycin ethylsuccinate, and (2) ampicillin trihydrate, amoxycillin trihydrate and cloxacillin sodium. The former have slightly higher levels of adsorption than the latter. A negative linear relationship was found between the amount of antibiotic adsorbed onto dry sorbitol and that originally added to sorbitol. When adsorption is expressed as the weight of drug adsorbed per unit weight of sorbitol, an ‘apparent’ Langmuir isotherm results. This suggests that there are a number of adsorption sites available for holding drug particles, these sites being different for the different antibiotics.
The Effect of Machine Speed on the Consolidation of Four Directly Compressible Tablet Diluents
Authors: Armstrong N Anthony , Palfrey Lynn P
Published: April 2011

The reduction in porosity of a powder bed on compression was found to be a function of the velocity of the punch of the press. Substances which consolidated principally by fragmentation showed relatively little velocity dependence. However, the more important deformation was in a powder’s consolidation mechanism, the greater the dependence on punch velocity and hence tablet press speed.
Transport characteristics of [3H]-chlorpromazine across rat small intestinal brush border membrane
Authors: Saitoh Hiroshi , Kawai Shinji , Iseki Ken , Miyazaki Katsumi , Arita Takaichi
Published: April 2011

The transport mechanism of chlorpromazine, a tertiary amine, has been investigated using brush border membrane vesicles isolated from rat small intestine. Chlorpromazine was taken up rapidly by the vesicles the uptake being mainly due to binding to the membrane. The transport of chlorpromazine into the intravesicular space was facilitated by the transmembrane electrical potential difference (inside negative) induced by valinomycin or sodium thiocyanate. This facilitating effect was observed only when the transmembrane electrical potential difference was induced after chlorpromazine uptake had reached a steady state. In the initial phase of chlorpromazine uptake, there was no effect. Therefore, it is suggested that both rapid binding to brush border membrane and transmembrane electrical potential difference (inside negative) across the membrane plays a significant role in the transport processes of chlorpromazine through the intestinal epithelium.
Phenolic analogues of diastereoisomeric 2-methyl reversed esters of pethidine
Authors: Casy A F , Dewar G H , Pascoe R A
Published: April 2011

The preparation and stereochemical characterization of α- and β-isomers of 1,2-dimethyl-4–m-hydroxyphenyl-4-propiony-loxypiperidine are described. Both the α (axial 4-aryl/chair) and β (equatorial 4-aryl/chair) isomers were of low potency or inactive in mice antinociceptive tests. Shortcomings of the α-isomer as a model for the 4-arylpiperidine moiety of morphine are discussed.
Biodegradation Rate of Embolized Protein Microspheres in Lung, Liver and Kidney of Rats
Authors: Willmott N , Chen Yan , Goldberg J , Mcardle C , Florence A T
Published: April 2011

The targeting and sustained release characteristics of cytotoxic drug-loaded protein microspheres may prove useful in the therapeutic chemoembolization of solid tumours. Because biodegradation rate of embolized particles will influence rate of incorporated drug release and duration of exposure, this parameter was studied for microspheres (10–30 μm mean diam.) prepared from the proteins albumin and casein, that we have previously used as carriers for doxorubicin. As a measure of microsphere loss in-vivo the radionuclide 125I was chosen because it can be covalently bound to proteins and also homogeneously distributed throughout the matrix. Radiolabelled microspheres were administered to rats both intravenously (lung as target organ, 1·4-2·2 mg/100 g) and via the hepatic artery (liver as target organ, 0·4-0·8 mg/100 g). In both cases it was observed that the casein system biodegraded more slowly than the albumin in-vivo. Thus, time taken for loss of 50% of embolized microspheres from lung was: albumin 2·0 days; casein 3·5 days and from liver: albumin 3·6 days; casein 6·8 days. Microsphere “debris” did not markedly accumulate in other organs. In-vitro experiments showed that microspheres were stable in serum and that albumin microspheres were not innately more sensitive to enzymic digestion than casein. The results may be useful in estimating duration of exposure of target organs to drug-loaded microsphere systems prepared from these proteins.
Study on Transport of Disopyramide into the Intestinal Lumen Aimed at Gastrointestinal Dialysis by Activated Charcoal in Rats
Authors: Arimori Kazuhiko , Nakano Masahiro
Published: April 2011

The characteristics of exsorption and/or excretion of disopyramide into the gastrointestinal lumen have been investigated after intravenous administration of the drug at doses of 10 and 30 mg kg−1 to rats by the in-situ single pass perfusion technique. Disopyramide was appreciably excreted into the bile where its levels were approximately ten-fold higher than those in the serum. The exsorption rate of disopyramide and mono-N-dealkyldisopyramide (MND) into the perfusate was increased with an increase in the serum level following an increase from 10 to 30 mg kg−1 in the dose of disopyramide. The average amounts of disopyramide exsorbed into the perfusate were 17·0 and 18·4% at the dose of 10 and 30 mg kg−1, respectively, whereas those of MND were less than 1 % at both doses of disopyramide. Oral administration of activated charcoal reduced the serum disopyramide levels after intravenous administration of the drug (20 mg kg−1) compared with the control treatment. By oral administration of activated charcoal, t 1/2 and AUC were decreased to 89 and 82%, respectively, and Cltot was increased to 122% compared with the corresponding control treatment. Vd was not different between the treated rats and control rats. These results suggest that the oral administration of activated charcoal can enhance the clearance of disopyramide and MND from the blood.
Effect of Pyridoxamine on Semicarbazide-sensitive Amine Oxidase Activity of Rabbit Lung and Heart
Authors: Buffoni F , Banchelli G , Bertocci B , Raimondi L
Published: April 2011

Rabbit lung and heart show clorgyline-resistant benzylamine oxidase activity which is sensitive to semicarbazide (SSAO) and α-amino-guanidine. This SSAO activity is inhibited by pyridoxamine with an IC50 of 6·3 × −6 M for lung and of 1·1 × 10−5 M for heart, the inhibition being non-competitive and only partially reversed by dialysis at 4°C. Semicarbazide, α-aminoguanidine and pyridoxamine show a similar time-dependent type of inhibition of rabbit lung and heart SSAO.
Protein Binding of Salicylic and Salicyluric Acid in Serum from Malnourished Children: The Influence of Albumin, Competitive Binding and Non-esterified Fatty Acids
Authors: Ashton J Michael , Bolme Per , Zerihun Getnet
Published: April 2011

The serum protein binding of salicylic and salicyluric acid has been determined by ultrafiltration in 60 children after administration of oral salicylate. The children were classified according to nutritional status: well-nourished (n = 12), underweight (n = 12), marasmic (n = 17) marasmic-kwashiorkor (n = 7) and kwashiorkor (n = 12). Salicylic acid free fractions were 0·106 ± 0·026, 0·114 ±0069, 0·141 ± 0·037, 0·285 ± 0·279 and 0·438 ± 0·190 in the five groups, respectively. Salicyluric acid free fractions were 0·184 + 0·057, 0·280 ± 0·282, 0·236 ± 0·114, 0·484 ± 0·497 and 0·646 ± 0·261, respectively. The degree of binding was dependent on serum albumin levels, ligand concentrations and non-esterified fatty acids (NEFA). The NEFA/albumin ratio ranged from 0·05 to 6·6. The fitting of a one-site Scatchard binding model to the collective data was improved when a decrease was allowed for in the number of binding sites in proportion to NEFA concentrations. Salicyluric acid binding could be fitted only when inhibition of the parent compound was included. Binding was not affected by age or sex. The major determinants of salicylate binding in sera from malnourished children have thus been identified.
Determination of microscopic dissociation constants of 3-hydroxy-α-(methylamino)methyl-benzenemethanol by a spectral deconvolution method
Authors: Quintero B , Baena E , Cabeza M C , Thomas J , Alvarez J M
Published: April 2011

Microscopic dissociation constants of 3-hydroxy-α-(methylamino)methyl-benzenemethanol have been calculated from the titration spectrophotomeric data (c = 3·8 × 10−4 M. Ionic strength = 0·16; buffer system: H3BO3/KOH) by application of a spectral deconvolution method. The results found (pKa = 9·48; pKb = 9·71; pKc = 10·12 and pKd = 9·88) are in good concordance with those obtained from the conventional regression linear method (pKa = 9·45; pKb = 9·77; pKc = 10·14 and pKd = 9·81).
Stimulation of postsynaptic D2− dopamine receptors by B-HT 958 is revealed by co-treatment with the D1− receptor agonist SKF 38393
Authors: Andén Nils-Erik , Grabowska-Andén Maria
Published: April 2011

The motor activity of reserpine-treated mice was used to study effects of B-HT958 (2-amino-6-(p-chlorobenzyl)-4H-5,6, 7, 8-tetrahydrothiazolo-[5, 4-d]-azepine) on postsynaptic dopamine and noradrenaline receptors. The motor activity was only slightly stimulated by B-HT 958 or by the D1− receptor agonist SKF 38393 but it was markedly increased by the two drugs given in combination. The effect of B-HT 958 peaked earlier following low rather than high doses. The enhanced motor activity was inhibited by the D2− receptor antagonist sulpiride or the D1− receptor antagonist SCH 23390, indicating that it was caused by stimulation of both receptor types. The results suggest that B-HT 958 stimulates postsynaptic D2− receptors in addition to D2− autoreceptors and that its blockade of postsynaptic α2-adrenoceptors is of no importance for the motor activity.
Hyperglycaemia as a factor affecting κ-opiate agonist-induced inhibition of the gastrointestinal transit in mice
Authors: Ramabadran K , Bansinath M , Turndorf H , Plug M M
Published: April 2011

The effects of highly selective κ-opiate agonists were assessed on the gastrointestinal motility in normoglycaemic and hyperglycaemic conditions in mice. Chronic hyperglycaemia was induced by streptozocin injection (200 mg kg−1 i.p.), 7–8 days before the experiment. Acute hyperglycaemia was induced by glucose injection (5 g kg−1 i.p.) at the time of opiate administration. The κ-opiate agonists, U-50488H and U-69593 (1, 3 and 10 mg kg−1) were injected (i.p.) just before the charcoal meal. The animals were killed 45 min later and the distance travelled by the test meal was measured. In the normoglycaemic mice, both κ-agonists significantly (P<0.05) inhibited the meal transit and this effect was significantly (P<0.05) augmented in acute hyperglycaemic animals. However, in chronic hyperglycaemic animals U-50488H failed to inhibit the charcoal meal transit, while U-69593 produced anti-transit effect comparable to that observed in normoglycaemic mice. These results demonstrate that κ-opiate agonists produce anti-transit effects in mice and that these effects are enhanced during acute hyperglycaemia. The disparity of anti-transit effects of κ-opiate agonists in acute vs chronic hyperglycaemia supports the hypothesis that elevated glucose levels are not the primary mechanism for the altered response to opiates observed in the experimental models of diabetes.
The Effects of Autoclaving on the Physical Properties and Biological Activity of Parenteral Heparin Preparations
Authors: Menzies A R , Benoliel D M , Edwards H E
Published: April 2011

Heparin ampoules have been autoclaved at 115°C, 121°C, 126°C and 130°C for time intervals up to 50 min and the biological potency and physicochemical integrity of the preparations assessed. The anticoagulant activity, determined with the APTT assay, did not change significantly for the autoclaved samples but a decrease was observed using the BP assay. Autoclaving was also associated with a depolymerization process, as confirmed by high performance liquid chromatography, and the formation of ‘species’ with an absorption in the UV spectrum. However, autoclaving had no detrimental effect on the integrity of the anionic sites on heparin. It is proposed that Maillard-type reactions are responsible for these observations and the results indicate that autoclaving could be used to sterilize parenteral heparin solutions.
Pharmacokinetic Modelling of the Effect of Activated Charcoal on the Intestinal Secretion of Theophylline, using the Isolated Vascularly Perfused Rat Small Intestine
Authors: de Vries Michiel H , Rademaker Carin M A , Geerlings Charles , van Duk Aalt , Noordhoek Jan
Published: April 2011

The effect of activated charcoal administration on the secretion of theophylline from the blood into the intestinal lumen has been examined by use of the rat isolated vascularly perfused small intestine. A closed two compartment model was used to analyse the vascular and luminal concentration-time curves obtained. An equation was derived to calculate the time-dependent intestinal clearance. From control experiments it was concluded that theophylline is secreted by a diffusional transport system through the intestinal wall. The intestinal clearance declined rapidly with time as a result of the concomitant increase in luminal theophylline concentration. After 120 min a steady state between the vascular and luminal perfusate was established. Administration of activated charcoal in the lumen had a profound effect on the kinetics of the drug. The vascular steady state concentration was depressed dramatically. The theophylline clearance remained nearly constant with time, because the blood to lumen concentration gradient was maximized. The maximal value for the intestinal theophylline clearance was estimated to be 0·88 mL min−1 and it equalled the value for the intestinal blood flow at the absorptive site. By use of the concept of absorptive site blood flow, the maximal effect of charcoal on systemic theophylline clearance could be adequately predicted for rats, dogs and man. Activated charcoal administration is only useful to enhance the systemic clearance of drugs or toxicants if that clearance is of the same order of magnitude as the absorptive site blood flow or lower.
Involvement of Different Receptors in the Central and Peripheral Effects of Histamine on Intestinal Motility in the Rat
Authors: Fargeas M J , Fioramonti J , Bueno L
Published: April 2011

The effects of histamine on intestinal motility have been investigated in conscious rats, fed or fasted, using an electromyographic method. Histamine peripherally administered (10 mg kg−1) in 15 h fasted rats induced an inhibition followed by a period of irregular spiking activity disrupting the duodenojejunal migrating myoelectric complexes (MMC) and suppressed the postprandial motor spiking activity when administered 50 min after a meal. The selective agonist of the H1receptors, 2-pyridylethylamine (2-PEA) induced an irregular spiking activity while dimaprit acting on H2-receptors, inhibited the MMC pattern. Effects of peripherally administered histamine were antagonized by previous administration of chlorpheniramine (0·5 mg kg−1 i.p.) and in a lesser extent by Cimetidine (10 mg kg−1 i.p.). Histamine (1–10 μg) administered intracerebroventricularly (i.c.v.) in fasted rats increased the motor cycle frequency and immediately restored the MMC pattern when given to fed rats. Among the three agonists of the H1-H2- and H3-receptors (2-PEA, dimaprit and R-α-methylhistamine, respectively) only R-α-methylhistamine (1–10 μg i.c.v.) was able to reproduce this effect. It is concluded that the effects of histamine on intestinal motility were centrally and peripherally mediated involving mainly Hi-receptors at the peripheral level and H3-receptors at the CNS level.
Effect of centrally administered prostaglandin D2 and some prostaglandin synthesis inhibitors on carrageenan-induced paw oedema in rats
Authors: Bhattacharya S K , Rao P J R Mohan , Gupta G Das
Published: April 2011

The putative modulatory role of central prostaglandins (PGs) on peripheral inflammation has been explored by investigating the effects of intracerebroventricularly (i.c.v.) administered PGD2, the major rodent brain PG, hydrocortisone, a phospholipase A2 inhibitor, and the cyclo-oxygenase inhibitors, paracetamol and mefenamic acid, on carrageenan-induced paw inflammation in rats. PGD2 produced a dose-related inflammation-augmenting effect, whereas hydrocortisone and the PG synthesis inhibitors, paracetamol and mefenamic acid, induced attenuation of the peripheral oedema. These findings confirm an earlier report from this laboratory which had indicated that central PGs may modulate peripheral inflammation and that conventional anti-inflammatory agents exert at least part of their effect by inhibiting central PG synthesis.
The effect of varying extents of Fluosol-DA or normal saline haemodilution on the dose dependent kinetics of phenytoin in the rat
Authors: Shrewsbury Robert P , Oliver Sharon R , Lewis Lee M , Anderson Wanda T , White Lisa G
Published: April 2011

Phenytoin kinetics were determined in rats in which the blood was moderately haemodiluted with 20 or 40 mL kg−1 of Fluosol-DA or normal saline. Rats received one of three intravenous phenytoin doses (10, 40, 50 mg kg−1) 0·5, 24, 48, or 72 h after haemodilution and were compared with non-exchanged controls. Haemodilution with either 20 or 40 mL kg−1 of Fluosol or saline had no influence on the dose-dependent kinetics of phenytoin. Haemodilution with 40 mL kg−1 of Fluosol decreased the half-life of phenytoin’s major metabolite, HPPH, after a 50 mg kg−1 dose. Neither Fluosol nor saline haemodilution affected the normal delay in biliary cycling of HPPH.
Solubilities of Adenosine Antagonists Determined by Radioreceptor Assay
Authors: Bruns R F , Fergus J H
Published: April 2011

The practical use of many adenosine receptor antagonists is limited by poor aqueous solubility. In some cases, solubilities are so low that they are difficult to measure by conventional means. To determine solubilities of adenosine antagonists, a sensitive radioreceptor method has been developed. Solubilities in Tris buffer (pH 7·7) ranged from 141 nM for 8−(2−amino−4−hlorophenyl)−1,3−dipropylxanthine to 945 μM for the amino-substituted xanthine PD 113,297. Ratios between solubility and adenosine receptor affinity varied from 15·8 for the A2-selective antagonist HTQZ to 169 000 for PD 113,297. From literature data on functional activity, it is apparent that useful adenosine antagonist activity in-vivo is only seen in compounds with solubility/affinity ratios greater than 100.
Pipequaline Transport from Blood to Brain and Liver: Role of Plasma Protein-bound Drug
Authors: Essassi Dalila , Urien Saik , Zini Roland , Tillement Jean-Paul
Published: April 2011

Brain uptake of pipequaline (45319 RP) has been studied in-vivo after a single capillary transit by intracarotid injection to rats. Pipequaline is extensively bound to plasma proteins: i.e. human serum albumin (HSA), α1-acid glycoprotein (AAG), lipoproteins and blood cells, mainly erythrocytes. The dialysable drug fraction as measured in-vitro by equilibrium dialysis at 37°C, was inversely related to the concentration of binding component. Similarly, the brain uptake of pipequaline was inversely related to the protein concentration of the injected solution. However, the measured brain uptake of pipequaline was higher than those predicted by in-vitro measurements of dialysable drug for all proteins and erythrocytes, except HSA. These results show that a fraction of bound pipequaline as measured in-vitro is available for transport through the blood brain barrier. HSA-bound pipequaline is an exception as it is restricted to the vascular space. Pipequaline was totally cleared by the liver through a single passage.