bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactions of aminoglutethimide with analgesics using antinociceptive tests in mice
Authors: Rao Sheila , Nicholls Paul J
Published: April 2011

The action of aminoglutethimide in alleviating bone pain in women with metastatic breast cancer may be due to either an inherent analgesic effect or an interaction with other analgesic drugs. These possibilities have been investigated in mice by conventional antinociceptive tests. In the abdominal constriction test, aminoglutethimide alone had a dose-related antinociceptive activity. A low dose (which had no pharmacological activity) when co-administered with an effective sub-maximal dose of the analgesic, potentiated the effects of the non-steroidal anti-inflammatory drugs (NSAIDs) tested. In the tail immersion test, aminoglutethimide was inactive and did not enhance the antinociceptive activity of the centrally acting analgesics. As cytochrome P450-dependent routes which are inhibited by aminoglutethimide are not involved in the metabolism of the NSAIDs studied, an interaction at the drug metabolism level cannot explain these results. The NSAID-like activity of aminoglutethimide provides some evidence that the drug's mode of action may involve more than the suppression of oestrogen biosynthesis.
An investigation of sex-linked differences to the toxic and to the pharmacological actions of difenacoum: studies in mice and rats
Authors: Winn M J , Clegg J A D , Park B K
Published: April 2011

We have investigated the actions of the coumarin anticoagulant, difenacoum, in male and female rats and mice. In our first experimnt difenacoum (0.5 mg kg−1) killed 50% of male mice within 9 days of its administration, whereas no female mice died during this study. In a second group of experiments, the anticoagulant effect of difenacoum in male and female rats was determined. Under resting conditions, the prothrombin complex activities (PCA) of male and female rats were not significantly different. Over the first 24 h after administration of difenacoum (0.4 mg kg−1 i.p.), there was a monoexponential fall in PCA in both sexes. However, 6, 12 and 24 h after difenacoum, the PCA in male rats was significantly (P <0.05) lower than in female rats. PCA began to recover over the subsequent 48 h in both sexes, during which time there was marked variability in recovery in female rats. The difference between the onset of action of difenacoum in male and female rats did not appear to be due to a greater rate of elimination of the drug in female rats, since the plasma concentrations of difenacoum 24 h after its administration were the same in both sexes. The concentration of vitamin K1 in rat liver was also investigated. Vitamin K1 levels were 35.1 ± 18.6 ng (g liver)−1 (male), and 29.4 ± 5.4 ng (g liver)−1 (females) in control rats, but 24 h after difenacoum, vitamin K1 levels were either very low, or undetectable in all rats. It is, therefore, possible that the difference between the responses to difenacoum in males and females was due to a greater rate of breakdown of vitamin K-dependent clotting factor precursors in male rats and mice, compared with female rats and mice.
Depression of oxidative metabolism of aspirin in mice via an interferon-associated mechanism in relation to Reye's syndrome
Authors: Dolphin C T , Caldwell J , Smith R L
Published: April 2011

Interferon synthesis was induced in inbred strains of mice with either polyriboinosinic-polyribocytidylic acid or Newcastle disease virus. The strains, BALB/cBy and C57BL/6By, respond to Newcastle disease virus by producing ‘low’ and ‘high’ levels of serum interferon, respectively. 24 h after interferon induction mice received [carboxyl-14C]-aspirin orally. The metabolic conjugation of aspirin was little changed after either treatment while the urinary excretion of gentisic acid, a minor product of metabolic oxidation, was significantly depressed after polyriboinosinic-polyribocytidylic acid in both strains and in C57BL/6By mice after Newcastle disease virus. The results suggest that such a metabolic impairment in aspirin metabolism would not significantly affect salicylate clearance and hence are unlikely to be directly related to the aetiology of Reye's syndrome which has been associated with both a prodromal viral infection and aspirin therapy.
Comparison of the effects of Fe2+ and Cu2+ on prostaglandin synthesis in rabbit kidney medulla slices
Authors: Fujita Tadashi , Ohtani Noboru , Aihara Midori , Nishioka Kazuyuki , Fujimoto Yohko
Published: April 2011

The effects of Fe2+ and Cu2+ on the generation of medullary prostaglandins E2 and F2α have been compared. Fe2+ markedly promoted the lipid peroxidation of rabbit kidney medulla slices. The lipid peroxidation induced by Fe2+ inhibited both prostaglandin E2 and prostaglandin F2α formation to a similar extent. While Cu2+ produced only a small increase in lipid peroxidation, it had a powerful inhibitory effect on prostaglandin E2 formation. Simultaneously, prostaglandin F2α production was increased. In the presence of Cu2+ the net increased amount of prostaglandin F2α was much smaller than the net decreased amount of prostaglandin E2 (15–20%). These results suggest that Cu2+ has the potential to modulate prostaglandins E2 and F2α synthesis by affecting endoperoxide E2 isomerase or endoperoxide reductase independent of its peroxidative action.
The relationship of the pharmacokinetics of chloroquine to dose in the rabbit
Authors: Aderounmu A Fadeke , Lindstrom Bjorn , Ekman Lena
Published: April 2011

Four albino rabbits were treated with 4 different doses of chloroquine phosphate (30–50 mg kg−1) given intragastrically and 10 others were given the hydrochloride (2.5–12.5 mg kg−1 i.v.). The i.v. doses were given as bolus into the median ear vein over 5–8 min. Samples (3–5 mL) of whole blood were subsequently collected at intervals for up to 6 weeks and analysed by HPLC. From the results, log concentration-time curves were drawn and the i.v. data fitted by computer to 3-compartment (8 rabbits) or 2-compartment curves (2 rabbits). The area under the curve (AUC) and half-lives were calculated for the different doses. A plot of AUC versus dose yielded a straight line but the half-lives showed wide inter-individual variation from the same doses.
On the mechanism of transport of salicylate and p-hydroxybenzoic acid across human red cell membranes
Authors: Joy M M , Cutler D J
Published: April 2011

The pH-dependence of efflux of salicylate and p-hydroxybenzoic acid (PHB) from human red cells indicates that the un-ionized species penetrates the membrane. No effect of the anion channel blocker 4,4′-diisothiocyano-2,2′-disulphonic stilbene was observed. The temperature-dependence of efflux suggests that the energy barrier to transport of salicylate and PHB is the transfer of the acids from water into the membrane, rather than transport through the membrane interior. Intracellular binding of both acids was found to be pH-dependent.
Anthelmintic properties of Polygonum glabrum
Authors: Muddathir A K , Balansard G , Timon-David P , Babadjamian A , Yagoub A K , Julien M J
Published: April 2011

A pure anthelmintic substance (PGA) has been isolated from the methanol-aqueous extract of the leaf of Polygonum glabrum Willd., a semi-aquatic Sudanese species of the family Polygonaceae. The antiparasitic in-vitro activity of several fractions isolated from the plant, has been examined comparatively with that of PGA. PGA also showed molluscicidal activity against Biomphalaria glabrata and Limnea truncatula Müll. Structural determination of PGA was attempted following data analysis of UV, IR, 13C NMR, 1H NMR and MS spectra and suggests that PGA is a terpenoid.
Selectivity and specificity for α1-adrenoceptor blocking activity of R(-)- and S(+)-YM-12617 orally administered to pithed, spontaneously hypertensive rats
Authors: Honda Kazuo , Momose Noriko , Nakagawa Chieko
Published: April 2011

The selectivity and specificity for α1-adrenoceptor blocking activity of the optical isomers of YM-12617 have been examined in pithed, spontaneously hypertensive rats. R(-)-YM-12617 and prazosin (1 mg kg−1 p.o.) produced 360- and 88-fold rightward shifts, respectively, of the dose-response curve of control to phenylephrine, whereas S(+)-YM-12617 (1 mg kg−1 p.o.) failed to cause a shift. Based on dose ratio, R(-)-YM-12617 was 320 times more potent as an α1-adrenoceptor antagonist than S(+)-YM-12617. This potency ratio corresponded to that formed in an in-vitro study. Both R(-)- and S(+)-YM-12617 hardly affected the UK-14304, angiotensin II, vasopressin and isoprenaline dose-response curves. These results suggest that R(-)-YM-12617 exerted selective α1-adrenoceptor blocking activity and its activity was specific for α1-adrenoceptors.
The in-vitro metabolism of [14C]pentobarbitone and [14C]phenobarbitone by hamster liver microsomes
Authors: SEAGO A , GORROD J W
Published: April 2011

The metabolism of [14C]pentobarbitone and [14C]phenobarbitone has been reinvestigated using an in-vitro hepatic microsomal system (Syrian hamsters, Aroclor 1254 induction). The incubation system was routinely supplemented with EDTA (1 mM) and a substrate concentration study revealed the metabolism of [14C]pentobarbitone to be concentration-dependent, with the greatest overall metabolism (>50%) occurring at 0.054 μmol per 3.5 mL. With [14C]phenobarbitone as substrate, overall metabolism was extremely low (3%) and independent of substrate concentration. Addition of further cofactors to the incubation mixture at 20 min intervals over an extended period resulted in almost complete metabolism of [14C]pentobarbitone (100 min), 3′-hydroxypentobarbitone and 3′-oxopentobarbitone being identified as metabolites together with many minor, unidentified products. With [14C]phenobarbitone as the substrate, cofactor addition up to 120 min resulted in 8% overall metabolism; p-hydroxyphenobarbitone was identified as a product of metabolism; other minor products were unidentified. The metabolism studies failed to produce a metabolite having the properties of the N-hydroxylated product of either [14C]pentobarbitone or [14C]phenobarbitone within the detection limits available (0.02% of 0.5 μmol per incubate).
Erythrocyte binding of cephalosporins
Authors: Derendorf Hartmut
Published: April 2011

A rapid sample preparation and HPLC technique was used to study the erythrocyte binding properties of six cephalosporins at therapeutic concentrations. The negligible red blood cell partition coefficients indicated that only small amounts of the cephalosporins were taken up by the blood cells at all drug concentrations. Thus, plasma concentrations were about twice as high as the respective blood concentrations. Blood/plasma ratios solely depended on the haematocrit and were independent of the extent of protein binding.
Inhibitory effect of phenothiazines on the binding of [3H]perazine to α1-acid glycoprotein
Authors: Schley J
Published: April 2011

A system is described which allows the determination of the afffinity constant of unlabelled drugs to α1-acid glycoprotein (α1-AGP) by displacing [3H]perazine from the binding protein with equilibrium dialysis. All drugs investigated appear to bind to only one site at the α1-AGP molecule. From experiments, in which the chemical structure of the displacers was varied, the fragment 21–31 of the amino acid sequence appears to be a candidate for hydrophobic interactions. The glutamic acids 177 and 178 of the α1-AGP molecule could be involved in ionic interactions with the side chain of phenothiazine derivatives. The relevance of α1-AGP for drug binding, distribution, and the possible reasons for insufficient correlation between psychotropic plasma concentration and therapeutic response is discussed.
Macrophage activation through phagocytosis of muramyl dipeptide encapsulated in gelatin microspheres
Authors: Tabata Yasuhiko , Ikada Yoshito
Published: April 2011

Gelatin microspheres containing muramyl dipeptide (MDP) were prepared by crosslinking with glutaraldehyde. They were added to mouse peritoneal macrophages (PMs) to potentiate the tumour growth inhibitory activity. The PMs which had internalized the microspheres exhibited growth inhibitory activity to syngeneic, allogeneic, and xenogeneic tumour cells. A similar effect was observed for PMs incubated with free MDP, but the MDP encapsulated in the microspheres was more efficient in enhancing the PM activity than the free MDP. In addition*** PMs were activated in much shorter periods upon incubation with the microsphere-encapsulated MDP. The duration of activity could be controlled for up to 7 days by changing the extent of crosslinking of microspheres. Dose-response experiments established that microsphere-encapsulated MDP is able to activate PMs to inhibit growth of tumour cells at concentrations approximately 2000 times lower than the free MDP present in media. The activity of PMs was also acquired on intraperitoneal injection of the microspheres, in contrast to PMs with the free MDP.
Probenecid-induced accumulation of 5-hydroxyindoleacetic acid and homovanillic acid in rat brain
Authors: Emanuelsson Britt-Marie , Paalzow Lennart , Sunzel Maria
Published: April 2011

The accumulation of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in rat brain has been examined after probenecid infusion over 8 h. At plasma probenecid concentrations of 200-400 μg mL−1 a steady state level in the accumulation of 5-HIAA and HVA was achieved, the increase above the endogenous levels being 135% and 65%, respectively. When the plasma concentration of probenecid rose above 400 μg mL−1 there was further accumulation of both 5-HIAA and HVA probably induced by increased neuronal activity or toxicity due to probenecid. The explanation for the plateau of 5-HIAA and HVA obtained over the plasma probenecid concentration interval of 200-400 μg mL−1 could be that the levels were reached when there was complete inhibition of active transport, and when the rate of formation of the metabolites equalled the rate of elimination by alternative routes i.e. bulk flow and diffusion. Therefore when probenecid is used to inhibit the active transport of acid monoamine metabolites across the blood-brain barrier, its plasma concentration should be within the range of 200-400 μg mL−1.
Desensitization of β-adrenoceptors following repeated injections of 2-substituted 4-phenylquinolines
Authors: Alhaider A A
Published: April 2011

The chronic effects of five 2-substituted 4-phenylquinoline derivatives on the sensitivity of the noradrenergic cyclic AMP-generating system in the rat brain cortex have been determined, and compared with those of the typical and atypical antidepressants imipramine and trazodone, respectively. Acute treatment (single i.p. dose of 20 mg kg−1) and sub-chronic treatment (20 mg kg−1 daily for 10 days) induced no significant desensitization of the β-adrenoceptors. However, chronic treatment (20 mg kg−1 daily for 3 weeks) significantly decreased the isoprenaline-induced increase in cyclic AMP, suggesting desensitization. This effect, coupled with previous findings, points to a potential role of these compounds as antidepressants.
Postsynaptic α1-adrenoceptor mechanisms in rat vas deferens and ageing
Authors: Takayanagi I , Maeda O , Koike K
Published: April 2011

Postsynaptic α1-adrenoceptor mechanisms in vasa deferentia isolated from 3, 6, 18 and 40 week-old rats were studied by analysis of the concentration-response curve of noradrenaline and the Scatchard plot of specific binding of [3H]prazosin to microsomal fractions. The maximum tension developed by noradrenaline also increased with age from 3 to 18 weeks. The efficacy of noradrenaline and capacity of the maximum binding sites of [3H)prazosin increased with increasing age, while the dissociation constants of noradrenaline (KA) and prazosin (Kd) were not changed with age. The increase of the maximum tension was proportional to the increase in efficacy. The increase of efficacy for noradrenaline in the vasa deferentia from rats of different ages is due to the increase in the total concentration of postsynaptic α1-adrenoceptors.
Comparative biodistribution of methotrexate and monoclonal antibody-methotrexate complexes in mice
Authors: Pimm M V , Caten Jane E , Clegg Jane A , Jacobs Elisabeth , Baldwin R W
Published: April 2011

The biodistribution of radiolabelled methotrexate and immune complexes of methotrexate and a murine monoclonal anti-methotrexate antibody has been compared in mice. Complexes formed in-vitro with the antibody, but not with control immunoglobulin. The complexes were, characteristically, acid labile. In-vivo, blood levels, organ distribution and whole body catabolism of methotrexate in immune complexes were similar to those of free antibody, and markedly different from those of free drug. These findings suggest the feasibility of prolonging the survival of drugs and altering in-vivo distribution using complexes with monoclonal antibodies.
The Effect of Drug-specific Active Immunization on Digoxin and Benzylpenicillin Disposition in the Bile Duct-cannulated Rat
Authors: Johnston P C , Stevenson I H , Hewick D S
Published: April 2011

Rats were immunized with a digoxin-human serum albumin conjugate i.m. This resulted in a several hundred-fold increase in plasma radioactivity and a 90% reduction in biliary drug elimination when [3H]digoxin (10 μg kg−1, i.v.) was subsequently injected into anaesthetized bile duct-cannulated rats. It was calculated that about 90% of the drug dose remained antibody-bound within the plasma compartment, with essentially no drug distributing into organs such as the heart and liver. Digoxin-specific antibody levels, determined by equilibrium dialysis, were high in the plasma but at least an order of magnitude lower in the bile. Immunization via Peyer’s patches did not increase antibody levels in the bile. Immunization (i.m.) with a benzylpenicillin-human serum albumin conjugate gave specific antibody plasma titres with values less than 10% of those obtained after immunization with a digoxin-protein conjugate. However, although subsequent injection of the hapten (40 μg kg−1, [14C]benzylpenicillin, i.v.) was associated with much lower increases and decreases in plasma and biliary radioactivity, respectively, they were still statistically significant. It appears that endogenously-formed drug-specific antibodies, when present in the blood, will inhibit drug distribution and elimination. It is unlikely that their secretion in the bile plays a significant role in mediating biliary drug hapten elimination.
Some Pharmacological Properties of the Circular Smooth Muscle Layer of the Rat Vas Deferens
Authors: Brito Alba R M Souza , Jurkiewicz Aron
Published: April 2011

Vas deferens preparations were perfused in-vitro through the lumen and externally with a modified Tyrode solution alone or containing drugs. Contractions of the circular (internal) smooth muscle layer were recorded as changes in the pressure of internal perfusion. Contractions of the longitudinal (external) layer were simultaneously recorded through a tension transducer. When the organ was perfused through the lumen, the circular layer contracted after addition of methacholine (pD2 = 413), and noradrenaline (pD2 = 5.00), and relaxed after addition of isoprenaline (pD2 = 5.22). These effects were also observed when the drugs were perfused externally, although with lower values of pD2 for noradrenaline and methacholine. The circular fibres were less sensitive when compared with the longitudinal fibres perfused externally with the above agonists. Methacholine-induced contractions of the circular layer were competitively antagonized by atropine (pA2 = 8.53), indicating the presence of muscarinic receptors. The effects induced by noradrenaline and isoprenaline were antagonized by indoramin (pA2 = 7.78), and timolol (pA2 = 8.68), respectively, indicating the presence of α- and β-adrenoceptors. The effect of noradrenaline was potentiated by cocaine and denervation, indicating the presence of neuronal uptake, and by corticosterone, indicating the presence of extraneuronal uptake in the circular layer.
Selectivity of Neutrophil 5-Lipoxygenase and Cyclo-oxygenase Inhibition by an Anti-inflammatory Flavonoid Glycoside and Related Aglycone Flavonoids
Authors: Moroney M-A , Alcaraz M J , Forder R A , Carey F , Hoult J R S
Published: April 2011

A newly described plant-derived flavonoid, hypolaetin-8-glucoside, which has anti-inflammatory and gastroprotective actions in-vivo, and its corresponding aglycone, hypolaetin, have been compared with 14 other flavonoids for inhibition of eicosanoid generation via the 5-lipoxygenase and cyclo-oxygenase pathways in elicited rat peritoneal leukocytes stimulated with calcium ionophore. Comparable results for the inhibitory profiles of the compounds were obtained using either radioimmunoassay of released eicosanoids or radio-TLC of metabolites formed from labelled arachidonate, but there were differences in absolute potency of the inhibitors. Hypolaetin-8-glucoside was a weak but selective inhibitor of 5-lipoxygenase (IC50 56 μM vs 5-lipoxygenase; > 1000 μM vs cyclo-oxygenase), whereas the aglycone hypolaetin was a more potent and selective 5-lipoxygenase inhibitor (IC50 4.5 μM vs 70 μM). Results with three other glycoside/aglycone pairs confirmed that addition of sugar residues greatly reduces inhibitory potency whilst retaining selectivity against 5-lipoxygenase. Analysis of 12 aglycone flavonoids showed that inhibitory potency and selectivity against 5-lipoxygenase is conferred by the presence of 3′4′-vicinal diol (catechol) in ring B as part of a 3,4-dihydroxycinnamoyl structure as proposed by others and by incorporation of additional hydroxyl substituents. In contrast, “cross-over” of inhibitory selectivity is observed in compounds containing few hydroxyl substituents (with none in ring B) which are selective against cyclo-oxygenase. These results are discussed in relation to possible mechanisms of hypolaetin-8-glucoside’s protective actions and the concept that these inhibitory effects of flavonoids cannot be ascribed to a unitary free radical scavenging action.
Effects of indomethacin and diclofenac on some functions of polymorphonuclear neutrophils
Authors: Berradia N , Marchand-Arvier M , Humbert J C , Vigneron C
Published: April 2011

The effects in-vitro of two non-steroidal anti-inflammatory drugs, diclofenac and indomethacin, have been studied on human polymorphonuclear functions. Adhesivity and chemotaxis were decreased by the two drugs, but in a manner that varied with the attractant used. As shown by the nitro blue tetrazolium slide test, all cells remained active but the production of oxygen metabolites by opsonized zymosan was decreased in the presence of diclofenac.
4-Methylpyrazole alters phenobarbitone hypnotic concentrations in rats
Authors: Ramzan Iqbal
Published: April 2011

The liver alcohol dehydrogenase inhibitor, 4-methylpyrazole, has been tested for its ability to change the hypnotic concentrations of phenobarbitone (phenobarbital) in rats. Following a single dose of 1 mmol kg−1 i.v., administered 60 min before phenobarbitone, 4-methylpyrazole shortened the onset time and reduced the dose of phenobarbitone required to produce loss of righting reflex. Consistent with this, phenobarbitone concentrations in serum (both total and free), brain and in cerebrospinal fluid at onset of hypnosis were about half in 4-methylpyrazole compared with saline-treated rats. These results suggest that acute 4-methylpyrazole pretreatment increases the central nervous system sensitivity to phenobarbitone and presumably other barbiturates; an effect apparently distinct from its inhibition of liver alcohol dehydrogenase.
Characterization of Sodium Carboxymethylcellulose-Gelatin Complex Coacervation by Viscosity, Turbidity and Coacervate Wet Weight and Volume Measurements
Authors: Koh Geok-Lay , Tucker Ian G
Published: April 2011

A sodium carboxymethylcellulose (SCMC) and gelatin coacervation system has been evaluated and characterized and the effects of pH and colloid mixing ratio on the coacervation process investigated. The colloid mixing ratio at which optimum coacervation occurred varied with the coacervation pH. A viscometric investigation of various isohydric SCMC-gelatin mixtures was used to predict optimum conditions for complex coacervation. Optimum coacervation occurred at pH 3.5 at a SCMC-gelatin weight ratio of 3:7 for the SCMC complex coacervation system. Turbidity data confirmed these viscometric results. Coacervate wet weight and volume measurements could not be used to predict optimal coacervation conditions due to changes in the coacervate morphology with mixing ratio. At pH values where coacervation did not occur, the viscosity showed unexpected positive deviations from additive behaviour.
Mechanisms of the Antiallergic Action of N-Methylmequitazine (LG 30435)
Authors: Subissi Alessandro , Del Monte Marco
Published: April 2011

LG 30435 (N-methylmequitazine) was assayed in passive lung (PLA) and cutaneous (PCA) anaphylaxis in guinea-pigs and rats. At doses from 0.3 to 3 μmol kg−1 i.v., it produced a dose-dependent inhibition of guinea-pig PLA and of rat PCA and PLA, while the parent compound was ineffective or poorly effective up to 3 μmol kg−1. An attempt was made to elucidate the mechanism of LG 30435′s action in these anaphylactic models, by means of various antagonists. It was tentatively concluded that different mechanisms are involved in the protective action of LG 30435 in each of the three models: histamine antagonism, possibly accompanied by an inhibition of the effects of peptido-leukotrienes in guinea-pig PLA; histamine antagonism in rat PCA and 5-hydroxytryptamine antagonism in rat PLA, possibly accompanied by a mast-cell stabilizing action in both cases. LG 30435 is devoid of smooth muscle relaxant effects on the airways and its demonstrated anticholinergic and anti-PAF effects do not appear to be involved in its antiallergic action.
The effects of interacting variables on the tensile strength, disintegration and dissolution of paracetamol tablets
Authors: Zubair S , Esezobo S , Pilpel N
Published: April 2011

A factorially designed scheme has been used to analyse the separate and combined effects of packing fraction (P), nature of binder (N) and concentration of binder (C) on the tensile strength, disintegration and dissolution (t50%) times of paracetamol tablets. In general, P has the greatest effect on tensile strength, disintegration and dissolution times followed by C then N. For the variables in combination, the ranking of the effects on tensile strength, for the PVP/gelatin formulations, are P × N > N × C > P × C and for the PVP/tapioca formulations are P × C = N × C > P × N. For disintegration and for dissolution, the ranking for the PVP/gelatin formulations are P × C > P × N = N × C and P × N > P × C > N × C, respectively, and for the PVP/tapioca formulations are P × N > N × C = P × C. The results also show that tapioca acts as a binding agent when included in paracetamol tablet formulations, but it is a weaker binder than either PVP or gelatin. It is thus required in a higher concentration to produce tablets of comparable physical properties with those formulated with PVP or gelatin.
Investigation into substrate cracking of a film-coated bilayered tablet
Authors: Breech Joseph A , Lucisano Leo J , Franz Robert M
Published: April 2011

Substrate cracking occurred during film coating of a bilayered tablet. The cause was traced to differences in the expansion characteristics of the two layers upon exposure to heat. Thermal mechanical analysis was used to determine the coefficients of thermal expansion of the respective layers.
Oral absorption of metronidazole in rabbits irradiated with cobalt-60 gamma radiation
Authors: Bhatt Padmanabh P , Nimbkar Anil Y
Published: April 2011

The absorption of oral metronidazole in control rabbits and in rabbits irradiated with cobalt-60 gamma radiation was studied. It was observed that the bioavailability of metronidazole was significantly reduced in irradiated animals the reduction being dependent on the dose of radiation. The maximum decrease in absorption was seen 48 h post-irradiation.
Zacopride, a potent 5-HT3 antagonist
Authors: Smith W W , Sancilio L F , Owera-Atepo J B , Naylor R J , Lambert L
Published: April 2011

The substituted benzamide derivative zacopride was found to antagonize competitively the effects of 5-hydroxytryptamine (5-HT) on the guinea-pig ileum, the rabbit vagus nerve and the von Bezold Jarisch reflex in the rat. The potency of zacopride was comparable with that of ICS 205–930 and it is concluded that zacopride possesses 5-HT3 receptor antagonizing properties.
Prolonged apparent half-life of Δ1-tetrahydrocannabinol in plasma of chronic marijuana users
Authors: Johansson Eva , Agurell Stig , Hollister Leo E , Halldin Magnus M
Published: April 2011

The aim of this study was to characterize the elimination half-life of Δ1-tetrahydrocannabinol in blood plasma in chronic marijuana users. The subjects smoked four cigarettes during a two day period, each cigarette containing 15 mg deuterium-labelled Δ1-tetrahydrocannabinol. The plasma concentrations of deuterium-labelled tetrahydrocannabinol were measured for 13 days using gas chromatography-mass spectrometry equipped with selected ion monitoring. The elimination half-life for Δ1-tetrahydrocannabinol in blood plasma was calculated to be 4.1 ± 1.1 days (range 2.9–5.0 days) from the two week plasma level curves. Albeit the present results are based upon a small sample, an elimination half-life of Δ1-tetrahydrocannabinol in blood plasma of about 4 days is more in line with apparent half-life excretion of Δ1-tetrahydrocannabinol metabolites in the urine of chronic marijuana smokers.
Buffer and pH Effects on Propranolol Binding by Human Albumin and α1-Acid Glycoprotein
Authors: Ravis W R , Parsons D L , Wang S J
Published: April 2011

Propranolol binding to isolated human α-1-acid glycoprotein (AGP) and human albumin (HSA) was studied by equilibrium dialysis at 37°C. With AGP (0.067%) and HSA (4%), total propranolol concentration was varied from 0.7 to 93 000 ng mL−1. Over this concentration range the percentage drug bound to HSA declined from 49 to 39% while that to AGP declined from 68 to 4%. Two classes of sites were identified on AGP with n1k1 = 8.50 × 104 M−1 and n2k2 = 3.12 × 104 M−1. With a pH 7.4 phosphate buffer, propranolol binding to AGP was greatest when the protein was initially dissolved in pH 7.4 water compared with pH 7.2 water or the phosphate buffer. Thus, the method of AGP solution preparation affected propranolol binding by this protein. For both AGP and HSA, greater drug binding was noted with phosphate buffers in comparison with a physiological buffer. With phosphate buffers, decreasing pH from 7.4 to 7.0 decreased propranolol binding by AGP, while decreasing pH from 7.7 to 7.4 had little effect. With HSA, the percent propranolol bound consistently decreased on lowering pH from 7.7 to 7.0.
The Effects of Salicylate Concentration on the Uptake of Salicylate and Cefmetazole into Rat Isolated Small Intestinal Epithelial Cells
Authors: Suzuka Takumi , Yata Noboru , Sakai Kiyoshi , Nishihata Toshiaki
Published: April 2011

The uptake of salicylate into rat isolated small intestinal epithelial cells reached an equilibrium within 15 min, but that of cefmetazole alone did not. The presence of salicylate at concentrations greater than 50 mM accelerated the uptake of cefmetazole, which reached equilibrium within 5 min. At equilibrium, the uptake clearance of salicylate (μmol (g protein)−1 M−1 initial salicylate concn) was greater than that of cefmetazole. The uptake clearance of salicylate during the first several minutes was concentration-dependent, and a ‘super-uptake’ clearance of salicylate, greater than equilibrium values, was observed when 100 mM salicylate was present. This indicates that some mechanism, other than a simple diffusion process, may be involved in salicylate uptake into these cells.
Sustained anti-adherence activity of taurolidine (Taurolin) and noxythiolin (Noxyflex S) solutions
Authors: Blenkharn J Ian
Published: April 2011

Taurolidine (2% w/v) and noxythiolin (1% w/v and 2.5% w/v) solutions inhibit the adherence in-vitro of Escherichia coli and Staphylococcus aureus to human epithelial and fibroblast cells. This effect, demonstrable after 30 min exposure of cells to test drugs, persists after removal of the active compound. Significantly reduced adherence of bacteria is apparent for 5 h after taurolidine treatment and for 6 h after treatment with 2.5% noxythiolin. Anti-adherence activity of taurolidine and noxythiolin may contribute to the observed clinical efficacy of these agents.
Verapamil and nifedipine effects on gastric acid secretion and ulcer formation in rats
Authors: Glavin Gary B
Published: April 2011

The calcium channel antagonists verapamil and nifedipine were examined for their effects on conscious basal gastric acid output, stress ulcer formation and on ethanol-induced ulcers. Both compounds significantly reduced gastric acid secretion, however verapamil did so in a dose-related manner. Both verapamil and nifedipine significantly attenuated stress gastric ulcer formation. Nifedipine, at a dose of 32.0 mg kg−1, virtually abolished stress ulcers. Verapamil exacerbated, while nifedipine, at 32.0 mg kg−1, attenuated ethanol-induced gastric ulcers. The differential gastrointestinal effects of these calcium channel antagonists support the existence of multiple classes of calcium channels in the gut and suggest an important role for intracellular calcium and hence, its blockade, in gastric pathophysiology.
Brain monoamines during carrageenan-induced acute paw inflammation in rats
Authors: Bhattacharya S K , Das Neeta , Rao P J R Mohan
Published: April 2011

Paw inflammation was induced in rats by sub-plantar administration of carrageenan. Significant inflammatory oedema was observed 1 h later and the peak effect was noted between 3–4 h. The oedema was markedly reduced after 12–24 h. Steady state levels of whole brain and hypothalamic monoamines were estimated spectrofluorometrically during the course of the carrageenan-induced paw inflammation. In addition, the rate of accumulation of the brain 5-hydroxytryptamine (5-HT) and noradrenaline (NA) was assessed in clorgyline-pretreated rats during the inflammation. The whole brain and hypothalamic concentrations of 5-HT and NA were augmented during the early phase of the inflammation, but fell below control values when peak inflammation was achieved. Thereafter, the monoamine levels tended to normalize by 24 h when the inflammation had virtually subsided. On the contrary, whole brain and hypothalamic dopamine levels remained largely unaffected. The rate of accumulation of brain 5-HT and NA were enhanced during carrageenan inflammation, indicating that the turnover of these monoamines is augmented during the inflammatory process. The results suggest that acute peripheral inflammation may significantly affect central 5-HT and noradrenergic activity in rats.
Dopamine-mediated behaviour following chronic treatment with B-HT 920
Authors: Darmani N A , Sewell R D E , Nicholls P J
Published: April 2011

Following subchronic (5-day) dosing with B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo(4,5-d)azepine (1 mg kg−1 day−1 i.p.) in rats there was a significant increase in both apomorphine-induced motor activity and stereotypy. On continued B-HT 920 treatment, however, the enhancement of apomorphine motor activity faded into insignificance but the increase in stereotypy persisted beyond 15 days. The results are discussed in terms of dopamine autoreceptor tolerance, postsynaptic D2 supersensitivity and possible differential effects in different brain loci on the above two receptor sub-classes.
Theophylline Metabolism by Human, Rabbit and Rat Liver Microsomes and by Purified Forms of Cytochrome P450
Authors: McManus M E , Miners J O , Gregor D , Stupans I , Birkett D J
Published: April 2011

The capacity of human, rabbit and rat liver microsomes and purified isozymes of cytochrome P450 to metabolize theophylline has been assessed. In all three species the 8-hydroxylation of theophylline to 1,3-dimethyluric acid (1,3-DMU) was the major pathway. In human, control rabbit and rat liver microsomes this metabolite accounted for 59, 77 and 94%, respectively, of the total metabolites formed. In both human and control rabbit liver microsomes the N-demethylation of theophylline to 1-methylxanthine (1-MX) accounted for 20% of the total metabolites formed. N-demethylation of theophylline to 3-methylxanthine (3-MX) accounted for 21% of theophylline metabolism in human microsomes but was a minor pathway in control rabbit and rat microsomes. Acetone and phenobarbitone pretreatment markedly increased the formation of 1,3-DMU by rabbit liver microsomes. Rifampicin and 2,3,7,8-tetrachlorodi-benzo-p-dioxin (TCDD) administration caused a slight but significant increase in this pathway. In general the N-demethylation pathways in rabbit liver microsomes were refractory to induction. In the rat, the metabolism of theophylline to 1-MX, 3-MX and 1,3-DMU were all significantly increased in Aroclor 1254, dexamethasone, phenobarbitone and 3-methylcholanthrene-treated microsomes. In reconstitution experiments the polycyclic hydrocarbon inducible rabbit cytochrome P450 Forms 4 and 6 and the constitutive Form 3b all metabolized theophylline to its three metabolites. In human liver microsomes from four subjects anti-rabbit cytochrome P450 Form 4 IgG inhibited the metabolism of theophylline to 1-MX, 3-MX and 1,3-DMU by approximately 30%. These data indicate that theophylline is metabolized by multiple forms of cytochrome P450 in human, rabbit and rat liver microsomes.
The Effect of Varying Percentages of Haemodilution with Fluosol-DA or Normal Saline on Antipyrine Metabolism in the Rat
Authors: Shrewsbury Robert P , Oliver Sharon R , Anderson Wanda T , Lewis Lee M , White Lisa G
Published: April 2011

Antipyrine disposition and metabolism in conscious, unrestrained rats after 25 or 50% haemodilution with Fluosol or normal (0.9% NaCl) saline is reported. Rats received an intravenous antipyrine dose (20 mg kg−1) 0.5, 24, 48, or 72 h after haemodilution and its pharmacokinetic parameters have been compared with non-exchanged control animals. Haemodilution 25% with Fluosol initially depressed antipyrine metabolism for 24 h by decreasing the antipyrine urinary excretion rate constant and the formation rate constants of 4-hydroxyantipyrine (4-OH) and 3-hydroxymethylantipyrine (3-OHME). Metabolism was then increased for 48 and 72 h with a slight increase in all rate constants. Haemodilution 50% with Fluosol produced a similar pattern but with significant increases in the 3-OHME formation rate constant found at 48 and 72 h. Haemodilution 25% with saline reduced 4-OH formation for 48 h. Haemodilution 50% with saline significantly reduced antipyrine urinary excretion at all times. After a significant increase in the 4-OH and 3-OHME formation rate constants at 24 h following 50% haemodilution with saline, the rate constants were significantly decreased at 48 and 72 h. Haemodilution 25% with Fluosol significantly reduced the antipyrine Vd at 0.5 and 72 h. After haemodilution 50% with Fluosol, the Vd alternated between values greater and less than control throughout the 72 h. Haemodilution 25 or 50% with saline had little influence on Vd.
The role of adrenoceptors in the mechanism of reserpine-induced stimulation of gastric acid secretion in the rat
Authors: Salim Aws S
Published: April 2011

The role of α- and β-adrenoceptors in the mechanism of reserpine-induced stimulation of gastric acid secretion in the rat has been examined. After 6 h reserpine (0.1 mg kg−1 i.p.) significantly stimulated acid secretion relative to control values (176 ± 4 vs 60 ± 3 μmol, mean ± s.e.m., n = 10, P < 0.001). Neither coeliac ganglionectomy nor propranolol (5–15 mg kg−1) influenced this action. Vagotomy prevented acid stimulation by reserpine and was associated with H+ output similar to that of vagotomy controls (13 ± 1 vs 14 ± 1 μmol, mean ± s.e.m., n = 10). Dose-dependent inhibition of the reserpine-induced acid secretion was produced by phenoxybenzamine or phentolamine; an inhibition similar to that achieved by vagotomy was noted with the 15 mg kg−1 dose (13 ± 1 and 15 ± 1 μmol, respectively, vs 176 ± 4 μmol, mean ± s.e.m., n = 10, P < 0.001). The similarity in action between vagotomy and large doses of phenoxybenzamine or phentolamine suggests that, in the rat, vagal α-adrenoceptor stimulation is directly involved in the mechanism of reserpine-induced stimulation of gastric acid secretion.
Thermal Studies on the Interaction of Water and Microcrystalline Cellulose
Authors: Fielden K E , Newton J M , O'Brien P , Rowe R C
Published: April 2011

The interaction between water and microcrystalline cellulose in the absence and presence of lactose has been studied by thermogravimetric analysis, differential thermal analysis and immersional calorimetry. The results indicate that most of the water held within a system used for the preparation of spherical granules by extrusion/spheronization is present as free water which may be readily lost by evaporation. There is approximately 0.856 mol of water per 100 g of microcrystalline cellulose which appears to be absorbed as structured water. Microcrystalline cellulose may therefore be described as a ‘molecular sponge’. The enthalpy of fusion of the ‘free’ water offers a simple method of estimating the effective surface area of the microcrystalline cellulose.
A Method to study the Kinetics of Oral Mucosal Drug Absorption from Solutions
Authors: Tucker Ian G
Published: April 2011

A method has been developed which allows the kinetics of oral mucosal drug absorption from solutions to be studied in a single 15–20 min test. This is an improvement over the traditional buccal absorption test which requires a separate experiment for each time point, thus taking days for each kinetic profile. It should also allow for disappearance of drug from the mouth and appearance in the plasma to be monitored simultaneously. The drug solution includes 8 μg mL−1 phenol red as a marker for salivary secretion. Samples are withdrawn at suitable times with a positive displacement pipettor and analysed for drug and phenol red. Salivary volume time data are described by least squares polynomials. Kinetic parameters are estimated by non-linear least squares regression. The method, which requires that phenol red is not lost during a test, provides an internal test for this. It also requires that phenol red and the drug do not interfere with each other’s assay, that saliva does not affect the assays of these materials, and that phenol red does not interfere with the absorption of the drug.
Evidence that the kappa agonist U50488H has non-opioid actions
Authors: Hayes A G , Birch P P , Cavicchini E
Published: April 2011

The antagonism of the antinociceptive effects of various κ-opioid agonists has been studied in the mouse abdominal constriction test. Naloxone produced a much smaller degree of antagonism of U50488H than it did of two other κ-agonists, U69593 and tifluadom. The κ-selective antagonist, norbinaltorphimine, also failed to shift the dose-response curve to U50488H in this test, despite producing considerable antagonism of the U50488H effect in the rotarod test and of U69593 in both experimental situations. These results are suggestive of a non-opioid component to the action of U50488H in the abdominal constriction test. At high concentrations, U50488H, but not U69593, also showed non-opioid effects in reducing contractile activity in the field-stimulated isolated guinea-pig ileum, as demonstrated by the profile of antagonism seen with β-chlornaltrexamine and naloxone. These results suggest that U69593, rather than U50488H, may be the κ-agonist of choice to use, particularly in in-vivo experiments.
Increased vasodilator response to acetylcholine of renal blood vessels from diabetic rats
Authors: Bhardwaj R , Moore P K
Published: April 2011

The vasodilator effect of acetylcholine (ACh) and nitro-prusside and the vasoconstrictor effect of noradrenaline was assessed in the perfused kidney of streptozocin diabetic rats. Compared with control animals injected with acidified saline, the renal vasoconstrictor effect of noradrenaline was increased in diabetic rats both in terms of the dose required to produce 50% of the maximal effect (EC50) and in the maximal response achieved. The renal vasodilator effect of ACh (but not nitroprusside) was similarly enhanced in diabetic animals. The effect of ACh (but not nitroprusside) in the perfused kidney of both control and diabetic rats was reduced or abolished by mepacrine (10 μM), metyrapone (10 μM) or methylene blue (100 μM) suggesting that ACh exhibits vasodilator activity in the rat kidney by virtue of releasing endothelium derived relaxing factor (EDRF). These results are in contrast to previous published reports demonstrating reduced biosynthesis of EDRF in the aorta of diabetic rats. The mechanism which underlies the increased renal vascular response to ACh is not known. However, increased endothelial cell turnover or cholinoceptor number, elevated activity of enzyme(s) which synthesise EDRF or hyperresponsiveness of vascular smooth muscle to released EDRF should all be considered.
The Interaction of Papain with Polycations
Authors: Mekras C I , Lawton J B , Washington R J
Published: April 2011

An investigation has been made of the interactions of the enzyme papain with the polycations protamine, polybrene, poly(L-lysine), spermine, spermidine and the neutral polymer polyvinylpyrrolidone (PVP). At low concentrations, each behaves as an inhibitor of the enzyme. As their concentrations increased above a certain level, the activity of the systems increased, and their inhibition of the enzyme appeared to be less pronounced. When acting by themselves in the presence of the substrate haemoglobin, each of the polycations was a weak proteolytic catalyst with a ranking of catalytic effectiveness of protamine > polybrene > poly(L-lysine) > polyvinyl-pyrrolidone > spermidine > spermine. This effect could explain the anomalous inhibition of papain by these polycations. The interaction of papain with dansyl protamine (DNSP) and the extent of complex formation were studied using a fluorescence polarization technique and the results showed that there was a strong interaction occurred. The strength of binding was assessed by determination of the critical electrolyte concentration (0·2 M, NaNO3). The stoichiometry of the DNSP-papain complex was found to be 63 base moles of DNSP to one mole of papain.
Comparative Studies of the Effects of RS-8359 and Safrazine on Monoamine Oxidase In-vitro and In-vivo in Mouse Brain
Authors: Yokoyama Tomihisa , Karube Toshio , Iwata Nobuyoshi
Published: April 2011

The effect of RS-8359, (±)-4-(4-cyanophenyl)amino-6,7-dihydro-7-hydroxy-5H-cyclopenta[d]-pyrimidine on monoamine oxidase (MAO) has been compared with a hydrazinic MAO inhibitor, safrazine (β-piperonylisopropylhydrazine hydrochloride,) which is a MAO inhibitor used clinically. In-vitro radiochemical determination of MAO activity showed that the IC50 of RS-8359 was 0·52 μM for the deamination of 5-hydroxytryptamine (5-HT) in the mouse brain mitochondrial preparation, while β-phenylethylamine (PEA) deamination was inhibited by only 20% at 100 μM of the drug. 5-HT deamination in the brain homogenate prepared from mice killed 60 min after administration of RS-8359 was inhibited significantly by 14 and 48%, at 30 and 100 mg kg−1 (p.o.), respectively, while deamination of PEA was little affected at the same doses. On the other hand, safrazine strongly inhibited both 5-HT and PEA deaminations, but showed no selectivity toward the substrate used. The extent of MAO inhibition by RS-8359, measured fluorometrically with kynuramine as a substrate in the brain homogenate, was independent of preincubation up to 80 min. In contrast, the inhibitory potency of safrazine was strengthened by preincubation in a time-dependent manner. Oral administration of RS-8359 (3-30 mg kg−1) caused a dose-dependent increase in endogenous monoamines in mouse brain, which disappeared a few hours after its administration. Increase in monoamine content caused by safrazine lasted for at least 24 h. These results indicate that RS-8359 is a reversible and specific inhibitor of MAO-A, while safrazine is an irreversible and non-specific MAO inhibitor, in-vivo and in-vitro in mouse brain.