bluuebunny/crossref_metadata_2025 huggingface dataset:
Potent lipophilic substituted benzamide drugs are not selective D-1 dopamine receptor antagonists in the rat
Authors: Fleminger S , van de Waterbeemd H , Rupniak N M J , Reavill C , Testa B , Jenner P , Marsden C D
Published: April 2011

The substituted benzamide drugs YM 09151-2 and clebopride potently inhibited apomorphine-induced stereotyped behaviour in the rat and caused displacement of the specific binding of [3H]spiperone to D-2 binding sites on striatal membranes in low nanomolar concentrations. Other substituted benzamide drugs including metoclopramide, sultopride and flubepride also inhibited stereotyped behaviour to a greater or lesser degree, but were less potent in displacing [3H]spiperone from D-2 sites. YM 09151-2 and clebopride only weakly displaced specific binding of [3H]piflutixol to D-1 sites on rat striatal membranes, and only weakly inhibited striatal dopamine stimulated adenylate cyclase activity, when compared with cis-flupenthixol. The other substituted benzamide drugs did not displace [3H]piflutixol or inhibit dopamine stimulation of adenylate cyclase activity in the concentration range used. Clebopride and YM 09151-2 were highly lipophilic with apparent partition coefficient (log P') values equivalent to those of classical neuroleptic compounds, such as cis-flupenthixol. In contrast, the other substituted benzamide drugs were markedly less lipophilic. A log P' value of approximately 2 was required before inhibition of adenylate cyclase activity or displacement of [3H]piflutixol binding occurred. However, in excess of this value there was no correlation between either inhibition of adenylate cyclase activity or displacement of [3H]piflutixol binding and the lipophilicity of the various compounds. We conclude that potent lipophilic substituted benzamide drugs, like other members of the substituted benzamide series, are selective D-2 receptor antagonists. Inherent steric factors within the drug series would appear to dictate activity at D-1 and D-2 sites, although lipophilicity may contribute to actions in these environments.
[3H]Noradrenaline release evoked by selegiline ((-)-deprenyl) in the isolated main pulmonary artery of the rabbit*
Authors: Török Tamás L , Bunyevácz Zsuzsanna , Nguyen Tinh Thi , Magyar Kálmán
Published: April 2011

High concentrations of selegiline((-)-deprenyl) (> 10−5  m) enhanced the nerve stimulation (2 Hz)-evoked release of [3H]noradrenaline from the isolated main pulmonary artery of the rabbit. This facilitation of stimulation-evoked [3H]noradrenaline release by selegiline was reduced by exogenous (-)-noradrenaline, an agonist of presynaptic α2-adrenoceptors. This inhibitory action of (-)-noradrenaline was partly antagonized by yohimbine, a selective α2-adrenoceptor blocker. When the stimulation-evoked [3H]noradrenaline release had already been incresed by inhibition of Na+-pump (K+-free solution), selegiline further enhanced the nerve-evoked release of labelled neurotransmitter.
Rifampicin induction of myopathy: lack of a direct effect on rat neuromuscular system
Authors: Renna G , Siro-Brigiani G , Conte-Camerino D
Published: April 2011

The effect of acute administration of rifampicin on neuromuscular transmission was tested, in-vivo, in the rat. Rifampicin did not alter the strength of contraction of the muscle indirectly stimulated at various frequencies. Additional isoniazid pretreatment did not alter the absence of effect of rifampicin on neuromuscular action.
Indirect adrenergic effect of histamine in human cerebral arteries: Influence of post-mortem period
Authors: Marco Emilio J , Balfagón Gloria , Conde María Victoria
Published: April 2011

Histamine (10−4 m) increased the radioactivity released from human cerebral arteries obtained within 6 h of death and preincubated with [3H]noradrenaline. In the presence of 10−6 m cocaine or if 7 or more hours had elapsed since death, 10−4 m histamine was unable to change basal levels of tritium outflow. The radioactivity retained by the tissue was higher when cerebral blood vessels were obtained within a post-mortem period of 6 h. These results suggest that histamine may release noradrenaline from the sympathetic innervation of human cerebral arteries and that the function of this innervation lasts only 6 h after death.
Analysis of the role of withdrawal state in morphine−induced supersensitivity to acetylcholine in mouse ileum
Authors: Ramaswamy S , Pillai N Padmanabha
Published: April 2011

An attempt has been made to study the possible role played by the withdrawal state in morphine−induced supersensitivity to acetylcholine in mouse isolated ileum. Chronic morphine treatment for 5 days produced a significant supersensitivity to acetylcholine in the ileum. This supersensitivity was not altered significantly by the addition of morphine to the bathing medium–−a measure to avoid the precipitation of the withdrawal state. This indicates that the supersensitivity obtained does not represent the state of withdrawal and is the result of chronic morphine treatment.
Encapsulated hydrophilic polymer beads containing indomethacin as controlled release drug delivery systems
Authors: Suryakusuma H , Jun H W
Published: April 2011

Encapsulated hydrophilic polymer beads containing indomethacin were prepared by a combined technique of bead polymerization and phase separation. The drug delivery system consisted of the copolymer of 2-hydroxyethyl methacrylate and acrylamide as the core matrix and ethyl cellulose as the barrier membrane. The drug was incorporated into the polymer matrix during the formation of the beads. The system was found to be useful as a sustained release dosage form. Release of drug from the coated beads followed a zero-order rate up to 40% of the drug released. A linear relationship exists between the rate of release and the reciprocal amount of ethyl cellulose used for coating, indicating that the drug release was controlled by the coating thickness. Addition of polyvinyl pyrrolidone in the formulation significantly increased the amount of drug released. Blood level studies showed that drug absorption from the encapsulated beads was slower than that of indomethacin powder. It appeared that indomethacin was completely absorbed from the encapsulated beads.
k-Opioid diuretic effects of tifluadom, a benzodiazepine opioid agonist
Authors: Leander J David
Published: April 2011

Tifluadom produced a dose-related (0·08–5 mg kg−1) diuresis in normally hydrated rats. This diuretic effect was antagonized by k-antagonist doses of naloxone and blocked by morphine administration. This is further in-vivo evidence that tifluadom is a fairly specific k-opioid agonist.
Light scattering studies on micelle formation by some penicillins in aqueous solution
Authors: Attwood D , Agarwal S P
Published: April 2011

The aggregation of a number of penicillins, both in water and in electrolyte solution, has been examined by total intensity light scattering methods. Micellar association was noted for carfecillin, flucloxacillin cloxacillin, phenethicillin and penicillin V and critical micelle concentrations and micellar aggregation numbers were determined. Association of penicillin G in water and electrolyte was limited to dimer and trimer formation.
Quantification of uptake of liposomal carboxyfluorescein by professional phagocytes in-vitro. A flow microfluorimetric study on the J774 murine macrophage cell line
Authors: Stevenson M , Baillie A J , Richards R M E
Published: April 2011

Unilamellar egg phosphatidylcholine/cholesterol liposomes containing carboxyfluorescein were prepared by an ether injection method. The ability of cells of the J774.2 murine macrophage cell line to incorporate the liposomal fluorophore during incubation at 37 °C was measured by flow microfluorimetry. Liposomes incorporating additional phosphatidyl-serine or phosphatidic acid were taken up much more avidly than those lacking these phospholipids and the greatest uptake of carboxyfluorescein was observed with the phosphatidylserine species. Calculation of the number of liposomes taken up, >0–2% of the number given, showed that this was an inefficient process. However these uptake data support previous findings based on the intracellular bactericidal activity of liposomal antibiotics determined in an identical in-vitro system.
Application of orthogonal functions to spectrophotometric analysis of the preservatives benzylalcohol, phenol and parabens in aqueous cyanocobalamin solutions
Authors: Girgis Ezzat H , Negm Fatma , Mahmoud Soad
Published: April 2011

The orthogonal polynomials P3 and P2, 12 and 8 points, at 2 nm intervals over certain wavelength ranges were used for the spectrophotometric analysis of benzylalcohol, phenol or parabens in aqueous cyanocobalamin solutions. The 12 point-methods proved to be more sensitive and direct and to have sufficient accuracy and precision.
Photoirradiation products of cyproheptadine and carbamazepine
Authors: Robson Julie K , Sharples D
Published: April 2011

Cyclobutyl dimer and 10,11-epoxide photoirradiation products of cyproheptadine and carbamazepine have been isolated by preparative tlc and identified by tlc, uv, pmr and mass spectroscopy.
On the usefulness of ultrafiltration in drug-protein binding studies
Authors: Zhirkov Yu A , Piotrovskii V K
Published: April 2011

Severe non-specific adsorption of verapamil, nifedipine, prazosin and nadolol was observed during ultrafiltration of the drug solutions through the Centriflo CF 50A, YMT, YMB and Visking membranes. The results question the adequacy of the ultrafiltration procedure for the protein binding assay of the tested drugs.
Murine lymphocytes lack clearly defined receptors for muscarinic and dopaminergic ligands
Authors: Wazer David E , Rotrosen John
Published: April 2011

[3H]Quinuclidinyl benzilate and [3H]spiperone binding to murine lymphocytes is displaceable but differs from binding to brain receptor sites for these ligands: (1) binding to intact lymphocyte preparations was not saturable; (2) disruption of intact lymphocytes was associated with a marked loss of displaceable ligand binding; (3) drugs differentially displace these ligands in lymphocytes compared to brain. Displaceable binding was increased following incubation of lymphocytes under phospholipid methylating conditions; however, marked effects on cell viability and cell recovery make it difficult to interpret these binding changes. If dopaminergic and cholinergic receptors do exist on lymphocytes, their binding characteristics are profoundly different from comparable ens receptors.
Aspects of the cardiovascular pharmacology of exaprolol
Authors: Hughes B , Kane K A , McDonald F M , Parratt J R
Published: April 2011

This study confirms that exaprolol is a potent β-adrenoceptor antagonist, having a pA2 value of 9·8 for the inhibition of the inotropic and chronotropic responses of guinea-pig isolated atrial preparations to isoprenaline. In the anaesthetized cat, exaprolol blocks both the myocardial stimulatory and vasodilating effects of isoprenaline, suggesting that it is a non-selective antagonist at β-adrenoceptors. Exaprolol also has direct electrophysiological effects on cardiac (Purkinje) tissue, reducing the rate of rise of phase 0 of the action potential. This direct action together with its marked blockade of β-adrenoceptors may explain the drug’s ability to markedly suppress the ischaemic ventricular arrhythmias that follow coronary artery occlusion in anaesthetized rats.
The effect of temperature on the α-adrenoceptor antagonist potency of indoramin and labetalol in the rat perfused mesenteric vascular bed
Authors: McAdams R P
Published: April 2011

The effect of reduction in temperature of perfusion from 37 to 27 °C and 20 °C on the ability of the adrenoceptor antagonists indoramin and labetalol to block pressor responses to noradrenaline in the perfused mesenteric vascular bed of the rat was examined. The results suggest that in the rat mesenteric bed, antagonist potency of both agents is increased at low temperatures.
Fluidized bed film coating of an ordered powder mixture to produce microencapsulated ordered units
Authors: Thiel W J , Nguyen L T
Published: April 2011

Very finely divided particulate salicylic acid (2–5 μm) was microencapsulated using conventional fluidized bed coating techniques. The process involved spray coating a preformed ordered mixture, in which the micronized particles are adsorbed on the surface of a coarser carrier material. The mixtures contained 0·1, 1·0 and 5·0% weight of microfine model drug (salicylic acid). Between 75 and 95% of the micronized particles were retained on the carrier surface beneath the film. This process offers a novel method of microencapsulating very fine particulate materials, which may find an application in the production of enteric coated and sustained release microdose products. A recent publication on electrostatic charge interactions in ordered mixtures reported that the addition of a third component can affect the stability of a binary ordered mixture. Addition of 2% talc increased the stability of some mixtures during coating and resulted in the microencapsulation of a significantly greater amount of micronized model drug. A 0·1% salicylic acid binary ordered mixture retained 74% of model drug beneath the film, the 0.1% ternary mixture (2% talc) gave a mean retention of 99%.
Amitriptyline and femoxetine, but not clomipramine or citalopram, antagonize hyperthermia induced by directly acting 5-hydroxytryptamine-like drugs in heat adapted rats
Authors: Pawłowski Leszek
Published: April 2011

5-HT uptake inhibitors and pirenperone (a 5-HT2 receptor antagonist), which in previous experiments antagonized fenfluramine (5-HT releaser)-induced hyperthermia in heat adapted rats, were tested against hyperthermia induced by the directly acting 5-HT agonist—m-CPP and quipazine. Pirenperone and—to a lesser degree—amitriptyline and femoxetine antagonized the hyperthermia. Citalopram and clomipramine were inactive. It is concluded that hyperthermia induced by 5-HT-like drugs in rats is due to the stimulation of the 5-HT2 receptor and that the antagonistic effect of citalopram and clomipramine against fenfluramine-induced hyperthermia might be connected with their effect on the uptake of 5-HT.
Effect of bupropion on dopamine and 5-hydroxytryptamine-mediated behaviour in mice
Authors: Muley M P , Joshi M A , Manekar M S
Published: April 2011

When bupropion (12·5–50 mg kg−1) was administered 30 min before methamphetamine it significantly antagonized methamphetamine-induced stereotyped behaviour in mice, but when given 5 min after methamphetamine it significantly potentiated the behaviour. When it was administered to mice pretreated with 100 mg kg−1 pargyline, intense locomotor stimulation and stereotyped behaviour was observed whereas when clomipramine was administered similarly the animals showed locomotor stimulation, head twitches and abduction and extension of hind limbs. Unlike clomipramine, bupropion failed to potentiate the 5-hydroxytryptamine-mediated behaviour seen after 5-hydroxytryptophan, 100 mg kg−1, i.v. These observations are in agreement with reports that bupropion is more potent as an inhibitor of dopamine uptake than as an inhibitor of 5-hydroxytryptamine uptake in-vitro.
The promotion of drug rectal absorption by water absorption
Authors: Shiga Masaharu , Muraoka Toshiko , Hirasawa Toyoto , Hayashi Masahiro , Awazu Shoji
Published: April 2011

The promotion of the rectal absorption of antipyrine by sodium taurocholate (TC-Na) or sodium ethylenediam-inetetraacetate (EDTA-Na) has been examined by in-situ recirculating perfusion in the rat. These promoters significantly increased water influx, efflux and antipyrine absorption clearance (CLAP). Ouabain treatment significantly reduced the increase in both rectal absorption of drug and water flux. Water absorption dependent on active sodium transport may thus possibly promote the rectal absorption of poorly absorbable drugs.
The affinity and efficacy of naturally occurring catecholamines at β-adrenoceptor subtypes
Authors: McPherson Grant A , Molenaar Peter , Malta Errol
Published: April 2011

The contribution of affinity and efficacy to the agonistic actions of the naturally occurring catecholamines, (-)-noradrenaline and (-)-adrenaline at β-adrenoceptor sites were assessed in guinea-pig driven left atrial (β1) and K+-depolarized uterine (β2) preparations. The dissociation constants of each agonist, required in these calculations, were calculated using radioligand binding techniques. [125I]Iodocyanopindolol bound to sites in membrane preparations of each tissue which have been shown to represent β1(atria) and β2-(uterus) adrenoceptors. It was found that (-)-noradrenaline was approximately 10-fold more selective for the β1- as opposed to the β2-adrenoceptor in the pharmacological studies. Affinity/efficacy calculations indicated that this selectivity was entirely due to a selective affinity for the β1-adrenoceptor subtype. (-). Noradrenaline, (-)-adrenaline and the reference compound (-)-isoprenaline all had approximately the same efficacy at either β-adrenoceptor subtype.
Effect of ergometrine on methamphetamine and apomorphine stereotypy in the guinea-pig
Authors: Balsara J J , Bapat T R , Gada V P , Nandal N V , Chandorkar A G
Published: April 2011

Pretreatment with the DAi receptor antagonist ergometrine (10, 20 mg kg−1 i.p.) significantly potentiated methamphetamine stereotypy and facilitated the induction of biting, gnawing or licking behaviour by amantadine. However, ergometrine (5–20 mg kg−1) did not significantly influence the stereotyped behaviour induced by the DAe receptor agonist apomorphine. The results suggest that the DAi antagonist ergometrine is effective in modifying the behaviours induced by methamphetamine and amantadine, agents which through released DA simultaneously activate both DAe and DAi receptors, but fails to modify the stereotyped behaviour induced by apomorphine which specifically activates only DAe receptors. However, the possibility that ergometrine might have potentiated methamphetamine stereotypy and facilitated the induction of biting, gnawing or licking behaviour by amantadine through modulation of the activity of the central noradrenergic and 5-hydroxytryptaminergic systems, which are reported to influence DA-mediated behaviours, also needs to be considered.
Enhanced bioavailability of insulin after rectal administration with enamine as adjuvant in depancreatized dogs
Authors: Nishihata Toshiaki , Okamura Yasufumi , Kamada Akira , Higuchi Takeru , Yagi Toshihito , Kawamori Ryuzo , Shichiri Motoaki
Published: April 2011

Rectal absorption of insulin by depancreatized dogs was significantly enhanced by the coadministration of enamine as a suppository adjuvant and if this was followed by a further suppository containing enamine alone, the insulin absorption was even further enhanced. The additional enamine suppository resulted in high serum insulin concentrations for a longer time and effected a significant decrease in serum glucose concentrations. To decrease serum glucose concentrations effectively in depancreatized dogs, serum insulin levels had to remain high for a long period of time, rather than be transient.
Absorption through human skin of ibuprofen and flurbiprofen; effect of dose variation, deposited drug films, occlusion and the penetration enhancer N-methyl-2-pyrrolidone
Authors: Akhter Sheikh A , Barry Brian W
Published: April 2011

The penetration of ibuprofen and flurbiprofen, non-steroidal anti-inflammatory agents, was investigated from drug films deposited by acetone evaporation on cadaver skin in an open cell ‘in-vivo mimic’ design. Increased dosage did not produce a proportional increase in the permeation and maximizing the skin-drug contact did not increase penetration: both factors indicate that absorption from deposited drug films was dissolution rate-limited. Occlusion of the skin did not increase the dissolution rate of the deposited drug film, but did elevate the penetration of drug already present within the skin at the time of occlusion. The diffusion coefficients for both drugs were calculated by two methods, yielding 1.8 ± 1.3 times 10−11 cm2 s−1 and 1.0 ± 0.56 times 10−11 cm2 s−1 for ibuprofen and 1.9 ± 0.59 times 10−11 cm2 s−1 and 0.77 ± 0.23 times 10−11 cm2 s−1 for flurbiprofen. Increasing the acetone-skin contact time from 2 min to 2 h did not significantly alter the permeability of the skin. Absorption of flurbiprofen was similar from 10 and 100% saturated aqueous solutions, suggesting that the skin has a limited capacity for flurbiprofen transport beyond which further increase in drug penetration may be difficult. N-Methyl-2-pyrrolidone enhanced the penetration flux of ibuprofen sixteenfold and flurbiprofen, over threefold. The ‘in-vivo mimic’ design for permeation experiments has thus proved to be useful for evaluating the kinetics of topical therapy and the mechanism of action of potential penetration enhancers.
A carrier-mediated transport system for benzylpenicillin in isolated hepatocytes
Authors: Tsuji Akir , Terasaki Tetsuya , Tamai Ikumi , Nakashima Emi , Takanosu Kazuhiro
Published: April 2011

The transport mechanism of benzylpenicillin was studied in freshly prepared rat hepatocytes. The initial uptake rate followed both saturable and unsaturable transport processes. The Arrhenius plot of the initial uptake rate gave an activation energy of 16.8 kcal mol−1 (69 kJ mol−1). The benzylpenicillin uptake by hepatocytes was significantly inhibited by antimycin A, sodium cyanide, rotenone, 2,4-dinitrophenol, phenoxymethylpenicillin, probenecid and Taurocholic acid. No significant inhibition was observed by acetylaminohippuric acid and several kinds of amino acids and dipeptides. The present study provides the first evidence for the the existence of a carrier-mediated and energy-dependent transport system of benzylpenicillin in the liver.
5-Hydroxytryptamine can antagonize the ability of metoclopramide and SCH 23390 to enhance electrical field stimulation-evoked contractions of guinea-pig isolated stomach muscle
Authors: Gunning S J , Naylor R J
Published: April 2011

Electrical field stimulation of guinea-pig stomach strips caused frequency related contractions that were enhanced by metoclopramide and SCH 23390 (10−7 −10−5 M) and antagonized by atropine (5 times 10−8 M. 5-HT (3 times 10−8 −3 times 10−5 M) antagonized the ability of metoclopramide and SCH 23390 to enhance the contractions. It is concluded that metoclopramide and SCH 23390 can enhance electrical field stimulation-induced contractions in the stomach strips by a 5-HT receptor blockade which can facilitate cholinergic mediated contractions.
The adhesion characteristics of some pigmented and unpigmented aqueous-based film coatings applied to aspirin tablets
Authors: Okhamafe Augustine O , York P
Published: April 2011

The adhesion of pigmented (with talc and titanium dioxide) and unpigmented aqueous-based films, derived from hydroxypropyl methylcellulose, to aspirin tablets and the effect of ageing on the measured adhesion have been assessed. The adhesion of hydroxypropyl methycellulose film attained maximum values at polyethylene glycol 400 and polyvinyl alcohol levels of 10 and 20 wt%, respectively. Above these concentrations, adhesion decreased. For solid loaded films it is proposed that the effect of pigments on film adhesion is dependent on the balance between their influence on the internal stress of the film coating and the strength of the film-tablet interface. Adhesion was enhanced when a pigment increased the strength of the interface faster than it increased internal stress, and vice versa. A simple relation between the measured adhesion and the incidence of edge splitting of film-coated tablets was not observed. Generally, film adhesion fell when the tablets were aged at 37°C and 75% r.h. as a result of swelling-induced stresses in the film and at the film tablet interface. The effect of ageing on the adhesion of the system plasticized with polyethylene glycol 400 was eased when the film was pigmented. Adhesion was largely unaffected with film-coated tablets stored in tightly closed bottles at 20°C for five months.
Drug delivery to the proximal colon
Authors: Hardy John G , Wilson Clive G , Wood Elizabeth
Published: April 2011

The transits of a capsule and a multiparticulate pellet system have been monitored through the gastrointestinal tract in six healthy volunteers. Both preparations moved together through the stomach and small intestine, reaching the colon, on average, 4 h after dosing. Within the colon the pellets dispersed and moved at a slower rate than the capsule. There was considerable intersubject variability in the large bowel transit times. The findings are discussed in terms of drug delivery to the colon.
Inhibition of prostaglandin generation in the rabbit brain in-vivo by AD-1590, a non-steroidal antiinflammatory agent with potent antipyretic activity
Authors: Nakamura Hideo , Yokoyama Yuichi , Motoyoshi Satoru , Seto Yasuhiro , Kadokawa Toshiaki , Shimizu Masanao
Published: April 2011

The inhibition of prostaglandin generation by AD-1590 was investigated in the rabbit brain in-vivo. AD-1590 (0ṁ4 mg kg−1 i.v.) markedly prevented both the increases in body temperature and PGE2 level in cerebrospinal fluid (CSF) caused by i.v. injection of lipopolysaccharide. On the other hand, 2,4-dinitrophenol (20 mg kg−1 i.v.)-induced hyperthermia, which was not affected by AD-1590, was not accompanied by an increase in PGE2 level in CSF. When injected intracerebroventricularly, AD-1590 dose-dependently inhibited the hyperthermia caused by arachidonic acid given by the same route; its ED50 was 1ṁ6 μg compared with about 35 μg for indomethacin. From these results, it is suggested that AD-1590 is more active than indomethacin in suppressing prostaglandin synthetase in rabbit brain.
Extraction efficiency and biliary excretion of hepatobiliary imaging agents in the rat perfused liver
Authors: Fritzberg Alan R , Reichen Juerg
Published: April 2011

A multitude of transitional metal complexes has recently been introduced into clinical practice as hepatobiliary imaging agents; the kinetics of these substances are often poorly understood. To gain better insight into characteristics of these different agents, we measured the extraction efficiency and mean biliary transit time of a variety of iminodiacetate derivatives in the in-situ rat perfused liver. First pass hepatic extraction efficiency averaged 59% for 99mTc N-(p-isopropylacetanilide) iminodiacetate, 73% for 99mTc N-(2,6-diethylacetanilide) iminodiacetate, 74% for 99mTc N-(3-bromo-2,4,6-trimethylacetanilide) iminodiacetate, 90% for 99mTc N-(p-butylacetanilide) iminodiacetate, and 93% for 99mTc N-pyridoxyl-5-methyltryptophan. By comparison, extraction of another organic anionic compound, 131I Rose bengal, was only 12ṁ4%. Mean hepatocyte transit times varied from 2ṁ3 to 7ṁ5 min. Shorter mean transit times were observed for diortho substituted and longer mean transit times for para substituted metal complexes. Radioactivity was quantitatively recovered in bile, and excretion kinetics overall were consistent with data generated in whole animals. These studies demonstrate the value of the in-situ rat perfused liver as a screening tool to characterize hepatobiliary imaging agents.
Baclofen is a potent activator of brown fat metabolism
Authors: Rothwell N J , Addae J I , Stock M J , Stone T W
Published: April 2011

The injection of (±)-baclofen intravenously or directly into the ventromedial hypothalamus of urethane-anaesthetized rats, produced an activation of brown fat metabolism. This was seen as an increase of brown fat and rectal temperatures, and an increase of GDP binding in brown fat mitochondria. The activation was mediated by the sympathetic supply.
The Disposition of Quinine in the Rat Isolated Perfused Liver: Effect of Dose Size
Authors: Coleman M D , Timony G , Fleckenstein L
Published: April 2011

We have investigated the pharmacokinetics of both free and total quinine in the rat isolated perfused liver at three doses, 6.25, 12.5 and 25 mg. The plasma concentrations of free and total quinine decayed biexponentially over 4 h. However, on increasing dose, the terminal half-life of free and total quinine showed marked increases ranging from 12.4 ± 3.7 min at 6.25 mg to 176.0 ± 153 min at 25 mg (total quinine). Quinine clearance was reduced approximately by half as the dose was doubled. At 10 min post dosage, quinine extraction at the 6.25 mg dose (56 ± 16.3%) was more than twice that of the highest dose (25 mg, 25.0 ± 6.5%). Free quinine at the 6.25 mg dose was cleared at ∼ 100% of perfusate flow, whereas at 25 mg, clearance was less than one fifth of that value. Unchanged quinine elimination in bile was low, with less than 1 % of the parent drug being detected at the 12.5 and 25 mg doses. Relatively little parent drug was recovered from the liver at 4 h. At the 25 mg dose, ≤ 6% was recovered as parent drug. HPLC analysis revealed some polar metabolites of quinine in the bile and in the liver homogenates. Dose dependent kinetics of quinine were demonstrated in this study, as hepatic extraction of quinine decreased with increasing dose and input concentration.
Stimulatory Effects of 5-Hydroxytryptamine on Fluid Secretion and Transmural Potential Difference in Rat Small Intestine are Mediated by Different Receptor Subtypes
Authors: Beubler E , Coupar I M , Hardcastle J , Hardcastle P T
Published: April 2011

The rise in transmural potential difference (PD) and the fluid secretion induced by 5-hydroxytryptamine (5-HT) were measured in rat small intestine in-vivo. Both cisapride and ketanserin abolished the 5-HT-induced rise in systolic blood pressure mediated by 5-HT2 receptors. Cisapride inhibited the 5-HT-induced increases in the transintestinal PD, but over the same dose range it had no effect on the fluid secretion induced by 5-HT. In contrast, ketanserin caused a dose-dependent reduction in 5-HT-induced fluid secretion at doses that failed to influence the rise in PD. It is concluded that different receptors are responsible for the effects of 5-HT on fluid secretion and electrical activity in the rat small intestine.
Improved synthetic routes to the novel thromboxane receptor antagonist ICI 192605: activity of synthetic 1,3-dioxane intermediates
Authors: Brown George R , Foubister Alan J , Hudson Julian A
Published: April 2011

A study of the synthetic routes to the thromboxane receptor antagonist ICI 192605 4(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl) hexenoic acid is described which led to an improvement in overall synthetic yield from 20 to 55%. In-vitro thromboxane receptor antagonist data are reported for the novel 1,3-dioxane synthetic intermediates. These data indicated that shortening of the side chain in an appropriately substituted 2,2-dimethyl-1,3-dioxane (e.g. ICI 180080) from a heptenoic acid, to a hexenoic acid, had little effect on thromboxane receptor antagonist potency (pA2 = 7.5 rabbit thoracic aorta for the heptenoic acid ICI 180080 and pA2 = 6.9 for the corresponding hexenoic acid. Human platelet aggregation pA2 values were 6.7 and 7.0, respectively).
The significance of removing oxygen-derived free radicals in the treatment of acute and chronic duodenal ulceration in the rat
Authors: Salim Aws S
Published: April 2011

Rats infused for 24 h with pentagastrin (4 μg kg−1 min−1) and carbachol (0.8 μg kg−1 min−1) developed acute duodenal ulceration (100%) and hyperchlorhydria (69 ± 5.3 μmol h−1 vs 14 ± 0.9 μmol h−1, P < 0.001, n = 10). The animals were then given daily by gavage, saline, allopurinol with dimethyl sulphoxide (DMSO) or cysteine with methyl methionine sulphonium bromide (MMSB). Two days after the infusion, 10 rats (100%) given saline and 7 rats (70%) given allopurinol and DMSO, or cysteine and MMSB, showed duodenal ulceration. Five days after the infusion, 8 rats (80%) given saline, 3 rats (30%) given allopurinol and DMSO, and 2 rats (20%) given cysteine and MMSB had duodenal ulceration. Seven days after the infusion, only 5 rats (50%) given saline still had duodenal ulceration. Daily intramuscular injection of reserpine (0.1 mg kg−1) for 6 weeks produced chronic duodenal ulceration (90%) and hyperchlorhydria (47 ± 31 μmol h−1 vs 12 ± 0.9 μmol h−1, P < 0.001, n = 10). Animals were then given daily by gavage, saline, allopurinol and DMSO, or cysteine and MMSB. Five days after reserpine, 10 rats (100%) given saline, 8 rats (80%) given allopurinol and DMSO, and 7 rats (70%) given cysteine and MMSB showed duodenal ulceration. Ten days after reserpine, 9 rats (90%) given saline, 3 rats (30%) given allopurinol and DMSO, and 4 rats (40%) given cysteine and MMSB had duodenal ulceration. Fifteen days after reserpine, 8 rats (80%) receiving saline and only one rat (10%) receiving allopurinol and DMSO or cysteine and MMSB had duodenal ulceration. Twenty days after the reserpine treatment only 6 rats (60%) given saline still had duodenal ulceration. The results show that removing oxygen-derived free radicals stimulates the healing of acute and chronic duodenal ulceration in the rat.
The Effect of Oral Activated Charcoal on the Systemic Clearance of Gentamicin in Rabbits with Acute Renal Failure
Authors: Hasan M M , El-Sayed Y M , Abdelaziz A A
Published: April 2011

The effect of oral administration of activated charcoal on total body clearance of gentamicin administered intravenously (2 mg kg−1) has been studied in normal rabbits and rabbits with induced renal failure. Gastric intubation of a single dose (10 g) of activated charcoal to normal rabbits produced a significant reduction in gentamicin serum concentrations compared to control. Significant differences between treated and control groups, compatible with enhancement of gentamicin elimination, were observed in the calculated pharmacokinetic parameters (Kel, t 1/2, CL and AUC). To examine whether renal failure could augment the effect of activated charcoal in enhancing the systemic clearance of gentamicin, uranyl nitrate was used (0.75 mg kg−1, i.v.) to induce acute renal failure in rabbits. The derived pharmacokinetic parameters of gentamicin during the control phase in these animals were consistent with severe renal failure. The administration of activated charcoal, 2.5 h following gentamicin injection, produced a steeper decline in gentamicin concentration-time profiles and significant changes in Kel, t 1/2 and CL. The Kel and CL values increased to about 200%, while the t 1/2 value decreased to about 50%. The apparent changes in the pharmacokinetic parameters induced by charcoal administration were more marked in rabbits with renal failure than in normal rabbits; however, induction of renal failure did not augment the charcoal-induced clearance of gentamicin quantitatively.
Liver Damage Induced by Intrabiliary Turpentine in Rats
Authors: Martinková J , Rýdlová I , Šubrtová D , Palička V
Published: April 2011

Inflammation of the rat bile duct induced by administration of turpentine into it has been used to study the influence of the impaired duct on liver function. Turpentine was dissolved in olive oil 1:1000 and 1:500. A 2 h ligation of the bile duct was used to promote a local effect. Contemporary groups of intact, sham-operated, control rats (given 0.9% NaCl by intrabiliary injection) and animals with total chronic obstruction were compared to assess the significance of changes. Serum concentrations of total and conjugated bilirubin, cholesterol and creatinine, activities of S-alanine-aminotransferase, S-aspartate aminotransferase and alkaline phosphatase, mortality of rats, and also total body weight compared with the weight of the liver, were investigated on days 1, 4, 8, 12, 16, 32 and 64 after surgery and turpentine, or following ligation of the bile duct. An increase in bilirubin and cholesterol, an augmentation of enzymatic activity and the histological changes were indicative of hepatotoxicity or cholestasis. The turpentine concentration - effect, manifested in body-weight change, suggests some specificity of the effect. There were no changes in serum creatinine arterial blood pressure, heart rate or portal blood pressure, when turpentine was administered by the intrabiliary route. These results suggest primary liver damage.
The Coating and the Encapsulation of an Interactive Powder Mixture and its Application to Sustained Release Preparations
Authors: Yoshizawa H , Koishi M
Published: April 2011

Fine cohesive isoprenaline HCl particles adhered to the surface of coarser potato starch particles to form interactive mixtures. These were coated with magnesium stearate by dry mixing. To check if there was a lowering of homogeneity in the latter stage, the degree of mixing was investigated before and after adding magnesium stearate. The surface appearance of magnesium stearate-coated interactive mixtures became smoother as mixing time increased or the temperature of the powder bed during mixing was raised. Ultimately, the magnesium stearate encapsulated the particles of interactive mixture. The coated interactive mixtures improved sustained release of isoprenaline HCl over the starch mixtures alone, the effect depending on the density of the magnesium stearate. Only in encapsulated mixtures was the release rate of drug decreased as the amount of magnesium stearate increased. The release of isoprenaline HCl from the interactive mixtures followed first-order kinetics. A linear relationship existed between the first-order rate constant and the reciprocal thickness of the magnesium stearate film, indicating a diffusion-controlled system with the film having some pores.
Comparison of the Antisecretory Effects of Loperamide and Loperamide Oxide in the Jejunum and the Colon of Rats In-vivo
Authors: Beubler Eckhard , Badhri Pramila
Published: April 2011

The antidiarrhoeal effect of loperamide is caused by its antimotility and antisecretory properties. In-vivo experiments in the rat jejunum and colon have been performed to compare the antisecretory effect of loperamide with the effect of its prodrug, loperamide oxide. Both loperamide and loperamide oxide administered intraluminally, equally and dose dependently (2 to 250 μg mL−1) reduced PGE2-induced net fluid secretion (32 ng min−1 i.a.) in the jejunum and colon. The antisecretory effect of both drugs is blocked by naloxone (1 mg kg−1 s.c). It is concluded that loperamide oxide administered intraluminally is reduced to loperamide and has the same antisecretory potency as loperamide in jejunum and colon. The effect appears to be mediated via opiate receptors. The observation that loperamide cannot be detected in the colonic lumen two h after oral administration suggests that the drug is delivered from the blood stream to the site of action after absorption in the small intestine.
Comparison of intestinal and peritoneal dialysis of theophylline and phenobarbitone in rats
Authors: Arimori Kazuhiko , Hashimoto Yoshiko , Nakano Masahiro
Published: April 2011

Intestinal dialysis of drugs by oral administration of activated charcoal has been compared with peritoneal dialysis in rats. The average amounts of theophylline transported over 120 min into the intestinal lumen and the peritoneal cavity were 15.7 and 16.5% of the intravenous dose (10 mg kg−1), respectively, showing no significant difference, whereas the amount of the same intravenous dose of phenobarbitone transported from the blood into the intestinal lumen (7.8%) was significantly smaller than that entering the peritoneal cavity (12.5%). The net water flux showed that secretion predominated in the peritoneal transport whilst absorption predominated in the intestinal transport for both drugs. However, the net water flux in the intestinal lumen after intravenous theophylline (as aminophylline) was significantly smaller than that following phenobarbitone. The differences in transport across the two membranes could be due to differences in the intrinsic properties of the membranes, such as the surface area, the thickness of the membrane and the distribution of blood vessels. Differences could also be due to differences in the pharmacological effects of the drugs.
Effects of clenbuterol treatment on the responses to vasodilators in urethane-anaesthetized rats
Authors: Kazanietz Marcelo G , Gutkind Jorge S , Enero María Amelia
Published: April 2011

Seven or 14 days of treatment with the β2-adrenoceptor agonist clenbuterol, 0.3 mg kg−1, s.c., twice daily, increased the basal mean blood pressure in normotensive urethane-anaesthetized rats. The elevated pressure values were maintained until 48 h after the end of the 14 day treatment. Clenbuterol treatment decreased the vasodilatory responses to the β-adrenoceptor agonist isoprenaline and adenosine, agents which act through an increase in intracellular cyclic AMP. Decreased responses were maintained until 48 h after a 14 day treatment with clenbuterol. On the other hand, its administration to rats for 14 days did not modify the vasodilator responses to acetylcholine or sodium nitroprusside, two agents that exert their effects by enhancing cyclic GMP. The increase in mean blood pressure in urethane-anaesthetized rats after clenbuterol treatment may be a consequence of a reduced vasodilator β2-adrenoceptor-mediated response to circulating catecholamines.
Mast Cell Degranulating Peptide: A Multi-functional Neurotoxin
Authors: Ziai M Reza , Russek Shelley , Wang Hsuei-Chin , Beer Bernard , Blume Arthur J
Published: April 2011

This review discusses our present knowledge of the structure and activities of the mast cell degranulating peptide (MCDP). This peptide is a basic, 22 amino acid residue component of honey bee venom with striking immunological and pharmacological activities. MCDP is a potent anti-inflammatory agent, but at low concentrations it is a strong mediator of mast cell degranulation and histamine release. MCDP is also an epileptogenic neurotoxin, an avid blocker of the potassium channels and can cause a significant lowering of the blood pressure in rats. Some of the biological activities of MCDP appear to have distinct mechanisms and may represent a good illustration of the structure-function relationship.
The influence of density on the gastrointestinal transit of pellets
Authors: Devereux J E , Newton J M , Short M B
Published: April 2011

The gastric emptying, intestinal transit and caecum arrival times of 1 mm pellets of density 1.5 and 2.8 g cm−3 have been assessed in fed and fasted volunteers by means of gamma-scintigraphy. The pellets were prepared by extrusion/spheronisation, coated with ethylcellulose and labelled with technetium-99m. The position of the pellets in the gastro-intestinal tract was followed by a double-headed gamma camera to allow detailed information over a period of up to 10 h. Analysis of variance established that there was a highly significant difference in the time for 50% of the pellets to empty from the stomach both in fed and fasted states. The 2.8 g cm−3 pellets had an extended resident time in both the fed and fasted states. The gastric emptying time was prolonged in the fed state. There was no significant difference in intestinal transit time between the two formulations nor whether the volunteers were fed or fasted. The caecum arrival time was therefore modified only by the gastric emptying time.
The in-situ absorption of antipyrine as a measure of intestinal blood flow in Fluosol-DA haemodiluted rats
Authors: Shrewsbury Robert P , White Lisa G
Published: April 2011

The effect of moderate Fluosol-DA haemodilution on intestinal blood flow has been investigated in the rat. Antipyrine in-situ intestinal absorption is blood flow limited, and did not alter 0.5, 24, 48, or 72 h after haemodilution with 40 mL kg−1 Fluosol. Thus the intestinal blood flow rate is maintained as part of the physiological response to ensure adequate perfusion of the vital organ.
Effect of Surface Characteristics of Theophylline Anhydrate Powder on Hygroscopic Stability
Authors: Otsuka Makoto , Kaneniwa Nobuyoshi , Kawakami Katsumi , Umezawa Osamu
Published: April 2011

The hygroscopicity of theophylline anhydrate has been investigated by gas adsorption and hydration kinetic methods. Type I theophylline anhydrate was obtained by recrystallization from distilled water at 95°C, and type II was obtained by dehydration of theophylline monohydrate. The X-ray diffraction pattern of types I and II agreed with the data of theophylline anhydrate. However, the diffraction peaks of the (200) and (400) planes of type I were much stronger than those of type II. The particles of type I were clear crystalline-like single crystals. However, the particles of type II had many cracks. The gas affinity balance (H/N) of type II, measured by gas adsorption, was about 7 times that of type I. After the hygroscopicity of types I and II had been tested at various levels of relative humidity (RH) at 35°C, type I was stable at less than 82% RH, but transformed into the monohydrate at more than 88% RH. Type II was stable at less than 66% RH and transformed into the monohydrate at less than 75% RH. The hydration data of type I at 88% RH and type II at 75% RH were calculated for hydration kinetics using various solid-state kinetic models, but no particular model could be preferred from these data.
Changes in Intracellular Ca2+ Produced in the Mouse Diaphragm by Neuromuscular Blocking Drugs
Authors: Kimura I , Kondoh T , Kimura M
Published: April 2011

Differences between the effects of depolarizing and competitive neuromuscular blocking drugs on Ca2+-aequorin luminescences (Ca2+ transients) emitted during twitches were compared in indirectly-stimulated diaphragm muscles of mice. Succinylcholine enhanced intracellular Ca2+ transients at concentrations of 1.3-2.5 μM and inhibited them at concentrations of 5.0–50 μM, demonstrating a biphasic response as in the case of twitch tensions. However, the response to Ca2+ transients was two to three times more sensitive than the response to twitch tension. Decamethonium 2.4–96 μM and carbachol 5.5–109 μM produced similar results. In contrast, pancuronium and (+)-tubocurarine inhibited them in the same concentration ranges. The relation between Ca2+ transients and twitch tensions was hyperbolic and was computer-simulated by the Hill equation in the case of succinylcholine, decamethonium and carbachol, whereas it was represented by a single exponential equation in the case of pancuronium, (+)-tubocurarine, and submaximal nerve-stimulation voltage. Spontaneous Ca2+ transients, on the other hand, were generated only in response to depolarizing drugs at concentrations having a neuromuscular blocking effect. These results suggest that depolarizing and competitive neuromuscular blocking drugs affect intracellular Ca2+ mobilization by different routes mediated by acetylcholine receptors.
The Preservation of Functional Activity of Smooth Muscle and Endothelium in Pig Coronary Arteries after Storage at −190°C
Authors: Schoeffter Philippe , Müller-Schweinitzer Else
Published: April 2011

Pig coronary arteries have been investigated in-vitro using fresh tissue or after storage at −190°C in foetal calf serum containing 1.8 M dimethyl sulphoxide. Attention was paid to modulation of contractile activity and endothelium-dependent relaxation. After cryopreservation of the arteries maximal contractile responses to both 5-hydroxytryptamine (5-HT) and prostaglandin F2α (PGF2α) were markedly reduced and the pD2 values for both agonists were slightly, but significantly, diminished. Nevertheless, 5-HT antagonism by ketanserin and pizotifen was unchanged. Endothelium-independent relaxant responses of precontracted arteries to isoprenaline, forskolin, 3-isobutyl-1-methylxanthine, nitroprusside, atriopeptin III and cromakalim were generally unchanged after storage. Mechanical removal of the endothelium by rubbing enhanced the contractile response to PGF2α in both fresh and stored arteries to a similar extent. In addition, endothelium-dependent relaxant responses to both 5-HT and substance P were well maintained, suggesting release of endothelium-derived relaxing factor by the stored arteries. The evidence suggests that after cryopreservation of pig coronary arteries at −190° C mechanisms of relaxation, in particular those which are endothelium-dependent, are well maintained.