bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of a myenteric 5-hydroxytryptamine-like receptor by metoclopramide
Authors: Sanger G J
Published: April 2011

Cholinergically mediated contractions were evoked by electrical field stimulation (EFS) of guinea-pig distal ileum longitudinal muscle-myenteric plexus strips. Metoclopramide, 0ṁ1–100 μM, dose-dependently increased the contractions, probably by increasing acetylcholine (ACh) release; contractions evoked by exogenous ACh in the presence of tetrodotoxin were not increased by metoclopramide. 5-Hydroxytryptamine (5-HT) 0ṁ3–30 nM similarly increased the height of the EFS-evoked contractions, although the maximum increase was less than for metoclopramide; higher concentrations of 5-HT (3 and 30 μM) had no effects or caused inhibition. The compound, ICS 205–930, 0ṁ001-1 μM, had no effect on the EFS-evoked contractions and caused inhibition at higher concentrations. Preincubation of the tissues with 5-HT, 0ṁ3–30 nM, did not affect the increase in EFS-evoked contractions caused by metoclopramide, 1 or 100 μM, whereas 5-HT, 3 and 30 μM, prevented the response caused by metoclopramide 1 μM, but not 100 μM. ICS 205–930, 0ṁ1 μM, had no effect on the increase in EFS-evoked contractions caused by metoclopramide 1 or 100 μM. The drug, at least in low concentrations, may therefore increase cholinergically mediated contractions of guinea-pig ileum by stimulating 5-HT-like receptors within the myenteric plexus, which differ from those antagonized by ICS 205–930.
Gossypol: a potent inhibitor of PAF-acether- and leukotriene-induced contractions of guinea-pig lung parenchyma strips
Authors: Touvay C , Vilain B , Sirois P , Soufir M , Braquet P
Published: April 2011

Gossypol, a substance extracted from cotton plants, markedly inhibited the contractile responses of guinea-pig lung parenchyma strips stimulated with leukotriene B4 (LTB4), leukotriene D4 (LTD4) and PAF-acether but not the responses to histamine (except at high concentration). It was slightly less potent than nordihydroguaiaretic acid (NDGA) and a PAF-antagonist (BN 52021). From previously reported effects of gossypol on the cyclooxygenase and lipoxygenases, and on the similarity of the inhibition produced by NDGA and gossypol on the lung parenchyma, it is suggested that the inhibition of the myotropic activity of the lung parenchyma by gossypol is due to interactions with the formation of cyclooxygenase products within the guinea-pig lung.
The oral clearance of zinc and triclosan after delivery from a dentifrice
Authors: Gilbert R J
Published: April 2011

Oral delivery and retention of zinc and triclosan were measured in man after use of an anti-plaque dentifrice containing these antibacterial agents. Triclosan (25% of the dose) and zinc (24%) were retained in the mouth immediately after toothbrushing and a single mouthrinse. Salivary concentrations fell from 7ṁ5 μg g−1 (triclosan) and 7ṁ0 μg g−1 (zinc) after 5 min to 0ṁ5 μg g−1 (triclosan) and 1ṁ2 μg g−1 (zinc), 2 h after brushing.
Autoregulation of renal blood flow during the infusion of acetylcholine or carbachol in anaesthetized dogs
Authors: Ogawa Nobuyaki , Ono Hiroshi
Published: April 2011

Whether renal blood flow autoregulation is abolished by acetylcholine was re-examined by kidney perfusion experiments in anaesthetized dogs. Renal blood flow was dose-dependently increased by the renal arterial infusion of acetylcholine (2 and 5 μg min−1) or another muscarinic agent, carbachol (2 and 5 μg min−1) and was maintained at an increased level during the infusion. When perfusion pressure was changed stepwise between 60 and 200 mmHg, the infusion of acetylcholine or carbachol caused no impairment of autoregulation. It is concluded that autoregulation is independent of muscarinic stimulation of vascular smooth muscle in the kidney.
Evaluation of sorghum starch as a tablet disintegrant and binder
Authors: Deshpande A V , Panya L B
Published: April 2011

The starch prepared from the seeds of Sorghum bicolor, Moench has been evaluated as a disintegrant and binder in tablets of magnesium sulphate, calcium carbonate, sulpha-dimidine, and chloroquine phosphate to represent soluble and insoluble inorganic and organic substances. The starch performed as well as maize starch in binding and disintegrating properties and better than acacia as binder.
Influence of pinacolyl dimethylphosphinate on soman storage in rats
Authors: Van Dongen C J , De Lange J
Published: April 2011

Atropinized rats pretreated with pinacolyl dimethylphosphinate (PDP) or saline were intoxicated with 6 x LD50 soman and, after 30 and 60 min, the absolute amounts of soman in diaphragms and lungs were measured gas chromatographically. The absolute amounts of free soman in both types of tissues were similar and were decreased after 60 min intoxication compared with the 30 min intoxication period. Pretreatment of rats with PDP reduced the amount of soman in the tissues by 63–78%. Incubation of isolated diaphragms and lungs with sodium fluoride (2ṁ5 mM) increased the amount of free soman in these tissues by 2ṁ6 X*** 103 and 16 times 103%, respectively. An assay to study the binding of tritiated PDP was developed. Although this assay was suitable to study the binding of tritiated quinuclidinyl benzilate to rat brain, no binding between tritiated PDP and diaphragm or brain tissue could be detected. It was concluded that PDP may counteract soman storage by another mechanism than occupation of binding sites.
The effects of acute reserpine administration on the sensitivity of the isolated pacemaker from rat heart to isoprenaline and noradrenaline
Authors: Spadari Regina C , Lamas José Luiz T , De Moraes Sergio
Published: April 2011

The effects of reserpine on the sensitivity of the isolated pacemaker from rat heart to the chronotropic effect of isoprenaline and noradrenaline were studied. A single large dose of reserpine (2ṁ5 mg kg−1) administered to rats 24 h before killing induces supersensitivity of the isolated pacemaker to isoprenaline, leaving unaltered the responsiveness of the pacemaker to noradrenaline. Reserpine at the dose of 1ṁ0 mg kg−1 did not alter the sensitivity of the pacemaker to the catecholamines. Only the larger dose of reserpine raised the corticosterone plasma level. It is possible that a corticosterone-mediated inhibition of the extraneuronal uptake process is responsible for the supersensitivity to isoprenaline. Large doses of reserpine should not be used in experiments aimed to study cardiac sensitivity to isoprenaline or extraneuronal uptake and metabolism of the catecholamine.
Identification of two metabolites of the cholinesterase reactivator HI-6 isolated from rat urine
Authors: Ligtenstein David A , Wils Eric R J , Kossen Simon P , Hulst Albert G
Published: April 2011

Two metabolites, isolated from the urine of rats given the cholinesterase reactivator HI-6 intravenously, still contained quaternary nitrogen atoms and therefore could not be extracted from aqueous solutions by organic solvents. Both metabolites were isolated by preparative high performance liquid chromatography and were identified using mass spectrometry, gas chromatography, infrared spectrometry, ultraviolet spectrometry and proton nuclear magnetic resonance spectrometry. The structures were confirmed by in-vitro preparation of the compounds. Both metabolites contained 2-pyridone moieties. One had an intact pyridinium-aldoxime moiety, and therefore could still be therapeutically active. The excretion of unchanged HI-6 together with the two identified metabolites does not provide for a 100% mass balance, indicating that in the rat, other, as yet unidentified, metabolites must be formed.
Central dopamine receptors and their role in digoxin-induced cardiotoxicity in the dog
Authors: Plunkett L M , Tackett R L
Published: April 2011

The role of the dopaminergic system in digoxin-induced cardiotoxicity has been examined. Specific dopaminergic agonists and antagonists were administered into the ventriculo-cisternal system of pentobarbitone-anaesthetized dogs before systemic administration of digoxin. Pretreatment with apomorphine, a specific dopamine agonist, did not significantly alter the arrhythmogenic or lethal doses of digoxin. However, the digoxin-induced increase in CSF noradrenaline was decreased significantly in apomorphine-pretreated animals. Pretreatment with pimozide, a specific dopamine antagonist, significantly decreased the arrhythmogenic dose of digoxin but did not alter the lethal dose. As with apomorphine, pimozide-pretreated animals accumulated significantly less noradrenaline in CSF compared with control dogs. These results suggest that dopamine receptors are not directly related to the cardiotoxic actions of digoxin. However, dopaminergic receptors may influence the balance of central catecholaminergic systems that influence the peripheral cardiovascular system.
Experimental pharmacological study of moroxybrate, a hypolipidaemic, antithrombotic, antiatheromatous agent
Authors: Moreau Pierre , Jacotot Bernard , Tillement Jean-Paul
Published: April 2011

Moroxybrate, a drug obtained by the reaction of clofibric acid with moroxydine, a biguanide with practically no effect on carbohydrate metabolism, has been examined for its effects on blood lipids, fibrinogen, in-vitro platelet aggregation, and also on experimental atherosclerotic lesions obtained by feeding the rabbits a diet containing 1% cholesterol. At the same dose, moroxybrate has an effect at least equal to those of clofibrate and moroxydine alone, on the lipidic parameters and haemostasis in rat and rabbit. The combination of these actions together with an effect on the prevention of experimental atherosclerosis lesions in the rabbit suggests moroxybrate should be examined for its effects in ischaemic cardiovascular disease.
The effect of polycarbophil on the gastric emptying of pellets
Authors: Khosla R , Davis S S
Published: April 2011

The influence of the putative bioadhesive, polycarbophil, on the gastric emptying of a pellet formulation, has been investigated in three fasted subjects. The pellets were radiolabelled with technetium-99m. Gastric emptying was measured using the technique of gamma scintigraphy. The pellets emptied from the stomach rapidly and in an exponential manner. Polycarbophil did not retard the gastric emptying of the pellets.
The Accumulation Mechanism of Cationic Mitomycin C-dextran Conjugates in the Liver: In-vivo Cellular Localization and In-vitro Interaction with Hepatocytes
Authors: Nakane Sachi , Matsumoto Satoshi , Takakura Yoshinobu , Hashida Mitsuru , Sezaki Hitoshi
Published: April 2011

To elucidate the mechanism of the accumulation of mitomycin C-dextran conjugate (MMC-D) in the liver, in-vivo cellular uptake and in-vitro cellular interaction of MMC-D have been studied. Localization of cationic and anionic MMC-D (MMC-Dcat. and MMC-Dan.) in different liver cell types following i.v. administration was examined in rats and the significant contribution of parenchymal cells demonstrated. In-vitro cellular interaction was determined by measuring the drug concentration in the medium after incubation with rat isolated hepatocytes. MMC-Dcat. was highly adsorbed on the surface of hepatocytes at pH 7.2, while the interaction between MMC-Dan. and hepatocytes was negligible. The percentage association of MMC-Dcat. with hepatocytes remained almost constant during the course of incubation and no significant difference was observed between the incubation at 4 and 37 °C. The adsorption phenomenon was shown to conform to Langmuir’s adsorption isotherm. The amount of MMC-Dcat. associated with hepatocytes increased as the molecular weight of the dextran chain increased. These results showed that MMC-Dcat. was adsorbed on the surface of hepatocytes by an electrostatic force and this binding was responsible for its remarkable accumulation in the liver in-vivo. Thus some physicochemical properties of the MMC-D conjugates are thought to play an important role in the disposition characteristics of the conjugates.
Formation and Release of [3H] Acetylcholine in the Rat Urinary Bladder Strip
Authors: D'Agostino G , Chiari M C , Grana E
Published: April 2011

The relationship between different frequencies of loading stimulation and [3H]acetylcholine (ACh) formation and release from nerve terminals has been investigated in extratrigonal strips of the urinary bladder of the rat. An increase in frequency (0.2, 0.4 and 0.8 Hz) for the 30 min incubations with [3H]choline produced an enhancement of storage of [3H]ACh from 19.5 to 34% of total tritium content in the tissue. Higher frequencies (1.6 and 3.2 Hz) failed to increase storage further on. The [3H]choline content did not vary significantly. Electrical field stimulation at 2 Hz (360 shocks) produced a release of tritium. The evoked outflow was higher when the strip was loaded at 0.8 Hz than at the other frequencies tested. Both [3H]ACh and [3H]choline were measured in the perfusate of strips preloaded at 0.8 Hz. Most of the induced outflow was found to be [3H]ACh, as in previous experiments carried out using 0.2 Hz as a loading frequency. The findings suggest that in the rat urinary bladder strip loading at 0.8 Hz is suitable for increasing the formation and the resulting release of [3H]ACh during electrical stimulation.
Interaction of the Anticonvulsants, Denzimol and Nafimidone, with Liver Cytochrome P450 in the Rat
Authors: Salmona M , Conti I , Testa R , Fracasso C , Caccia S
Published: April 2011

The presence of an imidazole moiety in the chemical structure of denzimol and nafimidone suggested that these new anticonvulsants might interfere with cytochrome P450-mediated mixed function monooxygenase activities. We therefore investigated their ability to bind reversibly to rat liver cytochrome P450. Both drugs displayed a type II spectra. The Ks values of binding were 6.66 and 7.00 mM, respectively, for denzimol and nafimidone. In other in-vitro studies the IC50 of the inhibition caused by denzimol and nafimidone was determined on carbamazepine (CBZ) epoxidation and diazepam C3-hydroxylation and N1-dealkylation. The IC50 values for CBZ epoxidation were 4.46 × 10−7 and 2.95 × 10−7 M, respectively, in the presence of denzimol and nafimidone. The IC50 values for diazepam C3-hydroxylation were 1.44 × 10−6 and 1.00 × 10−6 M, respectively, and those for N1-dealkylation 6.66 × 10−7 and 5.95 × 10−7 M. The inhibition of CBZ metabolism was also investigated ex-vivo and in-vivo after single oral doses (15 and/or 60 mg kg−1) of denzimol or nafimidone. Inhibition of CBZ-10,11-epoxidation by the two drugs was time- and dose-dependent. Further studies in-vivo showed that denzimol and nafimidone prolong pentobarbitone sleeping times indicating that both drugs bind to rat liver microsomes and are potent inhibitors in the rat of mixed function monooxygense activities both in-vitro and in-vivo.
Retention of Soman in Rats, Guinea-pigs and Marmosets: Species-dependent Effects of the Soman Simulator, Pinacolyl Dimethylphosphinate (PDP)
Authors: van Helden H P M , van der Wiel H J , Wolthuis O L
Published: April 2011

Whether the temporary retention of intact soman in the rat and its subsequent delivery from tissues into the circulation of the blood is also demonstrable in guinea-pigs and marmosets has been investigated as was whether the soman simulator PDP (pinacolyl dimethylphosphinate) prevented this retention. Electric eel AChE, intravenously injected 1.5 h after an intravenous soman intoxication into anaesthetized, atropinized and artificially ventilated guinea-pigs (150 μg kg−1 soman), marmoset monkeys (100 μg kg−1 soman) and rats (330 and 172.5 μg kg−1 soman) lost its activity faster than enzyme injected in non-intoxicated animals. Electric eel AChE incubated in the presence of pectoralis or diaphragm muscle isolated from soman-intoxicated rats, guinea-pigs and marmosets 0.5 or 1.5 h after the intoxication, was progressively inhibited, indicating that those muscles still delivered soman into the incubation medium. In rats, PDP (6.4 mg kg−1 i.v.) pretreatment was effective in preventing inhibition of intravenously injected electric eel AChE 1.5 h after intoxication with a high dose of soman (330 μg kg−1). But after intoxication with a low dose (172.5 μg kg−1), PDP pretreatment was ineffective in this action, however, it did lead to less soman delivery from muscle tissue isolated 30 min following the 172.5 μg kg−1 soman intoxication, suggesting that there was less soman in the tissue. In PDP (6.4 mg kg−1 i.v.)-pretreated marmosets (100 μg kg−1 soman) and guinea-pigs (150 μg kg−1 soman), to the contrary, the trend was for the injected AChE to be more inhibited, whereas only slightly less soman was delivered from isolated muscle tissue. It is suggested that after PDP treatment to rats the elimination of soman from the blood circulation is faster than in marmosets and guinea-pigs.
Enantiomer resolution of nefopam hydrochloride, a novel analgesic: a study by liquid chromatography and circular dichroism spectroscopy
Authors: Isaksson Roland , Sandström Jan , Eliaz Michal , Israely Zehorith , Agranat Israel
Published: April 2011

Nefopam, a potent analgesic, has been completely resolved into enantiomers on a preparative scale by low-pressure liquid chromatography on swollen, microcrystalline triacetylcellulose. The enantiomerically pure hydrochlorides were prepared from the base, and the circular dichroism spectra of the free base and the hydrochloride are reported.
Stereoselectivity of κ-opiate receptor ligands in inhibiting the binding of [3H][3-MeHis2]thyrotrophin releasing hormone to brain membranes
Authors: Bhargava Hemendra N , Das Sumantra , Gulati Anil
Published: April 2011

The effect of (±)-, (−)- and (+)-isomers of several ligands for κ-opiate receptors on the binding of [3H][3-MeHis2]-thyrotrophin releasing hormone ([3H]MeTRH) to rat brain membranes has been determined. [3H]MeTRH bound to rat brain membranes at a single high affinity site with maximal binding capacity (Bmax) of 48 ± 2 fmol(mg protein)−1, and an apparent dissociation constant, Kd of 4.6 ± 0.2 nM. At a concentration of 2 nM, the specific binding of [3H]MeTRH was 12.3 ± 0.6 fmol(mg protein)−1. The isomers of ketocyclazocine, tifluadom (1-methyl-2-(3-thienylcarbonyl) aminomethyl-5-(2-fluorophenyl) H-2,3-dihydro-1,4-benzodiazepine), and α-5,9-diethyl-2′-hydroxy-2-(3-furylmethyl)-6,7-benzomorphan [MR 2266 (−), MR 2267 (+)] were used for interaction studies. The (−)-isomer of each of the above drugs was more potent than the (+)-form in inhibiting the binding of [3H]MeTRH to brain membranes, whereas the (±)-forms had activity intermediate between (−)- and (+)-forms. The order of activity of κ-ligands was tifluadom > MR 2266 > ketocyclazocine. It is concluded that κ-opiate drugs inhibit the binding of [3H]MeTRH to brain membranes in a stereoselective manner with tifluadom being the most potent drug.
Structure-activity relationship of hylambatin and its fragments as studied in the guinea-pig ileum
Authors: Inoue A , Fukuyasu T , Nakata Y , Yajima H , Nomizu M , Inagaki Y , Asano K , Segawa T
Published: April 2011

Hylambatin (Hyl), a dodecapeptide isolated from the skin of the African frog, Hylambates maculatus, belongs to the family of tachykinin or physalaemin-like peptides. Hylambatin and its 12 fragments were tested in the guinea-pig ileum preparation for contractile activities. All fragments except 3 had contractile activities. The C-terminal fragment as short as the octapeptide sequence was at least as active as the parent molecules. The heptapeptide fragment (Hyl6-12) and the hexapeptide fragment (Hyl7-12) were less active and the C-terminal pentapeptide fragment (Hyl8-12) and the N-terminal hexapeptide fragment (Hyl1-6) were much less active. The N-terminal pentapeptide fragment (Hyl1-5) and the N-terminal fragment from which the N-terminal Asp or Asp-Pro residues were removed (Hyl2-6, Hyl3-6), were inactive at doses used.
The discrimination between human, porcine and bovine insulin with 1H NMR spectroscopy
Authors: Funke Carel W , Mellema Jan-Remt , Salemink Paul , Wagenaars Gerard N
Published: April 2011

The 1H- and 1H-1H correlation (COSY) NMR spectra of human, porcine and bovine insulin have been recorded. The 1.1–1.5 ppm regions of these spectra show the methyl signals of the alanine and threonine residues. The number of alanines and threonines differs for the three insulins and thus allows an easy discrimination with NMR.
Antidiarrhoeal activity of bisnordihydrotoxiferine isolated from the root bark of Strychnos trinervis (Vell.) Mart. (Loganiaceae)
Authors: Melo Margareth de F F , Thomas G , Mukherjee R
Published: April 2011

Bisnordihydrotoxiferine, a dimeric tertiary indole alkaloid obtained from the root bark of Strychnos trinervis (Vell.) Mart. (Loganiaceae), inhibited normal defaecation and castor oil, arachidonic acid, and magnesium sulphate-induced diarrhoea on intraperitoneal administration in mice. The effect may be related to the ability of the compound to decrease normal and castor oil-stimulated gastric emptying, small intestinal transit and water and electrolyte accumulation, and inhibition of normal colonic transit. As prostaglandins are involved in gastrointestinal functions, inhibition of their synthesis is likely to contribute to the anticathartic activity, which has never been reported before for an indole alkaloid.
Interaction of Memantine with Cholecystokinin Receptors in Mouse Brain
Authors: Verspohl E J , Koch R , Schatton W
Published: April 2011

The effect of memantine on CCK receptors in mouse brain has been investigated using particles of dissected cortex and striatum. Total binding of radio-labelled CCK33 was one-half maximal within 10 min of incubation and reached a maximum after 30 to 60 min when either cortex or striatum was used. Non-specific binding (presence of 100 μM unlabelled CCK8) was 50 to 80% of total binding at steady state conditions. CCK8 inhibited specific binding of radiolabeled CCK33 in a dose-dependent manner; the IC50 (half-maximal inhibitory concentration) was in the range 3 to 4 nM. Memantine increased CCK binding in a concentration-dependent manner, though at high concentrations. The EC50 (half-maximal effective concentration) of this effect was < 100 μM. The memantine effect is not due to an inhibition of labelled CCK degradation in the medium. The effect of memantine on CCK binding is unique for brain since it was not observed in pancreatic acinar membranes. These data, therefore, suggest a modulatory effect of memantine on CCK receptors in mouse brain (cortex and striatum) particles.
Agonist profile of ergometrine (ergonovine) on a population of postsynaptic α-adrenoceptors
Authors: Gibson A , Carvajal A
Published: April 2011

Ergometrine (0.02–5 μM) produced concentration-related contractions of the mouse anococcygeus muscle, which were unaffected by cocaine (2 μM) or by pretreatment of mice with 6-hydroxydopamine. Contractions were reduced by α-adrenoceptor antagonists; the rank order of potency was prazosin > phentolamine > yohimbine. With phenoxybenzamine as antagonist, the estimated dissociation constant (KD) for ergometrine was 0.41 μM. It is concluded that ergometrine causes direct activation of postsynaptic α1-adrenoceptors, and it is suggested that it acts on the same subtype of the receptor as imidazoline agonists.
Action of mefloquine on toad isolated rectus abdominis muscle
Authors: Lee H S , Go M L
Published: April 2011

The effects of mefloquine and quinine on acetylcholine-induced contractures of the toad rectus abdominis muscle have been investigated. Both drugs depressed acetylcholine-induced contractures in a dose-related and non-competitive manner. A partial reversal of the block was observed in the presence of 4-aminopyridine(10, 50 μM) and increased Ca2+ content (1.25 ×) of the Ringer solution. In both cases, the mefloquine-induced blockade was more readily reversed than that induced by quinine. Mefloquine and quinine at concentrations greater than 100 and 500 μM, respectively, also elicited a direct contractile response on the muscle. Quantitative differences in their contractile activity have been attributed to the greater lipid solubility and tissue binding affinity of mefloquine.
A selective inhibitor of cAMP-specific phosphodiesterase, Ro 20–1724, has no effect on the quantal release of acetylcholine from the mouse phrenic nerve
Authors: Chiou L C , Chang C C
Published: April 2011

The indirect twitch response of the mouse isolated phrenic nerve-diaphragm preparation, partially paralysed by tubocurarine, was restored only by about 10% by Ro 20–1724 at 2 to 280 μM. The solvent vehicle, dimethylsulphoxide, also showed the same effect to a similar extent. Intracellular recordings with glass microelectrodes revealed that Ro 20–1724 (40 μM) affected neither the resting membrane potential, the amplitude and frequency of miniature endplate potentials nor the amplitude of nerve-impulse evoked endplate potentials recorded in curarized preparations. The result indicates that Ro 20–1724 at a concentration four times the IC50 of phosphodiesterase inhibition has no effect on the quantal release of acetylcholine from a mammalian motor nerve and suggests that cAMP has no modulatory effect on the transmitter release.
N-Methylation of nicotine enantiomers by human liver cytosol
Authors: Crooks Peter A , Godin C Steven
Published: April 2011

Incubation of human liver cytosol with either R-(+)-[3H-N′CH3]nicotine or S-(−)-[3H-N′CH3]nicotine results in the formation of the corresponding N-methyl quaternary ammonium metabolite. A substrate stereoselectivity was observed in that the turnover number for the methylation of the S-(−)-isomer was 0.25 pmol mg 1 protein h−1, whereas that for the R-(+)-isomer was 2.11. The latter substrate exhibited an apparent Km value of 20.1 μM. Nicotine N-methylation appears to be species-dependent, since rat liver homogenates contained no ‘nicotine N-methyl-transferase’ activity, whereas with guinea-pig liver homogenates, a substrate specificity for only R-(+)-nicotine was observed.
Measurement of 5-Hydroxytryptamine Turnover Rate in Rat Cerebral Arteries
Authors: Soto Juan C , Marco Emilio J
Published: April 2011

Two methods for assessing 5-hydroxytryptamine (5-HT) turnover rate have been tested in the cerebral vessels of the rat. The pretreatment of the animals with benserazide 45 min before death brought about an increase in the levels of 5-hydroxytryptophan (5-HTP). When the MAO inhibitor pargyline was injected and the animals killed at different times, there was an exponential decrease in the concentration of 5-hydroxyindole acetic acid (5-HIAA) with time, whereas the increase in 5-hydroxytryptamine was linear only during the first 30 min, thereafter reaching a plateau. This pattern was similar to that obtained in the caudate nucleus after MAO blockade. In the hippocampus, pargyline induced a lineal accumulation of 5-HT throughout the experiment as well as an exponential decay of the 5-HIAA concentration. These results indicate that the turnover rate of 5-HT can be appraised in the rat cerebral arteries either after the rate of disappearance of 5-HIAA or from the accumulation rate of 5-HTP.
Paroxetine, a Selective 5-Hydroxytryptamine Uptake Inhibitor with Antidepressant Properties, Lacks Amphetamine-like Stimulus Properties in an Operant Drug Discrimination Bioassay in Rodents
Authors: Goudie A J , Dubicki W , Leathley M
Published: April 2011

To evaluate whether the novel antidepressant paroxetine has any possible amphetamine-like actions, rats were trained to discriminate (+)-amphetamine sulphate in a standard two lever operant drug discrimination (DD) procedure using a fixed ratio 10 schedule of food reinforcement with a quantal, lever selection, index of the amphetamine stimulus. The ‘training’ dose of amphetamine was 1 mg kg−1, i.p. Rats trained with this dose of amphetamine (n = 15) learned the drug discrimination rapidly over 30 training sessions and discriminative performance in these animals was subsequently maintained at a high level of accuracy (90% correct) over a prolonged time. In tests in these trained animals, amphetamine itself and the antidepressant agents nomifensine and tranylcypromine all produced clear, unequivocal dose-related generalization to amphetamine with ED50s of 0.2, 0.5 and 1.6 mg kg−1 respectively (as determined by probit analyses). In tests with paroxetine hydrochloride it was established that, over the dose range 0.3 to 10 mg kg−1, no evidence was seen of generalization to the amphetamine stimulus. These data confirm earlier studies which suggested that some antidepressants may possess abuse potential because of their ability to induce amphetamine-like internal states. In contrast, paroxetine is devoid of such properties.
A method for stabilization of monoamine oxidases in homogenates of rat intestine epithelium
Authors: Barwell C J , Canham C A
Published: April 2011

In a homogenate of epithelium isolated from the small intestine of male Wistar rats, the amine oxidase activity with 10−3M tyramine was 9200 ± 200 nmol (g tissue)−1 h−1 of which 91% was due to the A form of monoamine oxidase (MAO) and 9% to the B form. Semicarbazide-sensitive amine oxidase activity was not detected with either 10−3M tyramine or 10−4M benzylamine as substrate. However, it was detectable in the homogenate of the gut residue where the activity with 10−4M benzylamine was 3600±200 nmol (g tissue)−1 h−1. The MAO activity, in homogenates of epithelium prepared with 0.1 M sodium phosphate pH 7.4, was stable at 4°C for at least 6 h whilst at minus 20°C it decreased by 70% within 24 h. Incorporation of 10% (v/v) glycerol into the homogenization medium stabilized the enzymes. The total activity and proportions due to MAO-A and MAO-B and kinetic constants for tyramine and 5-hydroxytryptamine, did not alter during 5 weeks storage at −20°C. The ability to store tissue homogenates should facilitate studies of intestinal amine oxidases.
The serum amyloid P response in the mouse air pouch
Authors: Bottomley K M K , Rising T J , Steward A
Published: April 2011

Levels of the acute phase reactant serum amyloid P (SAP) have been measured in the mouse pouch model of rheumatoid arthritis. Implantation of cartilage resulted in a significant and rapid elevation in the SAP concentration, which remained high for the duration of the experiment (14 days). Initial studies with several clinically employed antirheumatic drugs indicated that dexamethasone and cyclosporin A had a marked inhibitory effect.
Formation and In-vitro Evaluation of Theophylline-loaded Poly(methyl methacrylate) Microspheres
Authors: Pongpaibul Yanee , Maruyama Kazuo , Iwatsuru Motoharu
Published: April 2011

Theophylline-loaded poly(methyl methacrylate) (PMM) microspheres were prepared by the solvent evaporation method. Increasing the drug to polymer ratio increased both the mean particle size of the microspheres and the release rate. Polyethylene glycol (PEG) 4000 was used to improve the release rate of theophylline from the microspheres. No marked effect was observed on particle size distribution of the microspheres as a function of PEG concentration but there was a pronounced effect on drug release. The different particle sizes of microspheres prepared from the same drug to polymer ratio showed no significant difference in drug content, indicating that the ratio between theophylline and PMM remained practically constant regardless of the size of microspheres. Release characteristics of the microspheres were influenced by drug to polymer ratio, the amount of PEG incorporated and the particle size of microspheres. The release rate was slightly higher in simulated gastric fluid than in simulated intestinal fluid. The release profiles of the drug were modified by mixing microspheres of different formulations in different ratios.
Pharmacological profile of a chromanamine analogue (DP-6OH-3CA) of the selective presynaptic dopamine agonist N, N-dipropyl-7-hydroxy-2-aminotetralin
Authors: Vermue Niek A , Dukstra Durk , Horn Alan S
Published: April 2011

The pharmacological profile of an oxygen isostere of the selective presynaptic dopamine agonist DP-7OH-AT, i.e. dipropyl-6-hydroxy-3-chromanamine (DP-6OH-3CA) has been evaluated in various receptor binding, neurobiochemical and behavioural experiments. The chromanamine displaced the 3H-labelled dopamine ligands, 5,6-DPAT and N-0437, with Ki values of 106 and 143 nM, respectively. In in-vivo biochemical models for presynaptic activity the chromanamine induced a half-maximal effect in the γ-butyrolactone reversal test at 6.8 μmiol kg−1 and had an ED70 value of 40 μmol kg−1 for HVA decrease in the striatum. In behavioural models for postsynaptic dopaminergic activity a half-maximal effect for the induction of stereotypy was reached at 100 μmol kg−1 and reversal of the effects of reserpine to a level of 200 counts was induced at 11 μmol kg−1. On comparison of these results with the results obtained with the carbon analogue of DP-6OH-3CA, i.e. DP-7OH-AT, it is apparent that the chromanamine has a reduced potency for dopamine D2 receptors in in-vitro and in-vivo models. The selectivity for presynaptic dopamine receptors was lower than with DP-7OH-AT and the isomeric chromanamine, DP-8OH-3CA, indicating that the optimal position of the hydroxyl group for presynaptic selectivity is in the 8 and not in the 6 position for the chromanamines.
Enhancement of adenosine-induced relaxant responses of the guinea-pig isolated taenia coli and aortae by a novel nootropic agent BY-1949: comparison with dipyridamole
Authors: Tanabe Shigeru , Ikeda Yugo , Shiraki Yasuyuki , Sakal Kazushige
Published: April 2011

In muscle strips of guinea-pig taenia coli and aortae, the effects of 3-methoxy-1 1-methyldibenz[b,f][1,4]oxazepine-8-carboxylate (BY-1949) on the relaxant response to adenosine have been compared with those of dipyridamole. BY-1949 (3 × 10−5–10−4 M) as well as dipyridamole (3 × 10−7–10−5 M) resulted in a significant potentiation of relaxant responses to a cumulative administration of adenosine (10−6–10−3 M), but the drugs did not affect the response to noradrenaline and acetylcholine. The results indicate that BY-1949 exerts a selective potentiating effect on reactivity to exogenous adenosine.
Brain penetration of orally administered sodium pyroglutamate
Authors: Chanal J L , Audran M , Sicard M T , Briley M
Published: April 2011

The absorption and brain penetration of [3H]pyroglutamate was determined after oral administration to rats. Gas-liquid chromatography of the methylated derivatives followed by mass fragmentometry was used to analyse the plasma and brain levels of pyroglutamate. [3H]Pyroglutamate was separated from other labelled compounds by thin layer chromatography. The administration of 500 mg kg−1 [3H]pyroglutamate resulted in a 30-fold increase in plasma levels and a doubling in the brain levels. Over 60% of the cerebral radioactivity was present as [3H]pyroglutamate demonstrating that pyroglutamate is not only well absorbed but also penetrates in significant amounts into the brain.
Identification of 5-HT3 recognition sites in the ferret area postrema
Authors: Barnes N M , Costall B , Naylor R J , Tattersall F D
Published: April 2011

The 5-HT3 receptor antagonist [3H]zacopride was used to identify 5-HT3 recognition sites in the ferret area postrema. Specific binding was determined by the inclusion of the 5-HT3 receptor antagonist BRL 43694 in the incubation media, and was shown to be much higher in the area postrema than in other brain regions. The increased binding in the area postrema may reflect either a greater number of binding sites, a higher affinity for such sites, or both. The results indicate that 5-HT3 recognition sites are present within the area postrema and may afford an antiemetic site of action for zacopride and other 5-HT3 receptor antagonists.
The Effects of 1-Methyl-4-phenylpyridinium Ion (MPP+) on the Efflux and Metabolism of Endogenous Dopamine in Rat Striatal Slices
Authors: Snape B M , Pileblad E , Ekman A , Magnusson T , Carlsson A , Engel J
Published: April 2011

1-Methyl-4-phenylpyridinium ion (MPP+) was shown to accumulate concentration-dependently in slices from rat striatum. At 10 μM, MPP+, the tissue concentration was found to be 118 ± 9 μM following 75 min of incubation. The accumulation of MPP+ was reduced in the presence of 10 μM of the selective dopamine uptake inhibitor GBR 12909 (−50%) or by destruction of the dopaminergic terminals by complete hemisection of the forebrain 4 days before the experiments (−75%). Accumulation of MPP+ in the catecholamine-poor occipital cortex and cerebellum was only 25% of that obtained in striatum. Reserpine pretreatment of the rats in-vivo did not modify the accumulation of MPP+ in the striatal slices. MPP+ (1–10 μM) increased the net efflux of dopamine and reduced the efflux of the dopamine metabolite DOPAC from the striatal slices. The effect on dopamine was readily diminished if MPP+, after a 15 min incubation, was then omitted from the medium. In contrast, the DOPAC efflux was reduced for 75 min even though MPP+ was present in the incubation medium only for the first 15 min. In the presence of the monoamine oxidase inhibitor, pargyline (350 μM), MPP+ also produced an increase in dopamine efflux. In normal medium, the presence of the dopamine uptake inhibitor GBR 12909 (10 μM), or the absence of calcium, failed to modify the MPP+-induced increase in dopamine efflux. MPP+ also increased dopamine efflux from slices from reserpinized rats. In normal medium, MPP+ (10 μM) was much more effective than GBR 12909 (10 μM) in increasing dopamine efflux, whereas in the presence of pargyline both drugs were equally effective. It is suggested that, in rat striatal slices, MPP+ is selectively accumulated within the dopaminergic nerve terminals by means of a carrier mediated transport, sensitive to GBR 12909. It is concluded that MPP+ increases dopamine efflux largely by inhibiting monoamine oxidase and by inhibiting dopamine uptake. These data are discussed in relation to the previously observed action of MPTP on dopamine metabolism in mouse brain in-vivo.
Importance of D-2 Mechanisms in the Reversal of Reserpine Hypothermia in the Mouse
Authors: Volterra G , Borsini F , Meli A
Published: April 2011

The D-2 agonist LY 171555 (0.05, 0.1, 0.2 mg kg−1 s.c.) but not the D-1 agonist SK&F 38393 (5, 10, 20 mg kg−1 s.c.) reduced reserpine-induced hypothermia (RIH) in mice. This effect was antagonized by the D-2 antagonist (-)-sulpiride (50 mg kg−1 i.p.) but not by the D-1 antagonist SCH 23390 (0.1 mg kg−1 s.c). SK&F 38393 (20 and 1 mg kg−1 s.c.) did not alter the effect of LY 171555 (0.1 and 0.2 mg kg−1) on RIH, but administration of both LY 171555 (0.2 mg kg−1 s.c.) and SK&F 38393 (1 mg kg−1 s.c.) antagonized the reserpine-induced sedation.
Sustained release of indomethacin from chitosan granules in beagle dogs
Authors: Miyazaki Shozo , Yamaguchi Hideki , Yokouchi Chizuko , Takada Masahiko , Hou Wei-Min
Published: April 2011

The potential of chitosan granules as an oral sustained-release dosage form of indomethacin has been compared with conventional capsules in beagle dogs. When a commercial capsule was administered orally, the plasma concentrations reached the maximum level in 30 min. The granules did not give a sharp peak to the plasma concentration, but produced a sustained plateau of the drug. This may be due to the slow rate of release and a longer residence time in the stomach. Thus, in terms of reducing the peak in plasma concentration and maintenance of drug concentration in plasma, the chitosan granules were superior to conventional capsules.
Enantioselective Metabolism During Continuous Administration of S-(−)- and R-(+)-Nicotine Isomers to Guinea-Pigs
Authors: Nwosu C G , Godin C S , Houdi A A , Damani L A , Crooks P A
Published: April 2011

The S-(−)- and R-(+)-nicotine isomers were administered subcutaneously via Alzet osmotic pumps to male Hartley guinea-pigs (n = 5 with each isomer) over a 23-day period. Estimated dosage rate throughout the experiment was 0.6 mg−1. Urine samples were collected over this time and the levels of urinary oxidative and N-methylated nicotine metabolites were measured by cation-exchange HPLC analysis. S-(−)-Nicotine formed only oxidative metabolites, whereas the R-(+)-isomer formed both oxidative and N-methylated metabolites. 3′-Hydroxycotinine and nicotine-1′-oxide were major metabolites of both enantiomers; cotinine and nornicotine were only minor metabolites. The major N-methylated metabolite of R-(+)-nicotine was N-methylnicotinium ion; N-methylcotininium ion and N-methylnornicotinium ion were also identified as metabolites of this nicotine isomer. Total N-methylated quaternary ammonium metabolites accounted for 15 to 20% of the administered dose of R-(+)-nicotine. An interesting enantioselective reduction in the percent of oxidative urinary metabolites formed from S-(−)-nicotine was observed over 23 days. This may indicate the enantioselective induction of an uncharacterized metabolic pathway for this nicotine isomer.
Orally administered κ but not μ opiate agonists enhance gastric emptying of a solid canned food meal in dogs
Authors: Gué M , Fioramonti J , Junien J L , Bueno L
Published: April 2011

The effects of oral administration of selective mu (D-Ala2, N-Me-p-nitro-Phe4 Gly5-ol-DAGO, morphine) and/or kappa (3,4 dichloro-N-methyl N [2-(1. fyrrolidinyl) cyclohexyl]-benzene acetamide-U-50488, tifluadom) or mixed agonist (N-desmethyltrimebutine) opioid on gastric emptying have been evaluated using a radiolabeled [57Co] canned food meal in dogs fitted with gastric cannulas. In control conditions (placebo) the percentage of solids emptied 1 h after feeding was 27.3 ± 41%. When given orally at doses of 0.01 to 0.5 mg kg−1, U-50488 increased significantly (P < 0.05) by 29.1 to 60.8% in a dose-related manner (r −0.94, P < 0.01) the amount of gastric emptying of the meal in 1 h. This effect was reproduced by oral administration of tifluadom (0.01 to 0.1 mg kg−1)and by N-desmethyltrimebutine (0.1 to 1 mg kg−1). In contrast, the gastric emptying was unaffected by DAGO and morphine at low doses (0.01 and 0.1 mg kg−1) but significantly (P < 0.05) slowed with higher doses of morphine. The increases in amount of gastric emptying induced by tifluadom, U-50488 and N-desmethyltrimebutine were abolished by previous administration of naloxone (0.1 mg kg−1 i.v.) and [(3-furylmethyl) noretazocine]-MR 22–66 (0.1 mg kg−1 i.v.). These results indicate that orally administered kappa, but not mu agonists at doses not exceeding 1 mg kg−1 enhance the amount of gastric emptying of a solid meal in dogs and suggest that this is due to a selective local stimulation of kappa mucosal or submucosal opiate receptors at antroduodenal level.
[3H]8-OH-DPAT labels the 5-Hydroxytryptamine uptake recognition site and the 5-HT1A binding site in the rat striatum
Authors: Alexander Beverley S , Wood Martyn D
Published: April 2011

The binding of [3H]8-hydroxy-2-(di-N-propylamino)-tetralin ([3H]8-OH-DPAT) to rat hippocampal and striatal membranes has been compared. In the hippocampus, low concentrations of [3H]8-OH-DPAT bound to a single, high affinity site which was sensitive to inhibition by spiperone, buspirone and ergotamine but not by mianserin, quipazine or (−)-propranolol. This is consistent with a selective labelling of the 5-HT1A receptor. In the striatum, [3H]8-OH-DPAT bound to two sites with high and low affinity (KD’s 1.18 and 109 nM). The high affinity component was blocked by low concentrations of buspirone, spiperone and ergotamine. The low affinity component was blocked only by high concentrations of buspirone and spiperone, and was not displaced by ergotamine at concentrations up to 1 μM. The ergotamine-resistant component of striatal [3H]8-OH-DPAT binding was blocked by low concentrations of the 5-HT uptake inhibitors fluvoxarmine and paroxetine, and by relatively low concentrations of 5-HT itself. Thus [3H]8-OH-DPAT labels the 5-HT transporter in the rat striatum. Unlike [3H]imipramine binding, the binding of [3H]8-OH-DPAT to the 5-HT transporter was independent of external sodium ions. It is therefore suggested that 8-OH-DPAT acts as substrate for the 5-HT transporter and labels the 5-HT recognition site of the transporter complex.
Effects of beclamide on isolation-induced aggression and locomotor activity in mice
Authors: Darmani N A , Sewell R D E , Nicholls P J
Published: April 2011

The anti-aggressive effects of orally administered beclamide (N-Benzyl-β-chloropropionamide) have been studied in male albino mice which were individually isolated for a 28-day period. Beclamide (50–250 mg kg−1 p.o.) caused an overall dose-dependent increase in the attack onset latency, a reduction in the percentage of animals attacking and the mean number of attacks/animal for this model of aggression. In addition, the highest dose of beclamide (250 mg kg−1 p.o.) did not significantly modify locomotor activity in mice. It was concluded that beclamide induced anti-aggressive effects at non-sedative doses. This anti-aggressive action was thought be at least partially mediated, through a beclamide-induced release of 5-HT from presynaptic sites.
Amelioration of the hypotensive effect of trypanocidal diamidines by use of heavy soluble salts
Authors: Steinmann U , Fritsch C
Published: April 2011

The influence of a heavy soluble dicaprylate salt preparation of a new trypanocidal diamidine (DiaPBF) on systolic and diastolic blood pressure and heart rate of rats has been compared with the effects of the easily soluble DiaPBF-dihydrochloride (DiaPBF-diHCl). After the dicaprylate the drop of the systolic blood pressure was 50% smaller than after an equimolar dosis of DiaPBF-diHCl.
Formulation Studies of Tableted Oral Rehydration Salt Mixtures
Authors: Ombaka Eva M A , Alkan M Hayat , Groves M J
Published: April 2011

Dehydration following non-specific diarrhoea may be prevented by oral administration of a simple glucose/salt mixture. A solution tablet of this mixture would have advantages of stability under environmental exposure and transport if the costs could be held within reasonable limits. The moisture adsorption and compression characteristics of Oral Rehydration Salts (ORS) ingredients have been studied. Combinations of ingredients resulted in a moisture adsorption higher than that of the individual components. This may be explained in terms of critical relative humidity, RHo, and environmental relative humidity RHi. Preparation of a stable ORS solution tablet therefore requires protection of moisture adsorbing components from the environment. The present UNICEF ORS mixture compacted easily by direct compression but gave fragile tablets, which were hygroscopic. This can be reduced by film coating the electrolyte component as granules with a resin (Eudragit L), or by simulating direct compression of the glucose as a compression-coating around the precompressed electrolytes. The packaging of compression-coated solution tablets in inexpensive polyethylene bags may lengthen the shelf-life and make the preparation less costly than the currently supplied ORS powders packed in laminated aluminium sachets. The increased dissolution lag time for the compacted tablet is a disadvantage that can be overcome by instructions to crush the product immediately before use.
Rectal Absorption of E-2078 (Dynorphin Analogue Peptide) in Rats
Authors: Murahashi Naokazu , Kato Akira , Koyama Noritoshi , Watanabe Sumio , Yuzuriha Teruaki , Miyake Yasuo
Published: April 2011

The plasma levels in rats of a dynorphin analogue peptide (E-2078) after rectal administration have been studied. The bioavailabilities of E-2078 after rectal administration, subcutaneous injection, intramuscular injection, and oral administration were 21·6, 67·8, 67·1, 0·7%, respectively. The effect of dose, pH, osmolarity and viscosity on the rectal absorption of E-2078 were studied. A sigmoid relationship between the dose and the AUC was observed on rectal administration, while there was a linear relationship on intramuscular administration. The AUC was increased in acidic solution and highly viscous solution. The osmolarity did not affect the absorption of E-2078. In microscopic studies, E-2078 caused little or no damage to the rectal mucosa in rats.