bluuebunny/crossref_metadata_2025 huggingface dataset:
Uptake of amino β-lactam antibiotics into rat intestinal brush border membrane vesicles
Authors: Iseki Ken , Iemura Akihiro , Miyazaki Katsumi , Arita Takaichi
Published: April 2011

Uptake of amino β-lactam antibiotics into rat intestinal brush border membrane vesicles has been examined for characterization of the transport of the antibiotics through the gut wall of the rat. The uptake of cephradine, cephalexin and ampicillin into membrane vesicles was similar, and there were no significant changes in the uptake in the presence of a NaCl or a KCl gradient. These results suggested that the carrier-mediated transport systems relating to amino acids and glucose were not concerned with the intestinal absorption mechanism of amino β-lactam antibiotics.
Comparative pharmacokinetics of theophylline and ethylenediamine following single and repeated doses of a sustained-release aminophylline preparation to volunteers
Authors: Cotgreave Ian A , Caldwell John
Published: April 2011

Plasma concentrations of theophylline and ethylenediamine have been measured by HPLC after a single dose and also after a further four consecutive doses at 12 h intervals of a tablet containing 225 mg aminophylline in a sustained release matrix (Phyllocontin) had been taken by volunteers. A dissolution study of the product showed the release of theophylline to follow zero-order kinetics, to be independent of bath pH, and to be complete in 6.5 h, while the release of ethylenediamine depended upon the pH of the medium and was more extensive in acid solutions. After one tablet, the plasma theophylline concentrations reached a maximum of 4 μg ml−1 at 5 h and fell slightly at 7 h. Immediately before the fifth dose, the trough plasma value was 4.7 μg mol−1, and this rose to 7.7 μg ml−1 5 h after the dose. The areas under the plasma level-time curves (AUC) were significantly (P < 0.001) increased by the chronic regimen, and although the individual values were highly variable, the increase in AUC from the first to the fifth dose was significantly (P < 0.001) correlated within each subject. Ethylenediamine concentrations after a single dose reached a peak of 0.16 μg ml−1 at 1 h, and returned to baseline values in 5–7 h. After the fifth dose, the plasma levels and kinetics were no different from those obtained with the first dose indicating that ethylenediamine did not accumulate as a result of chronic administration of aminophylline in a form designed to give steady-state levels of theophylline.
Absorption and metabolism of hexamethylmelamine and pentamethylmelamine in rat everted perfused gut segments: correlation with in-vivo data
Authors: Borm Paul J A , Frankhuyzen-Sierevogel Ank C , Weller Erwin B C , Noordhoek Jan
Published: April 2011

The intestinal oxidative metabolism of hexamethylmelamine (HMM) and pentamethylmelamine (PMM) has been studied in microsomes, isolated mucosal cells and intestinal perfused segments. (sub)Cellular systems revealed an almost equal Km (53–65 μM) and Vmax (5.6–7.0 nmol min−1 g−1 intestine) for both compounds. Detailed studies in everted intestinal perfused segments, showed that HMM is metabolized to a far greater extent than PMM (e.g. 11-times, at 80 μM substrate concentration) while PMM transport was 3 times greater than the transport of unchanged HMM. Only when perfused segments were used as an in-vitro tool was a good correlation observed between the in-vivo and in-vitro rate of intestinal metabolism of HMM and PMM. It is concluded that this is due to preservation of structural integrity of the mucosa for both absorptive and metabolic processes.
Vascular smooth muscle cells: a major source of the semicarbazide-sensitive amine oxidase of the rat aorta
Authors: Lyles Geoffrey A , Singh Iqbal
Published: April 2011

Several methods have been used to study the distribution of the semicarbazide-sensitive amine oxidase (SSAO) within the wall of the rat aorta. After separation of the smooth muscle-containing layers of the tunica media from the connective tissue of the tunica adventitia, much higher specific enzyme activity (measured with 1 μM benzylamine) was found in homogenates of the media than of adventitia. Similar results were obtained for MAO-A (with 1 mM 5-HT as substrate). SSAO activity was also considerably higher in homogenates of cells (predominantly smooth muscle) isolated from medial tissue by enzymatic dissociation with collagenase and elastase compared with homogenates of cells (mostly of connective tissue origin) from the adventitia. Histochemical staining resulting from SSAO activity (with benzylamine as substrate) occurred predominantly and intensely over the tunica media in rat aortic sections, although some occasional staining of adventitial sites was also observed. Staining was prevented by the SSAO inhibitors hydroxylamine (1 μM) and semicarbazide (1 mM), but not by the MAO inhibitor, clorgyline (1 mM). These results indicate that SSAO is associated predominantly, although not exclusively, with the smooth muscle cells in the rat aorta. Our findings that β-aminopropionitrile (BAPN) is a reversible, competitive inhibitor (Ki around 2 times 10−4 M) of SSAO, in contrast to the irreversible inhibition of the connective tissue lysyl oxidase by BAPN reported by others, provides further evidence that these enzymes are not identical.
Circadian changes in procainamide and N-acetylprocainamide kinetics in the rat
Authors: Bruguerolle B , Jadot G
Published: April 2011

The aim of this study was to investigate the possible influence of the time of administration on procainamide and N-acetylprocainamide (NAPA) kinetics in the rat. A single 50 mg kg−1 i.p. dose of procainamide was given to Wistar AF SPF adult male rats maintained under controlled environmental conditions (LD: 06.00h-18.00h) at four different fixed times i.e. 10.00, 16.00, 22.00 and 04.00h. Procainamide and NAPA plasma levels were determined by an immunoenzymatic method. Our data showed significant 24 h variation of the following pharmacokinetic parameters: highest elimination half-lives at l0.00h (t 1/2 β = 0.736 ± 0.020h) for procainamide and at 04.00h (t 1/2 β = 3.55 ± 0.08h) for NAPA (P < 0.001); highest apparent volume of distribution at 04.00h for procainamide (Vd = 2.35 ± 0.17 litre) (P < 0.05); highest ratio AUC NAPA/AUC procainamide at 04.00h (1.039 ± 0.056) (P < 0.001). Procainamide clearance and Cmax and AUC for procainamide and NAPA were not significantly dependent on time of day. These data indicate a 24 h variation in the metabolism of procainamide which is converted to NAPA, the N-acetylation being greatest at 04.00h.
Significance of particle size of mebendazole in the treatment of tapeworm infections
Authors: Gemmell M A , Johnstone P D , Oudemans G
Published: April 2011

Taenia hydatigena and Echinococcus granulosus in dogs have been used as a model to evaluate the response of these parasites to increasing doses of mebendazole in different dose forms (powder, micronized powder and tablets of micronized powder). Overall the micronized powder proved to be the most active, the tablets less so and the normal powder least active. Statistical confirmation was obtained that the use of this drug in different dose forms changed the rate of the response, suggesting that in the treatment of human hydatid disease caused by Echinococcus spp and cysticercosis caused by Taenia solium, the dosage form may be a vital factor in the drug's efficacy.
Effects of metoclopramide and domperidone on cholinergically mediated contractions of human isolated stomach muscle
Authors: Sanger G J
Published: April 2011

The experiments examine the actions of metoclopramide and domperidone on the responses evoked by electrical field stimulation or by acetylcholine, in longitudinal muscle strips obtained from human stomach. Electrical field stimulation evoked contractions which were predominantly cholinergically mediated; metoclopramide 0.28-28 μM caused a concentration-dependent increase in the height of these contractions. In the presence of atropine and barium chloride, electrical stimulation evoked relaxations of the stomach muscle, probably by stimulating non-adrenergic, non-cholinergic inhibitory nerves; metoclopramide 28 μM had no effect on these relaxations. Metoclopramide 0.003-2.8 μM had no effect on contractions evoked by exogenous acetylcholine, although higher concentrations of the drug increased the contractions. The results suggest that in human isolated stomach, low concentrations of metoclopramide may increase electrically evoked cholinergic activity by increasing the release of neuronal acetylcholine. Stimulation by metoclopramide of cholinergic activity in the gut may therefore be an important mechanism by which the drug increases gastrointestinal motility during therapy. Cholinergically mediated contractions were not increased by domperidone, and other mechanism(s) of action may therefore be important for this drug.
5-Hydroxytryptamine receptor antagonism by metoclopramide and ICS 205–930 in the guinea-pig leads to enhancement of contractions of stomach muscle strips induced by electrical field stimulation and facilitation of gastric emptying in-vivo
Authors: Buchheitt K H , Costall B , Engel G , Gunning S J , Naylor R J , Richardson B P
Published: April 2011

Contractions induced by electrical field stimulation of isolated circular muscle strips, taken from the guinea-pig stomach, were enhanced by metoclopramide, ICS 205–930 and MDL 72222 at concentrations similar to those shown to antagonize at neuronal 5-hydroxytryptamine receptor sites in a variety of preparations. Metoclopramide, MDL 72222 and ICS 205–930 also facilitated gastric emptying in-vivo. The abilities of metoclopramide, MDL 72222 and ICS 205–930 to enhance stomach muscle contraction processes and to facilitate gastric emptying may be the consequence of 5-hydroxytryptamine receptor antagonism.
Protective effect of GABA and sodium valproate on stress-induced gastric lesions in guinea-pigs
Authors: Miñano F J , Serrano J S , Durán J A , Sancibrián M
Published: April 2011

γ-Aminobutyric acid (GABA) and sodium valproate (VPA) inhibit the formation of stress-induced gastric ulcers in guinea-pigs. The present study was conducted to evaluate the effect of these drugs on the development of cold- and restraint-induced gastric ulcers in guinea-pigs. In control saline-pretreated animals, a 3 h exposure to cold and restriction resulted in the production of gastric ulcers in 9 out of 10 animals. GABA (200 mg kg−1 oral, i.p.) completely prevented the development of gastric ulcers. VPA (100 and 200 mg kg−1 i.p.) exerted no significant effects on the development of gastric ulcers. GABA (100 mg kg−1 oral and i.p.) and VPA (oral) also exhibited partially protective activity. It is suggested that GABA may participate in a physiological modulation of the gastric mucosal barrier, by increasing its resistance to stress-induced lesions.
The plasto-elasticity and compressibility of coated powders and the tensile strengths of their tablets
Authors: Ejiofor Obi , Esezobo S , Pilpel N
Published: April 2011

A study has been made of the effects produced on the tensile strength, brittle fracture index (BFI), ‘plasto-elasticity’ ratio, ER/PC, and yield pressure (1/KH derived from Heckel plots) of sodium salicylate and calcium carbonate as a result of coating their particles with increasing amounts of silicones and polysorbates before subjecting them to compression to form tablets. The coatings act as lubricants reducing bond formation due to plastic deformation of particles. They caused a reduction in the tensile strengths and yield pressures of the tablets but increased their BFI values and their ER/PC ratios. Tablets of calcium carbonate tended to cap or laminate when their BFI value was >0.7 and their ER/PC ratio was >7. Sodium salicylate whose BFI values were all <0.7 produced satisfactory tablets when their ER/PC ratio was <10 but tended to cap or laminate when it was >10.
The prophylactic efficacy of various simulators against intoxication with the organophosphate soman: structure-activity studies
Authors: Van Helden H P M , Benschop H P , Wolthuis O L
Published: April 2011

The effects were investigated of structural variations of the soman simulator pinacolyl dimethylphosphinate on its efficacy to prevent secondary failure of oxime-induced recovery of neuromuscular transmission and death after soman intoxication. The simulators were administered prophylactically to atropinized, HI-6 treated rats, dosed with 6 or 8 × LD50 soman. In these new simulators the pinacolyl moiety was varied, the phosphonyl oxygen atom was replaced by sulphur, or the phosphorous-bound methyl groups were replaced by ethyl or methoxy groups. All these variations appeared to be less active than pinacolyl dimethylphosphinate. Intravenously, the latter compound was very effective at a dose of 12 μmol kg−1; its i.v. LD50 appeared to be higher than 1 mmol kg−1.
In-vitro study of the enkephalinergic hypothesis for non-adrenergic, non-cholinergic innervation in the cat stomach
Authors: Lefebvre R A , Bogaert M G , De Schaepdryver A F
Published: April 2011

It has been suggested that enkephalins are involved in the gastric relaxation induced by stimulation of the non-adrenergic, non-cholinergic vagal fibres in the cat stomach. Experiments were therefore performed on strips of cat stomach. With longitudinal and circular gastric fundus and corpus strips from reserpinized cats, non-adrenergic, non-cholinergic relaxatory responses could be elicited by transmural electrical stimulation in Tyrode solution containing atropine and 5-hydroxytryptamine. Morphine, leu-enkephalin and met-enkephalin did not influence the tone of the strips or the relaxation evoked by stimulation at 8 Hz, and neither did the opioid antagonist, naloxone. These results do not support the enkephalinergic hypothesis for the non-adrenergic, non-cholinergic vagal fibres in the cat stomach.
The effect of glycerol-induced acute renal failure upon cardiac reactivity in the rat: influence of indomethacin treatment and renal pedicle ligation
Authors: Yates M S , Askey Elizabeth A , Wilmot Susan E , Bowmer C J
Published: April 2011

Cardiac chronotropic responses to isoprenaline, carbachol and electrical stimulation of the cervical sympathetic and vagal nerves were recorded in rats with glycerol-induced acute renal failure (ARF) and control rats. The experiments involving electrical stimulation of cardiac nerves were performed in rats which either had been pretreated with indomethacin (1 mg kg−1 twice daily for 2 days) or had undergone acute bilateral renal pedicle ligation. The findings from this investigation indicate that the reduced chronotropic responses to vagal stimulation in rats with glycerol-induced ARF are due to a reduction in acetylcholine release mediated by prostaglandins possibly originating from the damaged kidneys. The diminished response to cervical sympathetic stimulation results from a decreased postsynaptic response to β-adrenoceptor stimulation.
Pharmacokinetics of intravenously administered glutathione in the rat
Authors: Ammon H P T , Melien M C M , Verspohl E J
Published: April 2011

By means of an open two compartment model with a distribution and elimination phase, the pharmacokinetic properties of intravenously administered GSH (reduced glutathione) have been investigated in the rat. After a bolus injection of four various GSH doses (50 to 300 μmol kg−1), arterial plasma concentrations of GSH, GSSG (= oxidized glutathione), total thiols and soluble thiols minus GSH were elevated and then rapidly decreased non-exponentially. With increasing dose, the rate constant for drug elimination and plasma clearance increased from 0.84 to 2.44 ml min−1 and the half-life of the elimination phase decreased from 52.4 to 11.4 min. Both the apparent volume of distribution and the degree of penetration of GSH into the tissues were diminished with increasing dose (from 3.78 to 1.33 litres kg−1 and from 6.00 to 0.51 as k12/k21, respectively). The data indicate that GSH is rapidly eliminated. This is mainly due to rapid oxidation in plasma rather than by increased tissue extraction or volume distribution. Thus plasma GSH levels appear to be quickly regulated by which the body may maintain concentrations within narrow physiological limits.
Ketanserin potentiates the prejunctional inhibitory effect of 5-hydroxytryptamine on rat vas deferens
Authors: Moritoki Hideki , Fukuda Hiroshi , Kanaya Jun , Ishida Yukio
Published: April 2011

5-Hydroxytryptamine (5-HT) slightly inhibited the twitch contractions of rat vas deferens caused by single pulse field stimulation at 0.1 Hz. The inhibitory effect of 5-HT was much less in the epididymal portion than in the prostatic portion of the vas deferens. Ketanserin potentiated the prejunctional inhibitory effect of 5-HT and attenuated its stimulatory effect. This potentiation was observable only in the epididymal portion, of the vas deferens. Cyproheptadine and mianserin, but not methysergide, had essentially similar potentiating effects to those of ketanserin. These results suggest that the 5-HT receptor that mediates prejunctional inhibition is not of the 5-HT2 type, and that ketanserin acts by suppressing the 5-HT-induced stimulatory effect, which is possibly mediated by a postjunctional 5-HT2 receptor, thus unmasking the inhibitory effect of 5-HT.
Inhibitory effects of sympathomimetic drugs on cholinergically mediated contractions of guinea-pig isolated tracheal muscle
Authors: Kamikawa Yuichiro , Shimo Yasuo
Published: April 2011

The experiments examine the actions of sympathomimetic drugs on the responses evoked by electrical field stimulation or by acetylcholine in guinea-pig tracheal strip chains. Electrical field stimulation evoked contractions which were cholinergically mediated, in the presence of guanethidine (10 μm) and indomethacin (2 μm). All the sympathomimetic drugs tested caused a concentration-dependent reduction in the height of these contractions. Inhibitory effects of isoprenaline and terbutaline were largely prevented by propranolol (2 μm) alone, whereas those of clonidine, oxymetazoline, lidamidine and WHR1370 were prevented by yohimbine alone (2 μm). Treatments with both propranolol and yohimbine were required to prevent the inhibitory effects of noradrenaline, adrenaline and dopamine. Contractions evoked by exogenous acetylcholine (0.1–3 μm) were also inhibited by all catecholamines and terbutaline, but not by clonidine, oxymetazoline, lidamidine and WHR1370. The inhibitory effects were antagonized by propranolol (2 μm) alone. The results suggest that in guinea-pig isolated tracheal muscle, sympathomimetic drugs can inhibit cholinergic neurotransmission not only by postjunctional β2-adrenoceptors but also by prejunctional α2-adrenoceptors.
Analgesic and anti-inflammatory activities in rats of α-(3,5-di-t-butyl-4-hydroxybenzylidene)-γ-butyrolactone (KME-4), and its intestinal damage
Authors: Hidaka Takayoshi , Hosoe Kazunori , Yamashita Toshiaki , Watanabe Kiyoshi , Hiramatsu Yasuzo , Fujimura Hajime
Published: April 2011

α-(3,5-Di-t-butyl-4-hydroxybenzylidene)-γ-butyrolactone (KME-4), an anti-inflammatory drug, possesses analgesic activity in rat models. In the acetic acid-induced writhing test, the oral ED50 values for KME-4, indomethacin, naproxen and ibuprofen were 5.2, 3.8,7.0 and 18.6 mg kg−1, respectively, and the relative order of potency of these drugs correlated with their inhibitory effect on acetic acid-induced vascular permeability in rats. KME-4 also had analgesic activity in the tests of Randall-Selitto and adjuvant arthritic flexion, but the dose required was greater than that needed in the writhing test. KME-4 (10 mg kg−1 day−1 orally) has a preventive effect against adjuvant-induced arthritis in rats, and its efficacy was more potent than indomethacin (2 mg kg−1 day−1) as judged from various parameters determined. When administered orally to rats once daily for 12 days, KME-4 caused perforating ulceration of the small intestine but this action was less potent than the effect of indomethacin, naproxen and ibuprofen.
The effect of digoxin-specific active immunization on digoxin toxicity and distribution in the guinea-pig
Authors: Andrews M , Hewick D S , Stevenson I H
Published: April 2011

In guinea-pigs intravenously infused with digoxin, prior immunization using a digoxin-human serum albumin conjugate increased by 3- and 2.4-fold, respectively, the digoxin doses causing the first signs of cardiotoxicity and death. At death, serum digoxin concentration was four times higher in immunized than in control animals. In the immunized guinea-pigs 50% of the serum digoxin was protein bound, presumably mainly to digoxin-specific antibodies, since in the controls the bound fraction was only 1–2%. Generally, tissue digoxin concentrations were not increased to the same extent as the lethal dose, and in the heart and lungs the increase was not significant. With cardiac (ventricle) subcellular fractions, there was no difference between control and immunized animals in the digoxin concentration of the ‘microsomal’ pellet. This subfraction contains the plasma membrane and the associated sodium pumps which are considered to be the sites at which the pharmacologically active digoxin binds. It seems likely, therefore, that the greater digoxin resistance in the immunized animals can be explained on the basis of reduced drug access to the site of action within the heart.
The components of Melissa officinalis L. that influence protein biosynthesis in-vitro
Authors: Chlabicz J , Gałsiński W
Published: April 2011

An investigation of an inhibiting activity of a substance(s) in a tanninless extract from Melissa officinalis leaves on protein biosynthesis in-vitro has been made. At least two components which inhibited protein biosynthesis were present in the extract; these were caffeic acid and an unidentified glycoside. Freshly prepared buffered solutions of caffeic acid inhibited protein biosynthesis less than solutions stored for several days at room temperature (20 °C). In this case derivatives of caffeic acid were formed, which may be responsible for the increase in the inhibitory effect of stored caffeic acid solution. An inhibitor, in the homogeneous state, was also isolated from the glycoside fraction of M. officinalis. Studies on the mechanism of the action of this inhibitor revealed its effect is to use the result of a direct interaction with elongation factor EF-2, and the blocking of the binding reaction of EF-2 with ribosomes.
The effect of pH and concentration on α-methyldopa absorption in man
Authors: Merfeld A E , Mlodozeniec A R , Cortese M A , Rhodes J B , Dressman J B , Admidon G L
Published: April 2011

An open crossover study of the absorption of α-methyldopa has been conducted in normal healthy adult male volunteers in whom a triple lumen perfusion tube had been placed. Three volunteers were perfused on separate occasions with 0.1 mM α-methyldopa at pH 4.5, 6.0 and 7.4. Three other volunteers were perfused on separate occasions with 0.1, 1.0 and 10 mM α-methyldopa at pH 6.0. Two additional subjects were perfused with 0.1 mM α-methyldopa at pH 6.0. Absorption was not a linear function of concentration above 1 mM α-methyldopa. There was also a weak trend toward greater absorption near pH 6.0. At higher concentrations of drug in the perfusion solution (10 vs 1 mM), the free fraction of α-methyldopa in plasma samples was increased significantly. Thus, although absorption of α-methyldopa is more efficient at lower concentrations, bioavailability may not be substantially enhanced due to increased sulphation in the gut wall. Comparison of permeabilities with previous results from our laboratories suggests the rat is a good model for predicting the behaviour of α-methyldopa after its oral administration to man.
Effects of antimalarial drugs on interleukin 1-induced cartilage proteoglycan degradation in-vitro
Authors: Rainsford K D
Published: April 2011

Previous studies having shown that chloroquine and hydroxychloroquine could reduce interleukin 1 (IL-1)-induced cartilage degradation in-vitro, the effects of a range of antimalarial drugs on the cartilage proteoglycan degrading actions of porcine leucocyte (pI 4.8) α-interleukin 1 (syn. catabolin) have been examined using the standard bovine nasal cartilage culture system. The anti-IL-1 effects in this system were specific to several aminoquinoline and aminoacridine analogues having a side chain with a tertiary amino group similar to that of chloroquine. Aminoquinoline compounds devoid of this side chain and the tertiary amino, as well as pyrimidines or biguanides with antimalarial activity were without effect. Mefloquine, the most potent of the compounds active against porcine α-IL-1, was only equipotent with chloroquine and its hydroxyanalogue against human recombinant α-IL-1. This suggests that there may be subtle differences in the receptors for these drugs and interleukins in bovine cartilage. The results provide further evidence for the specificity and utility of antimalarial drugs in the treatment of chronic inflammatory conditions, especially in relation to actions on IL-1.
The effect of food on the bioavailability and kinetics of the anticancer drug amsacrine and a new analogue, N-5-dimethyl-9-[(2-methoxy-4-methylsulphonylamino)phenylamino]-4 acridinecarboxamide in rabbits
Authors: Paxton James W
Published: April 2011

Both amsacrine and its analogue, N-5-dimethyl-9-[(2-methoxy-4-methylsulphonylamino)phenylamino]-4-acridinecarboxamide (CI-921) are absorbed from the gastrointestinal tract in rabbits. The mean bioavailability for amsacrine was 50% ± 17 (s.d.) in non-fasting animals, and was significantly increased in fasting animals (mean, 90% ± 10). The bioavailability for CI-921 (mean, 26% ± 11) in the non-fasting animal was significantly less than that found for amsacrine, but this difference disappeared in the fasting animal when the bioavailability of CI-921 was significantly increased to 69% ± 23. Oral administration of both agents resulted in significantly prolonged elimination half-lives and mean residence times compared to the i.v. infusion, but no significant difference was observed in these parameters between the fasting and non-fasting state. This study suggests that oral dosing may be a possible alternative route for the administration of these anticancer agents.
Luminal acid in stress ulceration and the antiulcer action of verapamil in rat stomachs
Authors: Koo M W L , Cho C H , Ogle C W
Published: April 2011

The role of luminal acid and the influence of the antisecretory action of verapamil in stress ulcer prevention in rat stomachs have been studied. Intraperitoneally injected verapamil. 4 mg kg−1, inhibited gastric acid secretion and ulcer formation, however, a 2 mg kg−1 dose, which did not significantly influence acid output, also had an antiulcer effect. Intraperitoneal injection of bethanechol, 1.2 or 3.6 mg kg−1, increased gastric acid output, but did not influence stress-induced ulcer formation. Oral administration of HCl, 25 or 50 μequiv, aggravated stress ulceration in a dose-dependent manner; this lesion-worsening effect was prevented by pretreatment with verapamil or bethanechol. The gastric luminal acid content in 2 h pylorus-ligated rats was similar in the groups given either bethanechol or HCl. These findings indicate that the antisecretory action of verapamil may not account for its antiulcer effect. It is suggested that endogenous and exogenous luminal acid may have different influences on stress ulcer formation.
Liquid penetration as a method of assessing the wettability and surface energy of pharmaceutical powders
Authors: Buckton G , Newton J M
Published: April 2011

The use of a liquid penetration technique to assess the wettability and surface energy of a series of barbiturates, including the use of bicomponent systems, has been critically evaluated. Values of apparent contact angles (θ) obtained using the Washburn relationship (1921) and the Carli & Simioni correction (1979) were found to reflect the practically derived wettability of the powders. Values of γc obtained from modified Zisman plots and from Neumann's equation of state did not realistically describe the surface energies of the powders. The nature of alcohol-water mixtures has been examined to assist elucidation of the theoretical problems associated with the technique and to offer a possible explanation for the inadequacies of the surface energy results.
Content uniformity of microdose tablets (dosage 1 μg-10 mg) produced by fluid bed granulation of interactive mixtures
Authors: Thiel W J , Nguyen L T , Sberna F J
Published: April 2011

Tablets (100 mg), containing microdose quantities of micronized model drug (1 μg-10 mg), were produced from interactive powder mixtures which had been fluid bed granulated. Granulation prevents adhesion unit and constituent segregation occurring during compression. Single tablet assays were performed on 100 tablets from each batch. The content of tablets fell within ±15% of the mean, and the coefficient of variation was <5% (99% confidence) for all batches. Skewness in the content distribution showed little evidence of superpotent tablets and indicated the absence of significant agglomerates of particles of the micronized component. However, there was some indication that the mixtures produced were not totally agglomerate free. These results demonstrate that the true potential of interactive mixing may be realized, provided segregation in the mixture can be eliminated. The distribution of micronized model drug, as a function of carrier particle size, was determined for the different concentration mixtures before and after granulation. When 0.1–2% interactive mixtures were sieved gently, the proportions of micronized material adhering to the different size fractions of carrier were similar. However, the very low concentration mixtures (0.01–0.03%) proved to be relatively unstable, a significant proportion of the micronized component being transferred from the mixtures to the metal surfaces of the sieves. Granulation of the mixtures in a fluidized bed produced a uniform distribution of micronized material throughout the different sized granules. These granules were stable during vibration on the sieves and when compressed. All samples of tablets met the United States Pharmacopeia XXI content uniformity requirements.
Evidence that sensory neurons participate in the non-cholinergic, non-adrenergic contractile response of the guinea-pig ileum
Authors: Matušák Ondrej , Bauer Viktor
Published: April 2011

The possible role of non-cholinergic, non-adrenergic (NCNA) nerves in responses of the guinea-pig terminal ileum to transmural nerve stimulation (TNS) and that of sensory nerves in NCNA responses were investigated. The action of acetylcholine was almost abolished in the presence of histamine, whereas the contractions elicited by TNS were changed to frequency-dependent contraction followed by a secondary relaxation. Guanethidine did not alter the contractions or secondary relaxations. Atropine abolished the action of acetylcholine and transiently suppressed the responses to low (up to 2 Hz) and attenuated (by about 50%) those to high (4 to 20 Hz) frequency stimulation. The remaining complex NCNA response was the sum of the excitatory and inhibitory responses. During desensitization to capsaicin, and in its presence, the NCNA contractions were reduced, whereas the relaxations were not significantly enlarged. The present results suggest that besides the cholinergic innervation, the excitatory and inhibitory NCNA innervation also participates in the responses of the guinea-pig ileum to TNS even without suppression of cholinergic and adrenergic transmission, and that the sensory nerves are, at least to some extent, involved in the NCNA excitatory response.
Pharmacological activity of amantadine: effect of N-alkyl substitution
Authors: Dunn John P , Henkel James G , Gianutsos Gerald
Published: April 2011

Alkyl substitution on the nitrogen atom of the anti-parkinsonian drug amantadine resulted in changes in its pharmacological potency. Greater behavioural stimulation (i.e. increased motor activity) was observed following s.c. injection of several of the analogues, with optimal activity produced by N-n-propyl substitution. These molecular changes did not alter the activity of amantadine on inhibition of dopamine uptake or its weak affinity for dopamine receptors in-vitro. Several of the analogues were more effective than the parent compound in increasing the concentration of dopamine metabolites (suggesting an increase in dopamine utilization) following systemic injection, and these effects generally followed the same pattern as observed in the test of behavioural activity. These results provide further support for the concept that the activity of amantadine may be improved by molecular alterations, although the pharmacological basis for this activity remains obscure.
Immunological control of drug absorption from the gastrointestinal tract: the mechanism whereby intestinal anaphylaxis interferes with the intestinal absorption of bromthymol blue in the rat
Authors: Yamamoto Akira , Utsumi Eriko , Sakane Toshiyasu , Hamaura Takeshi , Nakamura Junzo , Hashida Mitsuru , Sezaki Hitoshi
Published: April 2011

Rats were immunized intraperitoneally with ovalbumin and the disappearance of bromthymol blue (BTB) from the intestinal lumen, its accumulation in the tissue, and its net absorption were examined by means of an in-situ recirculation technique during local anaphylaxis. The disappearance of BTB from the intestinal lumen and its net absorption were significantly reduced, but there was no significant effect on its accumulation in the tissue. The pH value of the luminal solution and the perfusate volume were not influenced by intraluminal challenge with the antigen in ovalbumin-immunized rats. In addition, no significant effect was observed on intestinal permeability to BTB in the in-vitro everted sac technique. The intestinal blood flow, measured by a hydrogen clearance method, was not reduced significantly by the intraluminal exposure to antigen. There was enhanced Evans Blue leakage and mucus release in the perfusate after intraluminal challenge with ovalbumin in ovalbumin-immunized rats, but not in non-immunized rats. A significant increase of BTB binding with macromolecular substances in the perfusate was observed during the local anaphylaxis. These findings suggest that the decreased absorption of BTB is due to the interaction with the macromolecular substances in the perfusate during local anaphylaxis.
Activities of novel polyhydroxylated cardiotonic steroids purified from nuchal glands of the snake, Rhabdophis tigrinus
Authors: Azuma Hiroshi , Sekizaki Satomi , Akizawa Toshifumi , Yasuhara Tadashi , Nakajima Terumi
Published: April 2011

Seven novel polyhydroxylated steroids were isolated from the nucho-dorsal glands of the snake, Rhabdophis tigrinus. Biological activities of these steroids in inhibiting (Na+ + K+)ATPase and in producing positive inotropic action were examined in comparison with those of ouabain and gamabufotalin. Gamabufotalin was approximately 10 times more potent than ouabain in inhibiting (Na+ + K+)ATPase. Two compounds, compounds III and XIII, of the seven, produced nearly equipotent enzyme inhibitory activity to ouabain. The activity of the remaining five was relatively low among the compounds tested. All compounds exhibited more or less positive inotropic action in the papillary muscle preparations. The ranking order of the potency was: gamabufotalin > ouabain and compound IV > compound III and XIII > compound I, II, XII and XIV.
Transport of phenobarbitone into the intestinal lumen and the biliary tract following i.v. administration to rats
Authors: Arimori Kazuhiko , Nakano Masahiro
Published: April 2011

The exsorption of intravenously administered phenobarbitone into the lumen of the small intestine of rats has been examined by an in-situ single-pass perfusion technique. The levels of the drug in the bile were about twice that in serum. Moreover, it was shown that the drug was appreciably exsorbed into the intestinal lumen. The exsorption rates of the drug into the perfusates were not very different between isotonic phosphate buffers at pH 6.0 and 8.0. The amounts of phenobarbitone exsorbed into the perfusate and excreted into the bile were 6.47 and 0.45% of the dose for isotonic phosphate buffer at pH 6.0, and were 6.09 and 0.54% of the dose for isotonic phosphate buffer at pH 8.0.
The effect of antidepressants on ethylmorphine and imipramine N-demethylation in rat liver microsomes
Authors: Daniel Wladyslawa , Melzacka Miroslawa
Published: April 2011

The effects of single and multiple doses of desipramine, amitriptyline or citalopram on the rat liver microsomal cytochrome P-450 level and on the rate of ethylmorphine and imipramine demethylation in-vitro have been investigated. Desipramine, amitriptyline or citalopram when given to rats as a single dose, did not affect the level of cytochrome P-450 in the liver microsomes, however, there was a tendency towards acceleration of imipramine, and particularly ethylmorphine, demethylation. Prolonged administration of desipramine and citalopram, but not amitriptyline, elevated the microsomal level of cytochrome P-450 and accelerated the rate of ethylmorphine demethylation. All the drugs investigated, when given chronically, inhibited the rate of imipramine demethylation. Since demethylation of ethylmorphine and imipramine in a CO atmosphere was inhibited by ca 90% for the former and only by 58% for the latter, it can be assumed that prolonged administration of the drugs investigated has two different effects on the oxygenase systems in rat liver microsomes: on the one hand they stimulate the cytochrome P450 oxygenase system involved in ethylmorphine demethylation and, on the other, they inhibit the other microsomal oxygenase system involved in demethylation of imipramine.
Cooling-induced augmentation of the contractile response of the golden hamster tracheal muscle to substance P in-vitro
Authors: Ishii Takeo , Shimo Yasuo
Published: April 2011

The effect of temperature on the substance P-induced contraction of the isolated tracheal strip-chain preparation from the golden hamster has been examined. A decrease of bath temperature from 37 to 20°C augmented the contractile response of the trachea caused by substance P. Similar cooling-induced augmentation was observed in the contractile responses to caffeine and carbachol, but not to fratassium chloride. The increased responsiveness with lowered temperature of the trachea to substance P may be due to the acceleration of Ca2+ release from an intracellular storage site.
[125I] Spiperone is not a useful ligand for studying the CHAPS solubilized dopamine D-2 receptor from rat striatum
Authors: Kilpatrick G J , Jenner P , Marsden C D
Published: April 2011

The interaction of [125I]spiperone and [3H]spiperone with CHAPS solubilized preparations of rat striatal tissue has been compared. Only about 15% of [125I]spiperone binding was displaced by sulpiride compared with about 67% of [3H]spiperone binding. In the presence of (+)-butaclamol the displacement of [125I]spiperone was twice that found with sulpiride suggesting an interaction with sites other than D-2 receptors. The specific binding of [125I]spiperone was not saturable within the maximum concentration range that could be employed and its affinity for soluble preparations was far lower than that of [3H]spiperone. Despite its very high specific activity [125I]spiperone offers no advantage over [3H]spiperone in the identification of dopamine receptors in soluble tissue preparations.
Mechanical properties of some pigmented and unpigmented aqueous-based film coating formulations applied to aspirin tablets
Authors: Okhamafe Augustine O , York P
Published: April 2011

The Brinell hardness and Young's modulus of pigmented and unpigmented films of hydroxypropyl methylcellulose alone, and in combination with either polyethylene glycol 400 (plasticizer) or polyvinyl alcohol, which were applied to aspirin tablets, have been measured. Generally hardness and modulus data showed similar trends. The hardness and modulus of hydroxypropyl methylcellulose fell in the presence of polyethylene glycol 400 as a result of its plasticizing action. On the other hand, the hardness and modulus of the film former rose slightly when polyvinyl alcohol was initially incorporated, probably due to the crystalline phase of the additive, and then decreased when the level of the additive was further raised. Hardness and modulus were higher in films pigmented with talc than in those containing titanium dioxide because of the plate-like shape of talc and its greater interaction with the polymer systems. Some correlation was found between the Young's moduli of the applied films and those of the corresponding free films, with the moduli of the latter two 2–5 times greater. Ageing at 37°C and 75% r.h. was found to cause a decrease in the mechanical properties of the unplasticized film coating systems probably as a result of decreased molecular order and enhanced polymer chain mobility.
Functional evidence for the existence of a capsaicin-sensitive innervation in the rat urinary bladder
Authors: Santicioli Paolo , Maggi Carlo Alberto , Meli Alberto
Published: April 2011

Capsaicin (0.03–3 μm) induces contractions of the rat isolated bladder which are unaffected by either atropine (3 μm) or tetrodotoxin (0.5 μm). In the presence of capsaicin (0.1 μm) an enhancement of field stimulation-induced contractions was observed. Capsaicindesensitization did not modify the height of these. The neurogenic nature of the capsaicin-induced contractions was proved by the observation that ‘chronic’ (48 h) denervation prevented, while ‘acute’ (2 h) denervation did not modify the effect of capsaicin. Denervated bladders maintained their responsiveness to acetylcholine but not to field stimulation. Isolated bladders from rat pups (1–2 days old) did not respond to capsaicin while strong contractile responses to acetylcholine or field stimulation were obtained in these preparations. In bladders from two week old animals, capsaicin produced similar contractions to those observed in preparations from adult animals. The bladders from rats receiving a high dose of capsaicin (50 mg kg−1 s.c.) at birth were heavier than those of their age-matched, vehicle-treated controls. Isolated bladders from 2 month old animals pretreated with capsaicin at birth were unresponsive to capsaicin while responsiveness to acetylcholine, substance P or field stimulation was unaffected compared with that of vehicle-treated controls. These experiments provide evidence that a capsaicin-sensitive innervation exists in the rat urinary bladder which undergoes a postnatal development at end organ level.
Effect of the anticonvulsant denzimol on the disposition of diazepam in the rat
Authors: Caccia S , Conforti L , Conti I
Published: April 2011

The influence of denzimol. a new imidazole derivative with anticonvulsant properties, on the disposition of diazepam (1 mg kg−1) was investigated in the rat. Denzimol pretreatment significantly increased plasma and brain concentrations of the benzodiazepine, consistent with reduced total clearance. The results suggest that the increase of diazepam brain concentrations by denzimol may produce enhancement of diazepam activity in the rat.
Enhancement of the dissolution rate of a poorly water-soluble drug (tolbutamide) by a spray-drying solvent deposition method and disintegrants
Authors: Takeuchi Hirofumi , Handa Tetsurou , Kawashima Yoshiaki
Published: April 2011

The dissolution rate of a poorly water-soluble drug, tolbutamide, was improved by spray-drying a diluted ammonia solution of the drug containing either a low-substituted hydroxypropylcellulose (L-HPC) or partly pregelatinized corn starch (PCS) as disintegrants. With L-HPC the resultant particles were agglomerates of disintegrant with drug on the surface and within the particles, while particles formed with PCS were composed of a single core of PCS on which the drug was deposited. The deposited drug crystals were very fine because the rapid solvent evaporation restricted crystal growth. The spray-dried particles prepared with PCS had a structure similar to that of an ordered mix. The drug dissolution rate from the spray-dried particles was more rapid than that of the powdered drug alone or with disintegrant and could be attributed to separation of the layer of fine drug crystals from the surface of the particles by swelling of disintegrant. PCS enhanced the drug dissolution rate compared with systems using corn starch. The dissolution rate also depended on the drug content of the particles which was higher than that in ordered mixtures or conventional solvent deposition systems. This system described also had the advantage of avoiding the use of organic solvents.
l-Dopa esters as potential prodrugs: effect on brain concentration of dopamine metabolites in reserpinized mice
Authors: Cooper D R , Marrel C , Van De Waterbeemd H , Testa B , Jenner P , Marsden C D
Published: April 2011

The intraperitoneal administration of l-Dopa and a series of ester prodrugs of l-Dopa to reserpinized mice produced elevations of striatal and tuberculum olfactorium homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. Differences in the pattern of change produced by individual drugs, compared with l-Dopa, were observed. Only the phenoxyethyl ester caused elevations of both striatal and tuberculum olfactorium HVA and DOPAC, greater than those measured following l-Dopa administration. Overall the m-trifluoromethylbenzyl, phenylethyl, p-chlorophenylethyl and p-methoxyphenylethyl ester prodrugs produced greater elevations of striatal and tuberculum olfactorium HVA, but not DOPAC, compared with l-Dopa. The administration of the 2-tetrahydropyranylmethyl derivative only enhanced striatal HVA and striatal and tuberculum olfactorium DOPAC concentrations. Changes of HVA and DOPAC tissue concentrations following administration of the 2-hydroxypropyl, n-propyl, methyl, ethyl and 2-(1-methoxy)propyl ester prodrugs were comparable with those produced by the administration of l-Dopa itself. The alterations in striatal and tuberculum olfactorium HVA and DOPAC levels observed did not correlate with the ability of these compounds to elicit locomotor activity in reserpinized mice.
Isolated tissue and binding studies of YM-17690, a novel and non-analogous leukotriene agonist
Authors: Tomioka Kenichi , Yamada Toshimitsu , Teramura Kyoko , Terai Michio , Hidaka Kazuyuki , Mase Toshiyasu , Hara Hiromu , Murase Kiyoshi
Published: April 2011

YM-17690, 3-[4-carboxymethoxy-3-[p-(4-phenylbutoxy)benzamido]phenyl]prpionic acid, produced a dose-dependent contraction of guinea-pig ileum and its EC50 value was 1·6 times 10−8M. The response was not affected by pretreatment with atropine, mepyramine, indomethacin, dazoxiben and AA-861 (a 5-lipoxygenase inhibitor), but was inhibited by FPL-55712 (an LTD4 and LTE4 antagonist). YM-17690 induced dose-dependent contractions of guinea-pig lung parenchyma and trachea with EC50 values of 3·9 times 10−9 and 2·2 times 10−8M, respectively. Pretreatment of these tissues with FPL-55712 resulted in a parallel shift of the YM-17690 dose-response curves to the right. The pA2 values for FPL-55712 in lung parenchyma and trachea were 7·41 and 8·21, respectively, and the slopes of the regression lines of Schild plots were 1·00 and 1·02, respectively. YM-17690 produced a dose-dependent inhibition of [3H]LTD4 binding to guinea-pig lung membranes and its pKi value was 9·28. However, the compound showed only 25% inhibition of [3H]TLC4 binding to guinea-pig hippocampus membranes, even at 10−5M. These results suggest that YM-17690 is a selective leukotriene (LTD4 and LTE4) agonist and that it will therefore be a valuable tool in the study of actions of leukotrienes and for the characterization of their receptors.