bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigations of the Possible Glycosylation of Monoamine Oxidase B from Pig Leucocytes
Authors: Balsa Maria Dolors , Gomez Néstor , Unzeta Mercedes
Published: April 2011

Monoamine oxidase B (MAO B) from pig liver has been reported to be a sialoglycoprotein. However, when that enzyme from pig lymphocytes and granulocytes was separated by polyacrylamide gel electrophoresis after labelling with the specific irreversible inhibitor [3H]pargyline, staining with 1-ethyl-2-[3-(1-ethyl-naphtho [1,2d] thiazolin-2-ylidene)-2-methylpropenyl] naphtho [1,2d] thiazolium bromide (“Stains-all”) failed to detect the presence of sialic acid residues. Treatment of the enzyme in disrupted lymphocytes and granulocytes, or in mitochondrial fractions prepared from them, with neuraminidase resulted in a decrease in MAO activity. However, after the enzyme was rendered soluble by treatment with octylglucoside, treatment with neuraminidase had no effect on the activity. These results indicate that sialic acid residues are not an intrinsic component of MAO B, although associated material containing such groups appears to affect the activity of the membrane-bound enzyme. The activities of membrane-bound preparations of MAO B from pig lymphocytes and granulocytes were unaffected by treatment with trypsin or β-chymotrypsin. After the preparations had been rendered soluble by treatment with octylglucoside there was a decrease in the activity on treatment with β-chymotrypsin, but trypsin treatment had no effect. Thus solubilization resulted in residues sensitive to cleavage by the former enzyme becoming accessible to it. Tryptic and chymotryptic peptides separated from the sodium dodecyl sulphate denatured enzymes by polyacrylamide gel electrophoresis revealed no differences between MAO B prepared from lymphocytes and granulocytes
The Extracellular Concentration of the Anti-epileptic Drug Valproate in the Rat Brain as Determined with Microdialysis and an Automated HPLC Procedure
Authors: Wolf J H , Van Der Duin L Veenma , Korf J
Published: April 2011

The cellular and extracellular brain concentration of valproic acid in freely moving rats has been estimated after intravenous injection of sodium valproate. Some rats were provided with a stereotaxically implanted dialysis probe in the striatum and a cannula in the heart through which the drug was injected and which allowed regular removal of blood. In other rats tissue levels of valproic acid were determined 5 and 90 min after drug injection. Valproic acid was determined by an automated precolumn derivatization procedure followed by HPLC separation and fluorimetric detection. Extracellular concentration was proportional to the blood concentration at every time interval, indicating rapid exchange of the drug between the two compartments. About 50% of the striatal content of valproate was in the extracellular space. The experiments demonstrated the usefulness of microdialysis to estimate both the extracellular concentration and the average cellular drug levels, provided a sensitive analysis procedure is available.
Extraction and Purification of Curcain, a Protease from the Latex of Jatropha curcas Linn
Authors: Nath L K , Dutta S K
Published: April 2011

A proteolytic enzyme, curcain, has been extracted from the latex of Jatropha curcas Linn. The enzyme was purified by chromatography on carboxymethyl cellulose and gel filtration on Sephadex G-200. The homogeneity of protein associated with curcain was established by non-denatured polyacrylamide gel electrophoresis using a discontinuous buffer system. The molecular weight of curcain was estimated by Sephadex G-100 gel filtration using a calibration curve of standard proteins to be around 22000 daltons.
External control of drug release and penetration: enhancement of the transdermal absorption of indomethacin by ultrasound irradiation
Authors: Miyazaki Shozo , Mizuoka Hideyuki , Oda Masako , Takada Masahiko
Published: April 2011

The effect of ultrasound (1 MHz) on transdermal absorption of indomethacin from an ointment has been studied in rats. Ultrasound energy was supplied for 10 min at a range of intensities (0.25, 0.5 and 0.75 W cm−2), energy levels commonly used for therapeutic purposes. The pronounced effect of ultrasound on transdermal absorption of indomethacin was observed for all three intensities studied. The mean AUC value (33.22 μg h mL−1) after irradiation at 0.75 W cm−2 was 3.4 times the control value (9.70 μg h mL−1).
The comparative bioavailability of cimetidine-alginate treatments
Authors: Britton A M , Nichols J D , Draper P R
Published: April 2011

The comparative bioavailability of cimetidine in cimetidine-alginate combinations has been investigated in twelve healthy volunteers in an open crossover study. Each volunteer received a single oral dose of a commercially available alginate-cimetidine combination tablet (Algitec) or cimetidine tablets (Tagamet), coadministered with a commercially available alginate reflux suppressant liquid or tablet (Gaviscon). No significant differences were observed between treatments for Cmax, tmax, AUC0–12 or AUC0-∞. The study demonstrated equivalent bioavailability of cimetidine when administered separately with alginate products and as a fixed dose combination product.
The influence of the γ-amino butyric acid (GABA) antagonist bicuculline on transport processes in rat small intestine
Authors: Hardcastle Jacqueline , Hardcastle P T , Mathias Wendy J
Published: April 2011

GABAergic involvement in the regulation of intestinal ion transport is suggested by the reduction in the short-circuit current generated by sheets of rat small intestine by the GABA antagonist bicuculline, although GABA itself caused no change. Bicuculline action was abolished by the inhibitor of Cl− secretion frusemide, suggesting that it involved a change in endogenous Cl− secretory tone. The effect of bicuculline appeared to be specific as it did not affect the electrical responses to glucose or exogenous secretagogues. The action of bicuculline was not observed in stripped intestinal sheets where the myenteric plexus is absent, and it was reduced by tetrodotoxin and atropine. It is suggested that endogenous GABA could be involved in the maintenance of a secretory tone in rat small intestine by acting on cholinergic mechanisms within the myenteric plexus.
α2-Adrenoceptor- and D2-dopamine receptor-mediated analgesic response of B-HT 920
Authors: Verma Anita , Kulkarni S K
Published: April 2011

The involvement of D2-dopamine receptors in the antinociceptive action of B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-(4H) thiazolo-(4,5d)-azepine) has been investigated in mice. B-HT 920 (0.1–2.0 mg kg−1) and apomorphine (0.1–2.0 mg kg−1) produced a dose-dependent increase in tail flick latency. Analgesia induced by apomorphine was blocked by the D2-antagonist, haloperidol (1 mg kg−1) but not by the opioid antagonist, naloxone(1 mg kg−1). The antinociceptive action of B-HT 920 was potentiated by the D1-agonist SKF 38393 (5 mg kg−1), an action antagonized by haloperidol. The selective α2-adrenoceptor blocking drug yohimbine (1 mg kg−1) and naloxone (1 mg kg−1) blocked the antinociceptive action of B-HT 920 (1 mg kg−1). Haloperidol, however, failed to modify the B-HT 920-induced increase in tail flick latency. B-HT 920 and apomorphine reversed reserpine (2 mg kg−1) 4 h-induced hyperalgesia. The reversing action of apomorphine was blocked by haloperidol but not by yohimbine. Thus, a role of α2-adrenoceptors and D2-dopamine receptors is postulated in the antinociceptive action of B-HT 920.
Effect of nifedipine on Leishmania donovani infection in-vivo and in-vitro: chemiluminescence responses of peritoneal macrophages and neutrophils
Authors: Ganouly N K , Sodhi S , Kaul N , Kaur S , Malla N , Mahajan R C
Published: April 2011

After peritoneal macrophages had been exposed to different concentrations of nifedipine (10–120 ng mL−1) there was a significant increase (P < 0.001) in the percentage of Leishmania donovani infected macrophages compared with controls. Parasite load was also significantly increased (P < 0.001) in nifedipinetreated, L. donovani infected, BALB/c mice, compared with untreated, infected mice, post-inoculation. Peak chemiluminescence responses were significantly depressed (P < 0.001) in nifedipinetreated infected mice compared with untreated mice post-inoculation. It is suggested that availability of intracellular calcium is a factor in the defense mechanism of inflammatory cells in L. donovani infections.
Plasma Protein Binding of Quinine: Binding to Human Serum Albumin, α1-Acid Glycoprotein and Plasma from Patients with Malaria
Authors: Wanwimolruk Sompon , Denton John R
Published: April 2011

The binding of quinine to human serum albumin (HSA), α1-acid glycoprotein (AAG) and plasma obtained from healthy subjects (10 Caucasians and 15 Thais) and from Thai patients with falciparum malaria (n = 20) has been investigated. In healthy volunteers, plasma protein binding expressed as the percentage of unbound quinine was 7·9–31·0% (69–92·1% bound). The mean percentage of unbound quinine found with essentially fatty acid-free HSA (40 g L−1) was 65·4±1 −5% (mean±s.d.) and was comparable with the value (66·3 ± 3·8%, mean ± s.d.) for Fraction V HSA (40 g L−1)- This suggests that fatty acids do not influence the plasma protein binding of quinine. Binding of quinine to 0·7 g L−1 AAG was high (mean unbound 61·0 ± 5·0%), indicating that quinine is bound primarily to AAG and albumin, although other plasma proteins such as lipoproteins may be involved. The mean percentage of unbound quinine was slightly less in Caucasians (14·8 ± 6·7% unbound), compared with healthy Thai subjects (17·0 ± 6·7% unbound). The higher binding of quinine in Caucasian subjects was associated with a higher plasma AAG concentration observed in Caucasians. Mean percentage of unbound quinine was significantly lower in Thai patients with malaria (10·9 ± 4·0%) than in the healthy Thai subjects. The increase in the extent of quinine binding corresponded with the increase in the acute-phase reactant protein, AAG in the patients with malaria. Overall, when the data were combined there was a significant correlation (r = 0·846, P < 0·005) between the binding ratio (bound/unbound) of quinine and the plasma AAG concentration. This suggests that plasma AAG concentration may serve as a useful index to predict alterations in quinine binding. Although quinine is bound to albumin, it was not bound to either site I or site II on HSA as indicated from equilibrium dialysis and fluorescent probe displacement studies. Binding displacement studies revealed that there was no marked displacement of quinine by a variety of highly bound acidic and basic drugs, including other antimalarial drugs at their therapeutic concentrations.
Receptors Involved in the Modulation of 5-Hydroxytryptamine Release in Bovine Cerebral Arteries
Authors: Barrús Maria T , Marín Jesus , Villamor Jose , Balfagón Gloria
Published: April 2011

The uptake of [3H]5-hydroxytryptamine (5-HT) in bovine cerebral arteries was reduced by cocaine (1 μm), ouabain (100 μm), pretreatment with 6-hydroxydopamine (6-OHDA) (1·46 Mm, 10 min) and metitepine (1 μm). Electrically-stimulated tritium release was decreased by tetrodotoxin (0·8 μm), Ca-free medium, denervation with 6-OHDA (1·46 Mm, 10 min), 5-HT (10 μm), noradrenaline (1 μm) and the agonist of α2-adrenoceptors B-HT 920 (0·1 and 1 μm), enhanced by metitepine (1 μm, antagonists of presynaptic 5-HT1 receptors) and rauwolscine (1 μm, antagonist at α2-adrenoceptors, and also of 5-HT,1d receptors) and not affected by ketanserin (1 μm, antagonist of 5-HT2 receptors), methysergide (0·1 μm, antagonist of 5-HT1 and 5-HT2 receptors) and phentolamine (1 and 3 μm antagonist of α-adrenoceptors and less potent of 5-HT1 receptors). The inhibitory action of 10 μm 5-HT was partially reversed by phentolamine (3 μm) and cocaine (1 μm) and completely reversed by both metitepine (1 μm) and rauwolscine (1 μm). Ketanserin (1 μm), methysergide (0·1 μm) or phentolamine (1 μm) had no effect. Rauwolscine (1 μm) antagonized the inhibition induced by both noradrenaline (1 μm) and B-HT 920 (0·1 and 1 μm). 5-HT induced tritium release which was inhibited by cocaine (an antagonist of 5-HT3 receptors) and denervation with 6-OHDA. These results suggest that 5-HT is mainly accumulated in adrenergic nerve endings, that evoked [3H]5-HT release is modulated by 5-HT1-like receptors, but the participation of α2-adrenoceptors cannot be discounted, or more probably both types of receptors have features in common, and evoked [3H]5-HT release elicited by 5-HT may be partially mediated by activation of 5-HT3 receptors.
The Effect of Serum Ca2+ Compensation on the Efficacy of Chlorpropamide in Alloxan-diabetic Rabbits
Authors: Nishihata Toshiaki , Sakai Kiyoshi , Tsutsumi Ayumi , Fukui Miyuki , Yata Noboru
Published: April 2011

A decrease in serum Ca2+ concentration was observed in alloxan-diabetic rabbits, with recovery of serum Ca2+ levels achieved following insulin therapy. This suggested that the diabetic condition directly relates to the decrease in serum Ca2+ levels. The efficacy of chlorpropamide in alloxan-diabetic rabbits after intravenous injection (150 μmol kg−1) was less than that in normal rabbits as measured by the serum insulin levels, and the efficacy did not change when the dose was increased. However, compensation of serum Ca2+ levels in alloxan-diabetic rabbits caused an increase in the efficacy of chlorpropamide observed as an increase in serum insulin and a decrease in serum glucose levels.
Effect of mammalian lignans on f MLP-induced oxidative bursts in human polymorphonuclear leucocytes
Authors: Morikawa Masako , Fukuchi Kazunori , Inoue Michiko , Tsuboi Minoru
Published: April 2011

We examined the effects of mammalian lignans, enterolactone, prestegane B and 2,3-dibenzylbutane-1,4-diol (DBB) on superoxide production and luminol-dependent chemiluminescence (LCL) response in human polymorphonuclear leucocytes (PMNs). The three lignans had no direct effect on the responses of human PMNs. DBB and prestegane B enhanced the superoxide production and LCL response induced by formylmethionyl-leucyl-phenyl-alanine (f MLP), but enterolactone inhibited f MLP-induced effects. The effects of DBB were stronger than those of prestegane B and the effects of DBB were inhibited by bromophenacyl bromide, mepacrine, N-(6-aminophenyl)-5-chloro-t-naphthalene sulphonamide and trifluoroperazine, but not by gossypol, nordihydroguaretic acid, indomethacin, staurosporine, 1-(5-isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride or (R,S)-2-methoxy-3-(octadecyl-car-bamoyloxy)-propyl-2-(2-thiazolio)-ethylphosphate. These results suggest that DBB primes the responses of human PMNs, and the priming effect is caused by the activation of phospholipase A2—and Ca2+ -calmodulin-pathways, but not by the activation of lipoxygenase, cyclo-oxygenase and protein kinase C or by the release of platelet activating factor.
Microsomal formation of N-benzyl-4-hydroxymethylaniline from N-benzyl-4-methylaniline
Authors: Ulgen M , Gorrod J W
Published: April 2011

The in-vitro metabolism of N-benzyl-4-methylaniline was re-examined using male hamster and rabbit hepatic microsomes; both species generated N-benzyl-4-hydroxymethylaniline, confirmed by TLC and HPLC, comparison with authentic compound. Further confirmation of the formation of this metabolite, was achieved by use of a rapid scan UV detector.
Selective Bronchodilators from 1-(5′-Oxohexyl)xanthines
Authors: Miyamoto Ken-Ichi , Sakai Ryosuke , Yamamoto Yasunori , Konno Kayo , Sanae Fujiko , Hasegawa Takaaki , Takagi Kenzo
Published: April 2011

A series of twenty one 1-(5′-oxohexyl)xanthines substituted with alkyl chains at the N 3 and N 7 positions of the xanthine nucleus were prepared and their relaxant activity in guinea-pig isolated tracheal muscle and positive chronotropic activity in isolated right atrium of guinea-pig were compared. The tracheal relaxant activities were markedly increased with alkyl chain length at the N 3 position, but decreased by the N 7 alkylation. The positive chronotropic activities in the right atrium were increased by introduction of an n-propyl group at the N 3 position but decreased by substitution of longer alkyl chains, and the action on the heart was diminished by N 7 substitution. The activities of compounds on cAMP-phosphodiesterase (PDE) and binding of [3H]8-cyclopentyl-1,3-dipropylxanthine were measured in the homogenate of tracheal muscle and the membrane preparation of cerebral cortex, respectively. No relationship among tracheal muscle relaxant activity, cAMP-PDE inhibitory activity and adenosine antagonism of these xanthines was observed, and other action mechanisms should be considered for their relaxant activities. This study indicated that N 3 alkylation is important for the selectivity for tracheal muscle, while the introduction of long alkyl chains such as n-butyl and n-pentyl groups at the N 3 and N 7 positions diminished the potency for the right atrium in guinea-pigs. 3-n-Pentyl- and 7-methy]-3-n-pentyl-1-(5′-oxohexyl)xanthines showed much higher bronchoselectivity than oxpentifylline and theophylline.
Pharmacokinetic Interactions Between Isoniazid and Theophylline in Rats
Authors: Zeruesenay D , Siegmund W , Zschiesche M , Franke G , Walter R , Bleyer H
Published: April 2011

Pharmacokinetic interactions between isoniazid and theophylline were studied in male Wistar rats, 206±17 g. Concomitant oral administration of 2 × 5 mg kg−1 isoniazid accelerated slightly the disposition of theophylline (10 mg kg−1, i.v.) whereas 2 × 25 mg kg−1 isoniazid slowed it marginally. The differences in distribution volume, systemic clearance and area under the concentration-time curve (AUC) between the high and the low dose, however, were statistically significant. One week pretreatment with 10 mg kg−1 isoniazid tended towards inhibition (significant decrease of systemic clearance, increase of AUC) and 50 mg kg−1 to acceleration (decrease of half-life, mean residence time and AUC, increase of systemic clearance) of theophylline disposition. After oral pretreatment with 20 mg kg−1 theophylline, neither the kinetics of free isoniazid (50 mg kg−1, i.v.) and the amount acetylated nor the acetylation indices differed from the controls. There was no evidence that concomitant or subacute administration of different doses of isoniazid affects major metabolic pathways of theophylline or that prolonged theophylline treatment interacts with the N-acetylation capacity.
Disposition of Heptabarbitone in the Rat: Identification of a New Metabolite by Tandem Mass Spectrometry
Authors: Stijnen A M , Heeremans C E M , Van Bezooijen C F A , Niessen W M A , Danhof M
Published: April 2011

The purpose of this study was to elucidate the structure of a metabolite of heptabarbitone, the occurrence of which was reported previously in a number of pharmacokinetic and pharmacodynamic modelling studies. By application of thermospray liquid chromatography (tandem) mass spectrometry, the identity of the metabolite was proposed to be 5-ethyl-5-(1′,[3′ or 6′]-cycloheptadienyl)-barbituric acid. By measuring the ratios between the areas under the concentration time curves of the metabolite and heptabarbitone after administration of three different intravenous dosages of heptabarbitone, it was shown that the exposure to the metabolite is directly correlated with the exposure of heptabarbitone.
Gastric H+, K+-ATPase inhibition by catechins
Authors: Murakami Shigeru , Muramatsu Makoto , Otomo Susumu
Published: April 2011

Five catechins, (+)-catechin, (–)-epicatechin, (–)-epicatechin gallate, (–)-epigallocatechin and (–)-epigallocatechin gallate, inhibited gastric H+, K+-ATPase activity with IC50 values ranging from 1·7 × 10−4 to 6·9× 10−8  m, with (–)-epigallocatechin gallate as the most potent inhibitor. The intensity of inhibitor activity paralleled the number of phenolic hydroxy groups in the molecule. The inhibition of the enzyme by (–)-epicatechin was competitive with respect to ATP and noncompetitive with respect to K+. These findings suggest that the anti-secretory and antiulcerogenic effects of catechins previously reported, are due to their inhibitory activity on gastric H+, K+ -ATPase.
High molecular weight protein aggregates formed in the liver of the rat following large doses of paracetamol
Authors: Minamide Yoshiyuki , Horie Toshiharu , Awazu Shoji
Published: April 2011

Paracetamol (200 and 500 mg kg−1) was given intraperitoneally to rats pretreated with 3-methylcholanthrene for 3 days. Glutamic oxalacetic acid transaminase (GOT) activity in plasma increased in rats receiving 500 mg kg−1 paracetamol. Plasma GOT activity was low at the dose of 200 mg kg−1, but the same dose to diethyl maleate pretreated rats increased the GOT activity. High mol. wt protein aggregates were found to be formed in liver homogenates and microsomes of rats which showed high plasma GOT activity, accompanied by depletion of hepatic glutathione. The formation of protein aggregates in the liver of rats following large doses of paracetamol suggests a contribution of lipid peroxidation to paracetamol-induced hepatotoxicity.
In-vitro protein binding interaction between a metabolite of triflusal, 2-hydroxy-4-trifluoromethylbenzoic acid and other drugs
Authors: Mis R , Ramis J , Conte L , Forn J
Published: April 2011

2-Hydroxy-4-trifluoromethylbenzoic acid (HTB) is the main active metabolite of triflusal, an antiplatelet drug. The in-vitro binding of HTB to human serum was studied in the presence of different drugs. The results indicate that no statistically significant changes are observed in the HTB binding in the presence of caffeine, theophylline, glisentide, enalapril, cimetidine or warfarin. The free fraction of HTB increases significantly in the presence of the nonsteroidal anti-inflammatory drugs studied: diclofenac, ibuprofen, indomethacin, naproxen, piroxicam and salicylic acid. At high concentrations, HTB displaces these anti-inflammatory drugs and also glisentide and warfarin from their protein binding sites.
The effects of calcitonin nasal preparations and their excipients on mucociliary clearance in an ex-vivo frog palate test
Authors: Braga P C , Piatti G , Dal Sasso M , Bernini A
Published: April 2011

The topical tolerability of the commercial preparation of 1–7 Asu-eel and salmon calcitonin with 2% ammonium glycyrrhyzinate and 0·01% benzalkonium chloride, respectively, and of their excipients mixture in solution with increasing concentrations of ammonium glycyrrhyzinate and benzalkonium chloride, respectively, were assessed by investigating their effects on the mucociliary transport velocity in the ex-vivo frog palate preparation. This preparation provides an integrated biological model readily usable in the laboratory which closely resembles human nasal mucociliary clearance mechanism and can be used for rapid testing and toxicity of agents proposed for topical administration in the upper and lower airways. Frog-Ringer control, 1–7 Asu-eel and salmon calcitonin commercial spray preparations and the excipients plus 2% ammonium glycyrrhyzinate and plus 0·01% benzalkonium chloride did not modify significantly the mucociliary transport velocity, confirming their very good tolerability on ciliated epithelium. Higher concentrations of ammonium glycyrrhyzinate (10 and 20%) caused significant slowing, on average —32 and —55%, respectively. Higher concentrations of benzalkonium chloride (0·05 and 0·1%) also caused significant slowing, on average, —43·5 and —87%, respectively.
The binding of the antimalarial arteether to human plasma proteins in-vitro
Authors: Wanwimolruk S , Edwards G , Ward S A , Breckenridge A M
Published: April 2011

The binding of the novel antimalarial drug, arteether, to human plasma, pure albumin and α1-acid glycoprotein has been investigated by ultrafiltration, using [14C]arteether. The protein binding in plasma obtained from 11 healthy male subjects ranged from 73·4 to 81·8% bound, with a mean of 78·7 ± 2·1%. The binding of drug in plasma was mainly accounted for by binding to albumin and α1-acid glycoprotein. Scatchard analysis of the binding data revealed that the binding affinity of arteether to α1-acid glycoprotein is much greater (20-fold) than that to albumin. This suggests that α1-acid glycoprotein is the more important binding protein in plasma. This may have clinical importance due to alterations in plasma protein binding in patients with malaria, as the concentration of α1-acid glycoprotein is markedly increased during malarial infection.
Development of a Prodrug of Salicylic Acid, Salicylic Acid-l-alanine Conjugate, Utilizing Hydrolysis by Rabbit Intestinal Microorganisms
Authors: Nakamura Junzo , Tagami Chieko , Nishida Koyo , Sasaki Hitoshi
Published: April 2011

The hydrolysis of salicylic acid-l-alanine conjugate (salicyl-l-alanine) following oral, intravenous, intracaecal and rectal administration (60, 10, 5 and 5 mg kg−1, respectively: salicylic acid equivalent) was examined in rabbits. Salicylic acid was detected in the blood 2 h after oral administration of salicyl-l-alanine and reached a maximum concentration at 10 h, whereas salicyl-l-alanine was rapidly eliminated. In contrast, unchanged salicyl-l-alanine only was found following intravenous administration of salicyl-l-alanine, suggesting that presystemic de-conjugation of salicyl-l-alanine was involved. The intestinal mucosal de-conjugation of salicyl-l-alanine was not recognized in the in-situ intestinal sac preparation with complete mesenteric venous blood collection. Immediate and very extensive salicylic acid formation in the caecum was found following intracaecal administration of salicyl-l-alanine. After oral pretreatment of rabbits with kanamycin sulphate, a significant inhibition of salicylic acid formation following intracaecal administration of salicyl-l-alanine was observed, indicating that the intestinal microorganisms were responsible for the biotransformation of salicyl-l-alanine. In-vitro incubation of salicyl-l-alanine with gut contents showed that the major source of its hydrolysis was the hind gut. Consequently, the blood concentration of salicylic acid was prolonged extensively following rectal administration of salicyl-l-alanine, suggesting the usefulness of salicyl-l-alanine as a prodrug of salicylic acid.
Comparison of Kinin-forming and Amidolytic Activities of Four Trimucases, Oedema-producing and Kinin-releasing Enzymes, from Trimeresurus mucrosquamatus Venom
Authors: Teng Che-Ming , Hsu Mei-Feng , Wang Jih-Pyang
Published: April 2011

Four kinin-releasing enzymes, trimucase I, II, III and IV, isolated from Trimeresurus mucrosquamatus venom (TMV) caused rat hind-paw swelling. Trimucase I and III were less potent than trimucase II and IV in this effect. Pretreatment with diphenhydramine or methysergide significantly reduced trimucase-induced paw swelling, while aspirin had no effect. Cellulose sulphate pretreatment suppressed the oedematous responses elicited by trimucases. The residual response was further depressed by diphenhydramine and methysergide. Trimucases also caused kinin generation in-vitro from rat plasma. This kinin-forming activity was in the order of trimucase II > IV ≥ III > I > TMV. All trimucases hydrolysed chromogenic peptides N-benzoyl-Pro-Phe-Arg p-nitroanilide, N-benzoyl-Phe-Val-Arg p-nitroanilide and dl-Val-Leu-Arg p-nitroanilide; the order of this amidolytic activity was trimucase I > II > III ≥ IV. These data indicate that the effects of venom kinin-releasing enzymes on plasma kininogen are not parallel to their amidolytic effects.
Decarboxylation of l-Dopa in the Rat Isolated Vascularly Perfused Small Intestine: Contribution to Systemic Elimination and Dose-dependent First Pass Effect
Authors: de Vries Michiel H , Hamelijnck M A Freeke , Hofman Gerard A , Koster Andries S , Noordhoek Jan
Published: April 2011

The contribution of the rat small intestine to systemic and presystemic elimination of l-dopa was studied. When l-dopa was administered into the vascular perfusate, a systemic extraction ratio of 0·38 was found, the major part being decarboxylated to dopamine. The intestinal l-dopa clearance was estimated to be 171 mL min−1 kg−1. Thus, l-dopa intestinal clearance in rat represents up to at least 20% of the total body clearance. After luminal administration of l-dopa 83–88% of the administered dose was absorbed within 60 min. The total amount of l-dopa appearing in the vascular perfusate increased more than proportionally to the increase in the dose. In contrast, the amount of dopamine increased less than proportionally to the dose. As a result, the intestinal first pass appeared to be strongly dose-dependent. Since the total percentage absorbed from the lumen was independent of the administered dose and the total amount that appeared in the vascular perfusate increased linearly with the dose, the dose dependency was probably due to saturation of intestinal l-dopa decarboxylation.
Effects of the Calcium Antagonists Diltiazem, Verapamil and Nitrendipine on the Contractile Responses of Guinea-pig Isolated Ileum to Electrical Stimulation or Carbachol
Authors: Staneva-Stoytcheva D , Venkova K
Published: April 2011

The effects of the organic Ca2+ antagonists nitrendipine, verapamil and diltiazem on the cholinergic contractile responses induced by field electrical stimulation or carbachol (0·1 μu) and on contractions evoked by high concentration KCl (30 Mm) were studied in isolated preparations from the guinea-pig ileum. The three Ca2+ antagonists dose-dependently suppressed the contractile responses showing the same order of potency (nitrendipine > verapamil > diltiazem) with the three different types of stimulation. Comparison of the IC50 values of the Ca2+ antagonists for carbachol-, KCl- and electrically-evoked contractions demonstrated that the carbachol-evoked contractions were most sensitive to the inhibitory action of the antagonists tested. The presynaptic inhibitory effect of (Met)enkephalin (10 Nm) on the electrically-evoked cholinergic contractions was only slightly potentiated by high concentrations (1 or 10 μm) of nitrendipine and diltiazem and remained unchanged by verapamil. The results suggest that the Ca2+ antagonists tested block mainly the carbachol-activated L-type Ca2+ channels on the smooth muscle cells, while the effects on the N-type Ca2+ channels are insignificant, except for the high concentrations of nitrendipine and diltiazem.
The Inhibitory Effect of Dopamine on Cat Gastric Smooth Muscle
Authors: Lefebvre R A
Published: April 2011

The inhibitory effect of dopamine has been studied in longitudinal and circular muscle strips of the cat gastric fundus. When tone was raised by transmural electrical stimulation and by administration of methacholine, dopamine concentration-dependently relaxed the strips but the inhibitory effect of dopamine was clearly more pronounced on electrically-induced tone. The effect of dopamine was not influenced by the presence of cocaine or hydrocortisone. The relaxant effect of dopamine, when tone was raised by methacholine, was not influenced by α- and dopamine receptor antagonists but it was significantly reduced by propranolol and ICI 118551 (erythro-dl-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol). The inhibitory effect of dopamine on the electrically-induced tone was significantly reduced by phentolamine; domperidone tended to reduce the effect of the lower concentrations of dopamine. In the presence of propranolol, phentolamine and rauwolscine concentration-dependently antagonized the inhibitory effect of dopamine on electrically-induced tone, while prazosin was without influence. These results indicate that the inhibitory effect of dopamine in the cat gastric fundus is mainly due to interaction with postjunctional β-adrenoceptors on the smooth muscle cells and with prejunctional α-adrenoceptors on the intramural cholinergic neurons
Efficacy of Verapamil against Ventricular Arrhythmias Induced by Programmed Electrical Stimulation in the Late Myocardial Infarction Phase in Dogs
Authors: Krejcy K , Krumpl G , Todt H , Raberger G
Published: April 2011

The aim of the present study was to investigate the antiarrhythmic potential of verapamil in the late myocardial infarction period in conscious dogs. Verapamil was administered in cumulative doses (0·3 + 0·3 mg kg−1). The drug significantly lowered systolic and diastolic blood pressure after both doses. ECG signals showed short-lasting significant decrease in RR and QT intervals together with an increase in QTc interval. The parameters of the atrioventricular conduction system (PQ interval, 2:1 AV-conduction point) were significantly prolonged over the entire observation period. Ventricular effective refractory periods remained unaltered. In contrast to results obtained during acute ischaemia and in the first week thereafter, the present study demonstrates that verapamil moderately increases intraventricular conduction time 14 days after acute myocardial infarction. Verapamil prevented the induction of arrhythmias by programmed electrical stimulation (PES) in only 11% of all induction attempts. The lack of lengthening of refractory periods in the presence of a prolongation of intraventricular conduction time may be responsible for the poor antiarrhythmic efficacy. We conclude that verapamil is only of negligible value for the management of PES-induced ventricular arrhythmias in the late myocardial infarction period.
The effect of intravenous pretreatment with small liposomes on the pharmacokinetics and metabolism of antipyrine in rabbits
Authors: Badiola Nekane , Al-Angary Ahmed N A , Halbert Gavin W
Published: April 2011

The effect of intravenous pre-treatment with empty small liposomes on the pharmacokinetics and metabolism of antipyrine in rabbits has been investigated. The measured half-life of antipyrine was 104 min and the volume of distribution was 830 mL kg−1. The excretion of metabolites in a 24 h urine sample was measured, the main metabolite 4-hydroxyantipyrine was excreted to a level of 10% with the free drug accounting for 4%. The norantipyrine and 3-hydroxymethylantipyrine metabolites were excreted to a level of 8 and 7%, respectively. The intravenous administration of liposomes at a dose equivalent to 8 mg of egg yolk phosphatidylcholine daily for one week, had no significant effect on any of the measured pharmacokinetic parameters. The half-life after liposome treatment was 110 min and the volume of distribution was 790 mL kg−1, the metabolic pattern in the urine was also unaltered. The results suggest that the repeated administration of low doses of liposomes do not affect the pharmacokinetics and metabolism of antipyrine.
Effect of Freezing on Iontophoretic Transport Through Hairless Rat Skin
Authors: Hadzija Boka W , Ruddy Stephen B , Ballenger E Scott
Published: April 2011

The influence of frozen storage of hairless rat skin on the constant-current iontophoretic transport of a model weak acid, salicylic acid, was examined. Nearly a threefold increase was observed in the steady-state flux of salicylic acid through previously frozen skin (217 ·1 nmol h−1 cm−2) when compared with fresh, excised skin (72·3 nmol h−1 cm−2). The iontophoretic permeability of skin to salicylic acid was also found to be dependent upon the length of time skin samples remained in the frozen state. Differential scanning calorimetry studies revealed distinct differences in the thermograms for fresh and frozen skin. These results suggest that storage of skin samples in the frozen state may contribute to physical or chemical changes in skin structure.
Dose-dependent Inhibition in Plasma Protein Binding of Valproic Acid During Continued Treatment in Guinea-pigs
Authors: Yu Hsiu-Ying , Shen Yu-Zen
Published: April 2011

Plasma protein binding of valproic acid over a wide range of steady-state plasma concentration (11·3 α 2·6–130·3–0 α 122·9 μg mL−1: s.e.m., n = 5) in guinea-pigs has been studied. Valproic acid was given by intravenous constant infusion. At steady-state the plasma protein binding of valproic acid was analysed. Nonlinear binding was observed. Unbound fraction (fu) of valproic acid increased from 25 to 95% with the increase of steady-state plasma concentration (Css). The plasma protein-bound drug concentration (Cb) of valproic acid increased initially with Css but decreased after the Css exceeded 345·0 μg mL−1, where the Cb was 152·5 α 26·8 μg mL−1. At a Css of 1303·3 α 122·9 μg mL−1 the Cb was significantly (P < 0·05) decreased to 72·8 α 20·2 μg mL−1. Binding characteristics of valproic acid in-vitro were studied using drug-free guinea-pig plasma with added valproic acid (10–1000 μg mL−1). The binding behaviour was also nonlinear in-vitro. The fu increased from 14 to 79% with the increase of valproate concentrations. No decrease in Cb was observed throughout the range. The study demonstrated that binding characteristics of valproic acid in-vivo and in-vitro are not parallel. The results suggest that valproic acid may produce or induce plasma protein binding competitors; metabolites of valproic acid may be implicated.
Pharmacokinetics of Moclobemide in Male, Virgin Female, Pregnant and Nursing Rats
Authors: øie Svein , Guentert Theodor W , Tolentino Lorna , Hermodsson Görel
Published: April 2011

The disposition of moclobemide, a reversible inhibitor of monoamine oxidase isoenzyme A was studied in male, virgin female, pregnant and nursing rats. The average clearance in control rats (male and female) was 36 mL min−1 kg−1, the initial volume of distribution 1·4 L kg−1, the volume of distribution at steady state 2·3 L kg−1 and the terminal half-life 59 min. The blood-to-plasma concentration ratio of moclobemide was 0·84 giving rise to an average blood clearance of 30 mL min−1 kg−1. The clearance values in rats were higher than in man but as a fraction of hepatic blood flow were similar (36 vs 45%). The volume of distribution at steady state was approximately twice as high as in man while the half-life was similar. Pregnant and nursing rats showed no statistically significant differences in their disposition parameters for moclobemide compared with virgin female rats. Nursing rats had statistically significantly lower concentrations of the moclobemide N-oxide metabolite than did pregnant and control rats. Generally lower concentrations of the lactam metabolite were also found in this group although the differences did not reach statistical significance. Moclobemide as well as the N-oxide and lactam metabolites were found in the amniotic fluid suggesting that moclobemide is capable of crossing the placental barrier.
Vasorelaxant Effect of Trapidil on Human Basilar Artery
Authors: Okumura Reiko , Hatake Katsuhiko , Wakabayashi Ichiro , Suehiro Akira , Hishida Shigeru , Kakishita Eizo
Published: April 2011

We have investigated the vasorelaxant effect of trapidil on human isolated basilar artery. Trapidil (10−5-10−4  m) dose-dependently caused relaxation in vascular strips with or without endothelium, with no significant difference between the two types of strips. The relaxation responses were not inhibited by atropine, propranolol or methylene blue. Trapidil increased the concentration of 6-keto-PGF1α, a prostacyclin degradation product, released from an artery ring in the incubation medium, but trapidil-induced relaxation was not inhibited by indomethacin. Pretreatment of vascular strips with 10−5  m trapidil increased the relaxation responses to forskolin and dibutyryladenosine cyclic monophosphate but not to sodium nitroprusside or 8-bromoguanosine cyclic monophosphate. Trapidil induced a significant increase in the cAMP concentration but not in the cGMP concentration in artery strips. These results suggest that the relaxation response to trapidil is not caused by prostacyclin release or an increase in cGMP in the smooth muscle, but possibly by an increase in the cAMP levels, probably via an inhibitory effect on cAMP phosphodiesterase.
Failure of Verapamil and Diltiazem to Attenuate the Pressor Response to Hypothalamic Stimulation: A Possible Mechanism
Authors: Eferakeya Adego E , Osunkwo Uche A
Published: April 2011

The effects of verapamil or diltiazem on pressor responses to posterior hypothalamic stimulation, injected noradrenaline or tyramine were studied in urethane-anaesthetized normotensive, deoxycorticosterone acetate (DOCA), renal and spontaneously hypertensive rats at the early and established phases of hypertension. Pressor responses to the pressor stimuli were significantly enhanced in the early and established phases of hypertension when compared with the normotensives. While the magnitude of pressor responses in the established phase of renal or spontaneously hypertensive rats was significantly higher (P < 0·05) than the corresponding value in the early phase, in contrast, the pressor response in the early phase of DOCA hypertension was significantly higher than that of the established phase. Verapamil or diltiazem significantly (P < 0·005) inhibited pressor responses to injected noradrenaline or tyramine in all groups of rats but not that to hypothalamic stimulation, irrespective of the stage of hypertension. When the probable mechanism of the hypothalamic pressor response's resistance to the calcium antagonists was studied in-vitro, ATP significantly (P < 0·005) inhibited the relaxant effect of the calcium antagonists in the rat aortic strips. Our data indicate that verapamil or diltiazem is ineffective in inhibiting the pressor response to posterior hypothalamic stimulation. The probable mechanism of the resistance and the clinical implication of the findings are discussed.
Iontophoretic permeation of sodium cromoglycate through synthetic membrane and excised hairless mouse skin
Authors: Li L C , Vu N T , Allen L V
Published: April 2011

The iontophoretic transport properties of sodium cromoglycate were characterized using a synthetic membrane and excised hairless mouse skin. The permeation rate of sodium cromoglycate through the synthetic membrane was found to be linearly dependent on the density of electrical current applied. Passive diffusion through the excised hairless mouse skin was not demonstrated for sodium cromoglycate; however, under iontophoresis, an appreciable permeation was exhibited by the drug through the animal skin, which was also found to be a function of the electrical current density.
Ageing influences haloperidol-induced changes in the permeability of the blood-brain barrier in the rat
Authors: Saija A , Princi P , Imperatore C , De Pasquale R , Costa G
Published: April 2011

The effect of the dopaminergic antagonist haloperidol on the permeability of the blood-brain barier (BBB) to [14C]α-aminoisobutyric acid was studied in 10–12- and 28–30-week old rats. Following the intraperitoneal injection of haloperidol (1 mg kg−1), an increase in the permeability of the BBB, with respect to younger animals, was observed within the occipital cortex, striatum, hippocampus and hypothalamus in the older rats. No correlation was found between haloperidol-induced changes and age-related differences in the permeability of the BBB. Such age-associated increase in the vulnerability of the BBB when challenged with haloperidol might be related to a deterioration of the dopaminergic control of cerebrovascular permeability.
Similar effects of nifedipine and hydralazine on anaesthesia and hypermotility induced by pentobarbitone in mice
Authors: Sansone Mario , Pavone Flaminia , Battaglia Mario , Daniel Władysława , Vetulani Jerzy
Published: April 2011

Nifedipine, a dihydropyridine calcium channel blocker, and hydralazine, a non-calcium channel antagonist vasodilatator, enhanced pentobarbitone-induced sleeping time and reversed locomotor hyperactivity induced by a subhypnotic dose of the barbiturate in mice. The similarity of the behavioural effects, exerted by nifedipine and hydralazine, suggest that haemodynamic factors may play an important role in the interaction of calcium channel antagonists with barbiturates.
Effect of Theophylline on the Intestinal Clearance of Drugs in Rats
Authors: Bair Chi-Horng , Huang Jin-Ding
Published: April 2011

Intestinal eχsorption of salicylic acid, urea and quinidine was measured during the perfusion of the rat intestinal lumen with Tyrode solution. The intestinal clearance (CLi) of the three compounds was measured by dividing the rate of appearance in the intestinal luminal perfusate by the plasma concentration of the compound. Co-administration of theophylline (0 −2 mg h−1) with the test agents increased the CLi of salicylic acid, did not alter the CLi of urea, but decreased the CLi of quinidine. The effect of theophylline on the CLi of quinidine was enhanced with increasing dose. Theophylline was found to increase microclimate-pH at the intestinal surface, but the magnitude of ΔpH alone could not explain the effect of theophylline on the CLi of quinidine. The data, together with previous observations, suggest that the intestinal eχsorption of drugs was affected by the microclimate pH and by the unstirred water layer. Theophylline affects CLi of salicylic acid and quinidine partly by increasing the microclimate pH of the intestine. Theophylline may also affect quinidine CLi by inhibiting the carrier-mediated pathway.
Effects of Calcium Antagonists on Rat Normal and Skinned Fundus
Authors: Burchés E , Cortijo J , OróN J D , Ortiz J L , Morcillo E J
Published: April 2011

Calcium chloride (CaCl2) (0·1−25 Mm, in K+-depolarized tissue), KCl (10−112 Mm) and acetylcholine (1 × 10−9 m−1 Mm) produced concentration-dependent contractions of rat isolated fundus. Verapamil (0·01−100 μm), cinnarizine (1−100 μm), trifluoperazine (10−500 μm) and dantrolene (50−250 μm) each produced a concentration-related rightward and downward shift of the log concentration-effect curve for CaCl2. The rank order of potencies of these antagonists, measured as the IC50 against Ca2+ (25 Mm)-induced contraction of depolarized fundus, was verapamil (2.5 μm) > cinnarizine (8·7 μm) > trifluoperazine (85·1 μm) > dantrolene (> 250 μm). Cinnarizine (0·5 Mm) and trifluoperazine (0·5 Mm), but neither verapamil nor dantrolene depressed Ca2+ (20 μm)-evoked contraction of rat skinned fundus preparations. In intact preparations of rat fundus, verapamil had greater inhibitory effects on contractions produced by KCl than against those elicited by acetylcholine while trifluoperazine depressed to the same extent the responses to these two spasmogens. Dantrolene was without effect on contractions elicited by KCl or acetylcholine. Cinnarizine inhibited acetylcholine-induced responses but enhanced contractions to KCl. Augmentation of KCl-induced responses by cinnarizine is resistant to verapamil (1 μm). This enhancing effect of cinnarizine was not observed for KCl-induced contraction of guinea-pig fundus or rat gastro-oesophageal sphincter. In the rat fundus, cinnarizine (1−100 μm) produced an additional and concentration-related contraction when added on the plateau contraction to KCl (100 Mm). The enhancing effect and the direct contraction produced by cinnarizine are at least partly dependent on extracellular Ca2+. It is concluded that distinct differences exist between the calcium antagonists examined. The action of verapamil is restricted to the plasmalemma whereas cinnarizine and trifluoperazine also act on the intracellular contractile machinery. Dantrolene is scarcely effective as a calcium antagonist in rat fundus.
Compatibility study between acetylcysteine and some commonly used tablet excipients
Authors: Kerc̆ J , Src̆ic̆ S , Urleb U , Kanalec A , Kofler B , s̆Mid-Korbar J
Published: April 2011

Differential scanning calorimetry (DSC), Fourier transform infra-red spectroscopy (FT-IR), HPLC and TLC were used to investigate the interactions between the mucolytic drug acetylcysteine and a number of commonly used tablet and capsule excipients. Acetylcysteine was found to be compatible with micro-crystalline cellulose (Avicel PH 101), sodium carboxymethylcellulose, amorphous silicon dioxide (Aerosil), PVP, cross-linked PVP (Polyplasdone XL), corn starch, saccharose and magnesium stearate. Acetylcysteine thermal stability (onset degradation temperature) was decreased in mixtures with corn starch, magnesium stearate, saccharose and lactose. Interactions of acetylcysteine with lactose, PEG 4000 and 6000, glycine, adipic acid and saccharin sodium were found using DSC and studied in detail with FT-IR, HPLC and TLC. The results suggest that acetylcysteine in mixtures with PEG 4000, glycine or saccharin sodium is degraded during storage at conditions of high temperature and humidity.