bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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 &gt; IV ≥ III &gt; I &gt; 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 &gt; II &gt; 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

Abstract
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

Abstract
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 &gt; verapamil &gt; 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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 &lt; 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

Abstract
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.