bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic Properties and Interactions with Blood Components of N4-Hexadecyl-1-β-d-arabinofuranosylcytosine (NHAC) Incorporated into Liposomes
Authors: Horber D H , Ottiger C , Schott H , Schwendener R A 
Published: April 2011

Abstract
N 4-Hexadecyl-1-β-d-arabinofuranosylcytosine (NHAC) is a new lipophilic derivative of 1-β-d-arabino-furanosylcytosine (ara-C) with strong antitumour activity. The interactions of NHAC incorporated into small unilamellar liposomes of different compositions with blood components were evaluated.
In comparison with ara-C, NHAC is highly protected against deamination to inactive arabinofurano-syluracil (ara-U) in human plasma, resulting in only 2% conversion into ara-U after 4 h incubation at 37°C, whereas from ara-C more than 80% was deaminated. In in-vitro incubations with human blood, it was found that NHAC was transferred from the liposomes at about 47% efficiency to plasma proteins, particularly to albumin and to the high and low density lipoproteins. The remaining part of NHAC was bound to erythrocytes (50%) and to leucocytes (3%). The addition of poly(ethylene) glycol-modified phospholipids to the liposomes (PEG liposomes), which were composed of soy phosphatidylcholine and cholesterol (plain liposomes), did not significantly prevent the fast transfer of NHAC from the liposomes to the blood components. Pharmacokinetic studies in mice revealed that NHAC had biphasic kinetics in blood with a t 1/2α of 16 min and a 1/2β of 3·8 h when the drug was formulated in plain liposomes and a t 1/2α of 15 min and a t 1/2β of 9·67 h in PEG liposomes, respectively. NHAC was predominantly distributed in the liver with 29% of the injected dose found after 30 min. However, no accumulation occurred in the liver and NHAC was eliminated with biphasic kinetics resulting in a t 1/2α of 53 min and a t 1/2β of 11·8 h. In spleen, kidney and bone marrow the levels of NHAC remained low.
In summary, NHAC is highly resistant against deamination and rapidly transferred from the liposomes to the blood components, independently of the liposome compositions tested.
The Effects of Racemic, (+)- and (-)-Pinacidil on the Membrane Potential of the Rat Aorta
Authors: Doggrell Sheila A , Bishop B E , Barnett Carolyn W 
Published: April 2011

Abstract
The endothelium-intact and -denuded rat aorta is hyperpolarized by racemic and (-)-pinacidil, probably by opening ATP-dependent potassium channels. (+)-Pinacidil caused depolarization of the endothelium-intact and -denuded rat aorta.
The depolarization induced by 20 mm KC1 in the endothelium-intact rat aorta was reversed by racemic and (-)-, but not by (+)-pinacidil. On the endothelium-intact rat aorta, isoprenaline produced hyperpolarization and ICI 118 551 (erythro-(±)-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol) had no effect alone but prevented isoprenaline from causing hyperpolarization. The hyperpolarization induced by isoprenaline was reversed by racemic and (+)-, but not by (-)-pinacidil. Glibenclamide depolarized the endothelium-intact rat aorta and prevented the hyperpolarizing action of racemic pinacidil and (-)-pinacidil. (+)-Pinacidil prevented the hyperpolarizing action of (-)-pinacidil. Glibenclamide is probably preventing the hyperpolarization associated with opening of the ATP-dependent potassium channel by blocking this channel.
Several mechanisms may underlie the depolarizing action of (+)-pinacidil, including blocking of ATP-dependent potassium channels.
High-performance Liquid Chromatographic Determination of Trazodone and 1-m-Chlorophenylpiperazine with Ultraviolet and Electrochemical Detector
Authors: Ohkubo Tadashi , Osanai Takako , Sugawara Kazunobu , Ishida Masayuki , Otani Koichi , Mihara Kazuo , Yasui Norio 
Published: April 2011

Abstract
A high-performance liquid chromatographic (HPLC) assay was developed for the determination of trazodone and its metabolite, 1-m-chlorophenylpiperazine (m-CPP), in plasma.
The high level of trazodone in plasma was detected by ultraviolet absorbance at 254 nm and the low level of m-CPP in plasma was detected by coulometric electrochemical detection at 840 mV on the series arrangement of two detectors. Pilsicainide as an internal standard for both compounds was monitored by both detectors. Trazodone and m-CPP in plasma were extracted by a rapid and simple procedure based on CN bonded-phase extraction, and C8 reversed-phase HPLC separation.
Determination was possible for trazodone in the concentration range 100–2000 ng mL−1 and for m-CPP in the concentration range 5–100 ng mL−1. The recoveries of trazodone and m-CPP added to plasma were 81·0–84·2 and 68·0–73·2%, respectively, with coefficients of variation of less than 7·3 and 8·2%, respectively. The method is applicable to high level monitoring of trazodone and low level monitoring of m-CPP in plasma of healthy volunteers and patients treated with trazodone.
Effects of Ageing on the Oral Absorption of D-Xylose in Rats
Authors: Yuasa Hiroaki , Kawanishi Koji , Watanabe Jun 
Published: April 2011

Abstract
The effects of ageing on the oral absorption of d-xylose were investigated in rats.
The pharmacokinetic analysis of d-xylose concentration in plasma after oral administration showed that the fraction absorbed was increased to 0·998 ± 0·002 and 0·950 ± 0·049, respectively, in old (52 weeks) and very old (102 weeks) rats, compared with 0·768 ± 0·052 in young (9 weeks) rats, while the absorption rate constant was not significantly changed: 0·944 ± 0·233, 0·844 ± 0·143 and 0·725 ± 0·004 h−1, respectively, in young, old and very old rats. The absorbed fractions estimated from faecal and urinary excretion were in agreement with those by the pharmacokinetic analysis. Thus, the present study demonstrated an increase in the extent of the oral absorption of d-xylose with ageing. The increase in the extent of absorption might be caused by a delay in the intestinal transit, because the absorption rate constant was unchanged.
These results suggest potential increases with ageing in the fractions absorbed of hydrophilic drugs such as d-xylose where oral absorption is incomplete.
Acute Moderate Hypoxia in Conscious Rabbits: Effect on Hepatic Cytochrome P450 and on Reactive Oxygen Species
Authors: Proulx Mario , Du Souich Patrick 
Published: April 2011

Abstract
This study aimed to document whether acute moderate hypoxia modifies the amount and activity of hepatic cytochrome P450 and in addition, induces changes in the production or the ability to neutralize oxygen reactive species (ORS).
Rabbits were exposed to a low partial pressure of oxygen (12%) for 8 or 24 h, killed, and the amount and activity of cytochrome P450, lipid peroxidation, microsomal chemiluminescence and enzymatic scavenger activity were assessed in the liver. After 8 h of hypoxia, total amount but not the activity of cytochrome P450 was decreased, although after 24 h of hypoxia, both the amount and the activity of cytochrome P450 were decreased. Hypoxia for 8 h increased the activity of glutathione peroxidase. However, after 24 h of hypoxia, lipid peroxidation, microsomal chemiluminescence and superoxide dismutase activity were increased, while hepatic glutathione and glutathione peroxidase activity were reduced, modifications that suggest an enhanced presence of ORS. In in-vitro studies, an ORS generating system reduced the activity of cytochrome P450 and enhanced lipid peroxidation of hepatic microsomal membranes, supporting the view that ORS can impair cytochrome P450.
The results of the present study show that hypoxia induces changes in the amount and activity of cytochrome P450, as well as in the production or the ability to neutralize ORS, and that these changes are time-dependent.
The Effects of Danshen (Salvia miltiorrhiza) on Warfarin Pharmacodynamics and Pharmacokinetics of Warfarin Enantiomers in Rats
Authors: Chan K , Lo A C T , Yeung J H K , Woo K S 
Published: April 2011

Abstract
The effects of Danshen (Salvia miltiorrhiza), a popular traditional Chinese medicinal herb on the pharmacokinetics and pharmacodynamics of R- and S-warfarin stereoisomers were studied in rats.
After a single oral dose of racemic warfarin (2 mg kg−1), treatment with oral Danshen extract (5 g kg−1, twice daily) for 3 days significantly altered the overall pharmacokinetics of both R- and S-warfarin and increased the plasma concentrations of both enantiomers over a period of 24 h and the prothrombin time over 2 days. At steady-state levels of racemic warfarin (0·2 mg kg−1 day−1 for 5 days) the 3-day treatment of Danshen extract (5 g kg−1, twice daily) not only prolonged the prothrombin time but also increased the steady-state plasma concentrations of R- and S-warfarin.
The results indicate that Danshen extracts can increase the absorption rate constant, area under plasma concentration-time curves, maximum concentrations and elimination half-lives, but decreases the clearances and apparent volume of distribution of both R- and S-warfarin. The pharmacokinetic and pharmacodynamic interactions of warfarin during co-treatment with Danshen extract observed in this study indicate an explanation for the clinically observed incidents of exaggerated warfarin adverse effects when traditional Chinese medicinal herbs or herbal products such as Danshen and Danggui (observed in a previous study) were co-administered.
Brain Distribution Characteristics of Xanthine Derivatives and Relation to their Locomotor Activity in Mice
Authors: Haghgoo Soheila , Hasegawa Takaaki , Nadai Masayuki , Wang Li , Ishigaki Takeo , Miyamoto Ken-Ichi , Nabeshima Toshitaka 
Published: April 2011

Abstract
The relationship between the brain distribution and motor activity in mice of the xanthines, theophylline, enprofylline, 1-methyl-3-propylxanthine (MPX) and oxpentifylline was investigated. Their plasma protein binding and hydrophobicity were also examined.
When these xanthines were administered orally, enprofylline and oxpentifylline had no effect on motor activity. While theophylline increased motor activity over 10 mg kg−1, MPX caused a decrease in such activity over 10 mg kg−1. The protein-binding behaviour varied among these xanthines and was closely related to their hydrophobicity, which is represented as a logarithmic partition coefficient (log PC). MPX had the highest hydrophobicity, while oxpentifylline had the lowest. Brain distribution characteristics varied among these xanthines, with the rank order of their brain penetration ratio, calculated as the ratio of brain to unbound plasma concentrations, being theophylline &gt; oxpentifylline &gt; MPX &gt; enprofylline. The inhibition constants (Ki) for adenosine A1 receptors and cyclic 3′,5′-adenosine monophosphate (cAMP)-phosphodiesterase (PDE) of these xanthines were 44·6 and 134, &gt; 1000 and 112, 26·4 and 49, and &gt; 1000 and 111 μm for theophylline, enprofylline, MPX, and oxpentifylline, respectively.
These findings suggest that the lack of effects of enprofylline and oxpentifylline on motor activity is probably due to their low brain penetration ratio or low adenosine A1 affinity in comparison with theophylline. The decrease in the motor activity by MPX may be, in part, mediated by cAMP or adenosine.
Pharmacodynamic Comparison of Regional Drug Delivery for Non-steroidal Anti-inflammatory Drugs, Using the Rat Air-pouch Model of Inflammation
Authors: Martin S W , Stevens A J , Brennan B S , Rowland M , Houston J B 
Published: April 2011

Abstract
The inhibition of prostaglandin E2 (PGE2) synthesis by S-(+)-ibuprofen and piroxicam have been assessed following intravenous and regional (intrapouch) drug delivery using the rat air-pouch model of inflammation. Anti-inflammatory response was defined as the decrease in the area under the exudate PGE2 concentration-time curve between 3 and 10 h, following regional administration of the irritant carrageenan.
Dose-response studies indicated that bolus regional administration of S-(+)-ibuprofen increased potency 30-fold compared with systemic administration and could be further improved 10-fold by regional infusion, whereas regional administration of piroxicam showed no therapeutic advantage. Examination of the concentration-response using AUC revealed that for a given response, average pouch concentrations for S-(+)-ibuprofen during the PGE2 inflammatory response (3 to 10 h) was similar, irrespective of route or mode of administration. In contrast, an advantage following systemic rather than regional administration was revealed for piroxicam, based on plasma concentration-response data, indicating a major systemic anti-inflammatory component for piroxicam but not for S-(+)-ibuprofen.
These observations stress the need to take account of both pharmacodynamics and pharmacokinetics when considering the potential advantages of regional administration.
Small Intestinal Absorption of Bropirimine in Rats and Effect of Bile Salt on the Absorption
Authors: Emori Hisatoshi , Yokohama Shigeharu , Nishihata Toshiaki 
Published: April 2011

Abstract
The intestinal absorption characteristics of a poorly water-soluble drug, bropirimine, were investigated by the in-situ small intestinal loop method using male Sprague-Dawley rats.
Bropirimine in solution was well absorbed in the overall small intestine, following first-order kinetics. The rate determining step for the disappearance of bropirimine from the small intestinal loop after dosing in the suspension was the dissolution process from suspension. Bropirimine was solubilized by sodium glycocholate.
The disappearance of bropirimine from the small intestinal loop was suppressed by sodium glycocholate contained in the solution, because of the loss of thermodynamic activity of bropirimine after its involvement in the micellar complex, not by the direct effect of bile salt on the permeability of intestinal mucosa. The disappearance of bropirimine was also suppressed by sodium glycocholate contained in the suspension.
The suppression by sodium glycocholate seemed to be caused by the greater influence of sodium glycocholate on the thermodynamic activity of bropirimine than on the dissolution from suspension.
Toxicodynamic Analysis of Inflammatory Reactions by an Angiotensin Converting Enzyme Inhibitor (Lisinopril) in Guinea-pig Skin
Authors: Ito Kaori , Ito Kiyomi , Sawada Yasufumi , Iga Tatsuji 
Published: April 2011

Abstract
There have been reports of rash and angioedema in the treatment of hypertension with angiotensin converting enzyme (ACE) inhibitors. To evaluate the inflammatory reaction, we continuously infused lisinopril for three days into the peritoneal cavity of ovalbumin-sensitized guinea-pigs and tested intradermal inflammation with ovalbumin. Inflammatory responses were measured in two perpendicular directions serially, and the areas of rash were used as an index of inflammatory reaction induced by lisinopril.
Inflammatory responses were dose-dependently enhanced by treatment with lisinopril. Plasma concentration of lisinopril required to produce 50% of the maximum potentiation of the inflammatory reaction in guinea-pig skin was 40 times plasma unbound concentration after the clinical treatment of lisinopril in patients.
Vascular β-Adrenoceptor-mediated Relaxation and the Tone of the Tissue in Canine Arteries
Authors: Begonha R , Moura D , Guimarães S 
Published: April 2011

Abstract
The aim of the present investigation was to study the influence of the tone in the response to β-adrenoceptor activation of four different canine arteries: coronary, pulmonary, mesenteric and splenic.
Five different levels of tone were produced (of about 35, 50, 65, 80 and 95% of the maximum) by adding phenylephrine (0·6, 1·0, 2·0, 4·0, and 10 μm, respectively) to the bath.
In the coronary artery at spontaneous tone, low concentrations of noradrenaline or adrenaline (1–3 nm) caused either relaxation or contraction, while after induced tone, both noradrenaline and adrenaline caused concentration-dependent relaxations, noradrenaline being more potent (EC50 of 0·16 (0·13–0·20) and 0·38 (0·28–0·67) μm, respectively; n = 6; P &lt; 0·05). Only in the coronary artery did isoprenaline relax the tissue irrespective of the previous level of tone. In all the other arteries, isoprenaline was able to cause concentration-dependent relaxations only if the previous tone was submaximal. At 80% of the maximum, isoprenaline caused relaxation in the mesenteric and pulmonary arteries, but in the splenic artery it caused relaxation only when the tone was of about 65% of the maximum or less.
While in the coronary artery atenolol and ICI-118,551 (erythro-dl 1(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol) were equipotent in antagonizing isoprenaline, noradrenaline and adrenaline, in the other vessels ICI-118,551 was from 58 (splenic artery) to 525 (mesenteric artery) times more potent than atenolol against the isoprenaline relaxant effect.
We conclude that: the tone of the vessel represents a critical factor deciding the sense of the response (coronary artery; low concentrations of noradrenaline or adrenaline), the level at which the relaxant effect is triggered (mesenteric = 80% vs splenic = 65%), and the magnitude of the relaxant effect (always). β-Adrenoceptors predominate in the mesenteric, pulmonary and splenic arteries, while β1-adrenoceptors predominate in the coronary artery. It is unlikely that adrenaline is able to cause vasodilation in any of the vascular beds studied.
Evidence against the Participation of μ- and κ-Opioid Receptors in the Analgesic Activity of Ketorolac in Rats
Authors: Granados-Soto Vinicio , Flores-Murrieta Francisco J , Castaáeda-Hernández Gilberto , Hong Enrique , López-Muñoz Francisco J 
Published: April 2011

Abstract
The possibility that activation of opioid receptors is involved in the analgesic activity of ketorolac was explored. The analgesic effects of ketorolac, of ketocyclazocine, the prototype κ-agonist, and of morphine, the prototype μ-agonist, were assayed in the pain-induced functional impairment model in the rat.
All three drugs induced a significant analgesic effect in this model. Naloxone was able to antagonize the effects of ketocyclazocine and morphine. However, the effect of ketorolac was not blocked by naloxone, although a high dose, 3·2 mg kg−1, capable of blocking κ-receptors was used.
It is concluded that activation of μ- or κ-opioid receptors, by either a direct or an indirect mechanism, does not play a role in the analgesic activity of ketorolac.
Precorneal Clearance of Mucoadhesive Microspheres from the Rabbit Eye
Authors: Durrani A M , Farr S J , Kellaway I W 
Published: April 2011

Abstract
The ocular disposition of hydrated 111In-labelled microspheres was investigated in the rabbit by gamma scintigraphy. Microspheres of cross-linked poly(acrylic acid) (Carbopol 907) were prepared by a w/o emulsification process.
An in-vitro mucoadhesion test of prehydrated microspheres showed that greater adhesion was achieved to a mucus gel at pH 5·0 compared with pH 7·4.
Clearance was a biphasic process with a rapid initial phase preceding a slower basal phase. When hydrated in pH 5·0 phosphate buffered saline, clearance during the basal phase was slower compared with a pH 7·4 buffered preparation. Both prehydrated preparations were retained on the preocular area during the basal phase for longer periods than non-hydrated microspheres.
The retention on the ocular surface of approximately 25% of the instilled dose would suggest this technology will have application for controlled ophthalmic drug delivery.
Synthesis and Inhibition of Human Leucocyte Elastase by Functionalized N-Aryl Azetidin-2-ones: Effect of Different Substituents on the Aromatic Ring
Authors: Joyeau R , Felk A , Guilaume S , Wakselman M , Vergely I , Doucet C , Boggetto N , Reboud-Ravaux M 
Published: April 2011

Abstract
N-aryl-3,3-difluoroazetidin-2-ones featured by a latent electrophilic methylene quinoniminium function have been synthesized and evaluated as inhibitors of human leucocyte elastase.
To promote hydrophobic interactions with the enzyme, to increase the rates of β-lactam ring opening and of benzylic group departure, or to induce hydrosolubility, these compounds incorporate on their aromatic ring either an alkyl moiety, a methoxy substituent or a carboxylic group.
Some of these β-lactams proved to be good inactivators of human leucocyte elastase.
Pharmacokinetic-toxicodynamic Relationships of Adriamycin in Rat: Prediction of Butylated Hydroxyanisole-mediated Reduction in Anthracycline Cardiotoxicity
Authors: Vora Jayesh , Boroujerdi Mehdi 
Published: April 2011

Abstract
Adriamycin, an anthracycline antibiotic, has broad antitumour activity with cumulative dose-dependent cardiotoxicity as its major side effect. This study was designed to quantify and correlate the cardiotoxicity and pharmacokinetics of adriamycin in-vivo in rat. The influence of antioxidant (butylated hydroxyanisole, BHA) co-therapy on the cardiotoxicity and disposition of adriamycin was also studied.
Cardiotoxicity was estimated by serially measuring serum creatine kinase (CK) levels after intravenous administration of adriamycin (4, 10, 20, and 30 mg kg−1) and adriamycin-BHA (10 and 30 mg kg−1 each). Peak serum CK concentrations (CKmax) and area under serum CK-time curves (AUCCK) were used as cardiotoxicity indices. Pharmacokinetic studies were undertaken by sampling plasma and urine from distinct groups of rats treated with [14C]adriamycin (at the above doses) and [14C]adriamycin-BHA (10 mg kg−1 each). Co-administration of BHA resulted in a significant reduction in CKmax and also resulted in a significant reduction in the renal clearance of adriamycin which was fully compensated by an increase in its metabolic clearance. A linear increase in the area under the plasma adriamycin concentration-time curves (AUC) with increasing adriamycin doses suggested dose-independent disposition of the drug. The most significant pharmacokinetic-toxicodynamic relationships included: CKmax = 2.25 × 102 exp(4 × 10-4 AUC), r2 0.941, P &lt; 0.05 and AUCCK = 1.3 × 104 exp(2 × 10-4 AUC0-tmax), r2 = 0.918, P &lt; 0.05 where, AUC0-tmax is the area under the adriamycin concentration-time curve from time 0 to the time of the peak CK level.
The results strongly indicate that the drug-induced cardiotoxicity is initiated shortly after dosing when drug concentrations are high and accumulates with continued exposure. The predicted cardiotoxic indices, obtained from altered adriamycin pharmacokinetic parameters as a result of BHA co-therapy, compared favourably with the observed values.