Showing papers by "Rhône-Poulenc published in 2000"
TL;DR: Irinotecan combined with fluorouracil and calcium folinate was well-tolerated and increased response rate, time to progression, and survival, with a later deterioration in quality of life.
3,176 citations
TL;DR: The survey results support the value of in vivo toxicology studies to predict for many significant HTs associated with pharmaceuticals and have helped to identify HT categories that may benefit from improved methods.
1,699 citations
TL;DR: Over the last five years, industrial and academic researchers have made the unique exploratory power of some reactions into one of the most efficient and cost-effective tools for combinatorial and parallel synthesis.
Abstract: With the emergence of high-throughput screening in the pharmaceutical industry in the early 1990's, organic chemists were faced with a new challenge: how to prepare large collections of molecules (the libraries) to "feed" the high-throughput screen? The unique exploratory power of some reactions (such as the 40 year-old Ugi four-component condensation) was soon recognized to be extremely valuable to produce libraries in a time- and cost-effective manner. Over the last five years, industrial and academic researchers have made these powerful transformations into one of the most efficient and cost-effective tools for combinatorial and parallel synthesis.
993 citations
TL;DR: The aim of this study was to evaluate the efficacy of docetaxel as first-line chemotherapy in patients with unresectable metastatic metastatic or locally advanced pancreatic adenocarcinoma and to further characterise the safety and pharmacokinetic profiles of docentaxel.
778 citations
TL;DR: The authors examine the growing role that is being played by computational methods in this filtering process, with a particular focus on the prediction of intestinal absorption and blood-brain barrier penetration.
493 citations
TL;DR: It is shown that Bloom's syndrome gene product BLM and hTOPO IIIα, one of two human topoisomerase III homologues, co-localize in the nucleus of human cells and can be co-immunoprecipitated from human cell extracts.
322 citations
TL;DR: ROI play a key role in cationic lipid-mediated toxicity, cause a release of ROI which are responsible for the pulmonary toxicity and cause oxidative burst induced by the liposomes.
Abstract: Purpose. The objectives of this study are to investigate the toxicityassociated with polycationic liposomes and to elucidate the underlyingmechanism. We tested the hypothesis that the positive charge of liposomesis a key determinant of toxicity by testing differently chargedliposomes in mice.
311 citations
TL;DR: The quality-of-life descriptors were in favor of docetaxel, and the difference was significant for pain, dyspnea and emotional functioning, and there was a significantly longer time to progression in the docetrixel versus the BSC arm, and statistically significant improvement of clinical symptoms with docetAXel compared to BSC.
305 citations
TL;DR: It is proposed that age-dependent reduction in hypoxia-induced VEGF expression results from reduced HIF-1 activity and may explain the previously described age- dependent impairment of angiogenesis in response to ischemia.
302 citations
Journal Article•
TL;DR: Data indicate that AdNIS is very efficient in triggering significant iodide uptake by a tumor, outlining the potential of this novel cancer gene therapy approach for a targeted radiotherapy.
Abstract: The Na+/I- symporter (NIS) present in the membranes of thyroid cells is responsible for the capacity of the thyroid to concentrate iodide. This allows treatment of thyroid cancers with 131I. We propose to enlarge this therapeutic strategy to nonthyroid tumors by using an adenoviral vector to deliver the NIS gene into the tumor cells. We constructed a recombinant adenovirus encoding the rat NIS gene under the control of the cytomegalovirus promoter (AdNIS). Infection of SiHa cells (human cervix tumor cells) with AdNIS resulted in perchlorate-sensitive 125I uptake by these cells to a level 125-225 times higher than that in noninfected cells. Similar results were obtained for other human tumor cell lines, including MCF7 and T-47D (mammary gland), DU 145 and PC-3 (prostate), A549 (lung), and HT-29 (colon), demonstrating that the AdNIS vector can function in tumor cells of various origins. In addition, AdNIS-infected tumor cells were selectively killed by exposure to 131I, as revealed by clonogenic assays. To assess the efficiency of this cancer gene therapy strategy in vivo, we injected the AdNIS vector in human tumors (SiHa or MCF7 cells) established s.c. in nude mice. Immunohistological analysis confirmed the expression of the NIS protein in the tumor. Three days after intratumoral injection, AdNIS-treated tumors could specifically accumulate 125I or 123I, as revealed by kinetics and imaging experiments. A quantitative analysis demonstrated that the uptake in AdNIS-injected tumors was 4-25 times higher than that in nontreated tumors. On average, 11% of the total amount of injected 125I could be recovered per gram of AdNIS-treated tumor tissue. Altogether, these data indicate that AdNIS is very efficient in triggering significant iodide uptake by a tumor, outlining the potential of this novel cancer gene therapy approach for a targeted radiotherapy.
258 citations
TL;DR: An update on the current state of PK/PD‐modeling from an academic, industrial and regulatory perspective is presented.
Abstract: The two domains in clinical pharmacology dealing with optimizing dosing recommendations are pharmacokinetics and pharmacodynamics. However, the usefulness of these disciplines is limited if viewed in isolation. Pharmacokinetic/pharmacodynamic (PK/PD) relationships and modeling builds the bridge between these two classical disciplines of clinical pharmacology. It links the concentration-time profile as assessed by pharmacokinetics to the intensity of observed response as quantified by pharmacodynamics. Thus, the resulting so-called integrated PK/PD-models allow the description of the complete time course of the desired and/or undesired effects in response to a drug therapy. PK/PD-modeling can elucidate the causative relationship between drug exposure and response and provide a better understanding of the sequence of events that result in the observed drug effect. This information can then be used to streamline the drug development process and dose optimization. This consensus paper presents an update on the current state of PK/PD-modeling from an academic, industrial and regulatory perspective.
TL;DR: In this article, a new method based on the auto-correlation function is proposed, which provides quantitative information about the characteristic time and the axial dimension of the flow structure in the prevailing regime.
TL;DR: The study of presenilin physiological functions and the pathological mechanisms underlying their role in pathogenesis clearly advanced the understanding of cellular mechanisms underlying the neuronal cell death and will contribute to the identification of novel drug targets for the treatment of AD.
TL;DR: The Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events (ESSENCE) study as mentioned in this paper showed that enoxaparan therapy significantly reduced the rates of recurrent ischemic events and invasive diagnostic and therapeutic procedures in the short term with sustained benefit at one year.
TL;DR: The performances of four chronic toxicity tests, comprising the Daphnia magna 21-day (d) (crustacean), Brachionus calyciflorus 2-d (rotifer), Pseudokirchneriella subcapitata 72-h (green algae), and the Microtox chronic 22-H (bacteria) tests, were compared.
TL;DR: Transgenic rodent gene mutation models provide quick and statistically reliable assays for mutations in the DNA from any tissue, and Sequencing data would not normally be required but might provide useful additional information in specific circumstances.
Abstract: Transgenic rodent gene mutation models provide quick and statistically reliable assays for mutations in the DNA from any tissue. For regulatory applications, assays should be based on neutral genes, be generally available in several laboratories, and be readily transferable. Five or fewer repeated treatments are inadequate to conclude that a compound is negative but more than 90 daily treatments may risk complications. A sampling time of 35 days is suitable for most tissues and chemicals, while shorter sampling times might be appropriate for highly proliferative tissues. For phage-based assays, 5 to 10 animals per group should be analyzed, assuming a spontaneous mutant frequency (MF) of ∼3 x 10 -5 mutants/locus and 125,000-300,000 plaque or colony forming units (PFU or CFU) per tissue. Data should be generated for two dose groups but three should be treated, at the maximum tolerated dose (MTD), two-thirds the MTD, and one-third the MTD. Concurrent positive control animals are only necessary during validation, but positive control DNA must be included in each plating. Tissues should be processed and analyzed in a block design and the total number of PFUs or CFUs and the MF for each tissue and animal reported. Sequencing data would not normally be required but might provide useful additional information in specific circumstances. Statistical tests used should consider the animal as the experimental unit. Non parametric statistical tests are recommended. A positive result is a statistically significant dose-response and/or statistically significant increase in any dose group compared to concurrent negative controls using an appropriate statistical model. A negative result is statistically nonsignificant with all mean MF within two standard deviations of the control.
TL;DR: Bacteria artificial chromosomes that can be shuttled among Escherichia coli and a suitable Streptomyces host and introduced into genetically accessible S. lividans, where they are stably maintained in integrated form in its chromosome are developed.
Abstract: Bacteria belonging to the order Actinomycetales produce most microbial metabolites thus far described, several of which have found applications in medicine and agriculture However, most strains were discovered by their ability to produce a given molecule and are, therefore, poorly characterized physiologically and genetically Thus, methodologies for genetic manipulation of actinomycetes are not available and efficient tools have been developed for just a few strains This constitutes a serious limitation to applying molecular genetics approaches to strain development and structural manipulation of microbial metabolites To overcome this hurdle, we have developed bacterial artificial chromosomes (BAC) that can be shuttled among Escherichia coli, where they replicate autonomously, and a suitable Streptomyces host, where they integrate site-specifically into the chromosome The existence of gene clusters and of genetically amenable host strains, such as Streptomyces coelicolor or Streptomyces lividans, makes this a sensible approach We report here that 100 kb segments of actinomycete DNA can be cloned into these vectors and introduced into genetically accessible S lividans, where they are stably maintained in integrated form in its chromosome
TL;DR: Results suggest that hpttg is induced by, and may have a role in, regulatory pathways involved in the control of cell proliferation, and hPTTG is phosphorylated during mitosis.
Abstract: We recently isolated a cDNA for hpttg, the human homolog of rat pituitary tumor transforming gene. Now we have analysed the expression of hpttg as a function of cell proliferation. hPTTG protein level is up-regulated in rapidly proliferating cells, is down-regulated in response to serum starvation or cell confluence, and is regulated in a cell cycle-dependent manner, peaking in mitosis. In addition, we show that hPTTG is phosphorylated during mitosis. Immunodepletion and in vitro phosphorylation experiments, together with the use of a specific inhibitor, indicate that Cdc2 is the kinase that phosphorylates hPTTG. These results suggest that hpttg is induced by, and may have a role in, regulatory pathways involved in the control of cell proliferation.
TL;DR: Escherichia coli recombinants are constructed, which contain the alk genes from the OCT plasmid of P. oleovorans [E. coli HB101 (pGEc47)], encoding alkane hydroxylase and xylene oxygenase, respectively, which are versatile mono-oxygenases for stereo- and regioselective oxidation of aliphatic and aromatic hydrocarbons.
Abstract: The Pseudomonas oleovorans alkane hydroxylase and xylene oxygenase from Pseudomonas putida are versatile mono-oxygenases for stereo- and regioselective oxidation of aliphatic and aromatic hydrocarbons. Pseudomonas oleovorans and alkanol dehydrogenase deficient mutants of Pseudomonas have previously been used to produce alkanols from various alkanes and optically active epoxides from alkenes. Similarly, P. putida strains have been used to produce aromatic alcohols, aromatic acids, and optically active styrene oxides. A limitation in the use of Pseudomonas strains for bioconversions is that these strains can degrade some of the products formed. To counter this problem, we have constructed Escherichia coli recombinants, which contain the alk genes from the OCT plasmid of P. oleovorans [E. coli HB101 (pGEc47)] and the xylMA genes from the TOL plasmid of P. putida mt-2 [E. coli HB101 (pGB63)], encoding alkane hydroxylase and xylene oxygenase, respectively. Escherichia coli HB101 (pGEc47) was used to produce octanoic acid from n-octane and E. coli HB101 (pBG63) was put to use for the oxidation of styrene to styrene oxide in two-liquid phase biocatalysis at high cell densities. The alk(+) recombinant strain E. coli HB101 (pGEc47) was grown to 40 g/L cell dry mass in the presence of n-octane, which was converted to octanoic acid by the alkane oxidation system, the product accumulating in the aqueous phase. The xyl(+) recombinant E. coli HB101 (pBG63) was grown to a cell density of 26 g/L cell dry mass in the presence of around 7% (v/v) n-dodecane, which contained 2% (v/v) styrene. The recombinant E. coli (xyl(+)) converted styrene to (S)-(+)-styrene oxide at high enantiomeric excess (94% ee) and this compound partitioned almost exclusively into the organic phase. Using these high-cell-density two-liquid-phase cultures, the products accumulated rapidly, yielding high concentrations of products (50 mM octanoic acid and 90 mM styrene oxide) in the respective phases.
TL;DR: This paper describes a Monte Carlo search procedure that allows the selection of a near-combinatorial subset in which all library members satisfy the design criteria and illustrates how consideration of calculated log P, molecular weight, and polar surface area in the design of a combinatorial library can lead to compounds with improved absorption characteristics.
Abstract: In this paper we address several issues in the design of lead optimization libraries. Multipharmacophore descriptors were first developed in the context of designing diverse compound libraries. One reason for favoring such descriptors is the importance of the pharmacophore hypothesis in understanding the interaction of a compound with a protein target. Allied to this is the proposal that sampling over all potential pharmacophores leads to diversity in a biologically relevant space. We present results in support of this argument and also demonstrate that such methods are applicable to the design of focused libraries where the aim is to design the library toward a known lead or leads. This portability is important because it means that the same descriptors can be used for diverse library design, screening set selection, and focused library design, giving a consistent approach. We also examine the question of designing libraries with improved pharmacokinetic properties and show that it is possible to derive ...
TL;DR: The relationship between PON1 and atherosclerosis development in transgenic rabbits overexpressing human apolipoprotein (apo) A-I and nontransgenic littermates fed a pro-atherogenic diet is examined.
TL;DR: The purpose was to determine, in patients with metastatic colorectal carcinoma treated with irinotecan single-agent after 5-FU failure, the most significant predictive parameters for tumour response, progression-free survival and toxicity.
Abstract: Our purpose was to determine, in patients with metastatic colorectal carcinoma treated with irinotecan single-agent after 5-FU failure, the most significant predictive parameters for tumour response, progression-free survival and toxicity. Between October 1992 and April 1995, 455 patients with 5-FU resistant metastatic colorectal carcinoma entered four consecutive phase II trials. The first two studies assessed tumour response, the other two were randomized studies which assessed the efficacy of racecadotril to prevent irinotecan-induced diarrhoea. Due to homogeneous main eligibility criterias, data from those studies could be pooled for statistical analysis. Potential clinical and biological predictive factors (PF) for toxicity, tumour growth control, e.g. response or stabilization and progression-free survival (PFS), were studied in multivariate analysis. 363 patients were evaluable for response, 432 were evaluable for PFS, 368 for neutropenia and 416 for delayed diarrhoea, respectively. Normal baseline haemoglobin level (Hb), time since diagnosis of colorectal carcinoma, grade 3 or 4 neutropenia or diarrhoea at first cycle and a low number of organs involved were the most PF for tumour growth control (P< 0.05). Significant prognostic variables for PFS were WHO Performance Status, liver and lymph-node involvement, time since diagnosis, age and CEA value (P≤ 0.02). Six groups of patients based on the number of unfavourable prognostic factors are presented. Baseline bilirubin, haemoglobin level, number of organs involved and time from diagnosis were PF for neutropenia; PS, serum creatinine, leukocyte count, time from 5-FU progression and prior abdominopelvic irradiation were PF for delayed diarrhoea (P≤ 0.05). These PF should help clinicians to anticipate for a given patient the probability to observe a response/stabilization or a toxicity. These results should also be prospectively confirmed in ongoing or future trials using irinotecan, both as a single agent and in combination with other drugs. © 2000 Cancer Research Campaign
TL;DR: A method to measure quantitatively epithelium thickness is described and compared with those seen with the use of cetirizine (an antihistamine) and another oral intranasal corticosteroid, beclomethasone dipropionate (BDP).
Abstract: Background: The main objective of this long-term prospective local safety study was to evaluate endoscopic and histologic changes in nasal epithelium after 6-month treatment with triamcinolone acetonide (TAA). We describe here a method to measure quantitatively epithelium thickness. Results were compared with those seen with the use of cetirizine (an antihistamine) and another oral intranasal corticosteroid, beclomethasone dipropionate (BDP).
Methods: Patients were examined by an ENT specialist who first performed an endoscopic evaluation of the nasal cavities, assessing any morphologic abnormalities and the aspect of the mucosa. Biopsies were taken from the inferior turbinate before and after 24 weeks of treatment. Biopsies were immediately fixed in cold acetone (−20°C) and embedded in glycolmethacrylate; sections of 2 µm were cut on an ultramicrotome. Morphometric evaluations were done in a blinded fashion by computerized image analysis to measure an epithelial area over a minimum length of 50 µm. The thickness was ascertained by the ratio of area to length.
Results:
For all three treatment groups, the nasal epithelium thickness decreased slightly from pretreatment to the end of treatment.
No statistically significant differences between the three treatment groups were found in epithelium thickness.
Macroscopically, nasal tissues in all treated groups were normal.
Conclusions: These results clearly indicate that long-term treatment with TAA has no atrophic effect on nasal mucosa.
TL;DR: The solid-phase synthesis of a 10,000 member combinatorial library of 1,5-benzodiazepine-2-one derivatives is reported and the Irori system was used to remove the compounds of lower purity.
Abstract: The solid-phase synthesis of a 10 000 member combinatorial library of 1,5-benzodiazepine-2-one derivatives is reported. The 3-amino-1,5-benzodiazepine-2-one scaffold was prepared in solution, and the benzamide nitrogen was used as a point of attachment to the resin. The 5-aniline and 3-amine were then used as points of diversity. A 10 000 member library was synthesized using the Irori directed sorting system, and after analysis of a representative sample from the library, the Irori system was used to remove the compounds of lower purity.
TL;DR: The aim of this review is to impartially present the state of the art in telomerase with the pros and the cons of the current scientific situation of this fast-growing and fascinating topic for answering the key question asked by experimental and medical oncologists: Will telomersase be a therapeutic target for the third millenium?
Abstract: Telomerase offers the potential opportunity to control cell proliferation by interfering with a totally new and unique biological process which is cell senescence. The aim of this review is to impartially present the state of the art in telomerase with the pros and the cons of the current scientific situation of this fast-growing and fascinating topic for answering the key question asked by experimental and medical oncologists: Will telomerase be a therapeutic target for the third millenium? The most convincing argument (which is a scientifically documented one) for going ahead with this target is obviously the strong correlation existing between the level and frequency of telomerase expression and the malignant properties of tumors. This has been now largely documented in established tumor cell lines and fresh tumor samples obtained from patients. Noteworthy is the very important difference of telomerase expression between malignant and normal tissues. This difference is much higher than those observed for classical enzymatic targets of chemotherapy such as thymidylate synthetase, dihydrofolate reductase and topoisomerases. If this translates to the clinical situation, telomerase inhibitors might display a good selectivity for tumor cells with a minimal toxicity for normal tissues. The most appealing criticism (which is still purely speculative) is obviously the clinical relevance of inhibiting telomerase in cancer patients. According to the paradigm currently proposed for telomeres and telomerases, it can be predicted that telomerase inhibition will not affect a tumor until its telomeres reach the critical size for entering senescence. This means that during anti-telomerase therapy, the tumor cells will continue grow undergoing 20-30 divisions until the telomeres reach a critical size leading to tumor senescence. Does this make sense, especially in patients with advanced tumors at the beginning of the therapy? Ultimately, the definitive answer to the question will not come from intellectual speculation but from the properties of telomerase inhibitors, first in tumor bearing animals, then finally in cancer patients! Several institutions are very active in the development of telomerase inhibitors. Different stategies are used: direct inhibition of telomerase, interference with telomeres (G quartets), interaction with other proteins involved in the regulation of telomerase and telomeres.
TL;DR: A new tetrafluorophenol activated resin that facilitates the use of 19F NMR to quantitate loading is presented, and provides a useful tool for acylation, and a novel activated polymeric sulfonate ester to generate sulfonamides.
Abstract: A new tetrafluorophenol activated resin that facilitates the use of 19F NMR to quantitate loading is presented. This new resin provides a useful tool for acylation, and a novel activated polymeric sulfonate ester to generate sulfonamides. This activated resin reacts with a wide scope of N-nucleophiles including primary and secondary amines, and anilines. This new activated resin methodology provides a powerful tool for pure single-compound library synthesis.
TL;DR: In this paper, the effect of water and excess versatic acid ([versatic acid]/[Nd]-3] on polybutadiene polymerization performance was investigated.
TL;DR: The link between the degree of nigral degeneration and the sequential activation of dopaminergic compensatory mechanisms in the nigrostriatal pathway is explored and a rethink of the paradigm applied to these mechanisms is proposed.
Abstract: Although several adaptive mechanisms have been identified that mask the existence of Parkinson's disease and delay the onset and aggravation of motor symptoms, the timescale and implications of this compensatory process remain an enigma. In order to examine: (i) the nature of the dopaminergic adaptive mechanisms that come into action; (ii) their sequential activation in relation to the severity of degeneration; and (iii) their efficacy with regard to the maintenance of a normal level of basal ganglia activity, we analysed the brains of mice treated daily with 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP, 4 mg/kg, i.p.) and killed at 5-day intervals from day 0 (D0) to D20. Our results demonstrate the sequential activation of two compensatory mechanisms: (i) an increase in striatal tyrosine hydroxylase (TH) protein content attested by the persistence of TH immunolabelling up to D15, contrasting with the decrease observed in both the number of nigral TH-immunoreactive neurons (-70.2%) and striatal dopamine content (-38.4%); (ii) a downregulation of DA uptake in surviving terminals at D20 (73.4% of nigral degeneration). At this point, the failure of adaptive mechanisms to maintain striatal dopaminergic homeostasis is also illustrated by an increase in the cytochrome oxidase activity of substantia nigra pars reticulata, a marker of neuronal function. It has been postulated that an increase in dopamine release per pulse could constitute an adaptive mechanism. The data we present from our MPTP mice model infirm this hypothesis. This study explores the link between the degree of nigral degeneration and the sequential activation of dopaminergic compensatory mechanisms in the nigrostriatal pathway and, in so doing, proposes a rethink of the paradigm applied to these mechanisms.
TL;DR: In this paper, a range of N-benzyl tertiary amines with aqueous ceric ammonium nitrate was treated with N-debenzylation to afford the corresponding secondary amine.
Abstract: Treatment of a range of N-benzyl tertiary amines with aqueous ceric ammonium nitrate results in N-debenzylation to afford the corresponding secondary amine. Chemoselective mono-N-debenzylation of N-benzyl tertiary amines is shown to occur in the presence of N-benzyl amides, O-benzyl ethers, O-benzyl esters, O-benzyl phenolates and S-benzyl ethers.
TL;DR: It is suggested that continuous infusion of AMP579 at R is more potent than adenosine in attenuating R injury, andAMP579-induced cardioprotection involves inhibition of PMN-induced vascular and myocardial tissue injury.
Abstract: Objective: The purpose of this study was to compare protective effects of AMP579 and adenosine (Ado) at reperfusion (R) on inhibition of polymorphonuclear neutrophil (PMN) activation, PMN-mediated injury to coronary artery endothelium, and final infarct size. Methods: In anesthetized dogs, 1 h of left anterior descending coronary artery occlusion was followed by 24 h R and drugs were administered at R. Control ( n =8, saline control), AMPI ( n =7, AMP579, 50 μg/kg i.v. bolus followed by 3 μg/kg/min for 2 h), AMPII ( n =7, AMP579, 50 μg/kg i.v. bolus), AMPIII ( n =7, AMP579, 3 μg/kg/min i.v. for 2 h), and Ado ( n =7, adenosine, 140 μg/kg/min i.v. for 2 h). Results: AMP579 in vitro directly inhibited superoxide radical (O−2) generation (nM/5×106 PMNs) from PMNs dose-dependently (from 17±1* at 10 nM to 2±0.2* at 10 μM vs. activated 30±2). However, inhibition of O−2 generation by Ado at each concentration was significantly less than for AMP579. The IC50 value for AMP579 (0.09±0.02 μM) on O−2 generation was significantly less than that of Ado (3.9±1.1 μM). Adherence of unstimulated PMN to postischemic coronary artery endothelium (PMNs/mm2) was attenuated in AMPI and AMPIII vs. Control (60±3* and 58±3* vs. Control 110±4), while Ado partially attenuated PMN adherence (98±3*). Accordingly, endothelial-dependent vascular relaxation was significantly greater in AMPI and AMPIII vs. Ado. At 24 h R, myocardial blood flow (MBF, ml/min/g) in the area at risk (AAR), confirmed by colored microspheres, in AMPI and AMPIII was significantly improved (0.8±0.1* and 0.7±0.1* vs. Control 0.3±0.04). Infarct size (IS, TTC staining) in AMPI and AMPIII was significantly reduced from 38±3% in Control to 21±4%* and 22±3%*, respectively, confirmed by lower plasma creatine kinase activity (I.U./g protein) in these two groups (27±6* and 32±2* vs. 49±3). Cardiac myeloperoxidase activity (MPO, Abs/min) in the AAR was significantly reduced in AMPI and AMPIII vs. Control (36±11* and 35±10* vs. 89±10). However, changes in MBF, IS and MPO were not significantly altered by Ado. Conclusions: These data suggest that continuous infusion of AMP579 at R is more potent than adenosine in attenuating R injury, and AMP579-induced cardioprotection involves inhibition of PMN-induced vascular and myocardial tissue injury. * P <0.05 vs. Control.