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P Bruneau

Publications and source records attributed to P Bruneau.

At least 19 recordsLinked to original sources
PubMed1996

[Magnetic resonance angiography. Value for evaluating the patency of aortocoronary bypass].

OBJECTIVE: Assessment of coronary bypass patency with conventional angiography can be limited by difficulties in selective catheterism. The aim of this work was to determine whether ultrarapid sequences proposed for imaging coronary arteries could be used to evaluate bypass patency. METHODS: Twenty patients (mean age 66 +/- 7 years) with 42 aorto-coronary bypasses (32 venous and 10 mammary bypasses) underwent conventional angiography and magnetic resonance angiography within a 1 week interval. All patients were evaluated 1 to 15 years after bypass surgery. Magnetic resonance imaging (MRI) was performed in ventral supine position using a flexible surface coil. Breathhold electrocardiogram-synchronized sequences were acquired using a 1.5 T magnet, with TR = 156 ms, TE = 8 ms, slice thickness 5 mm, 126.256 matrix, and a 7 to 11 segmentation per cardiac cycle. At most, 24 transverse slices were acquired for each patient. RESULTS: Twenty-six patent bypasses were correctly identified with MRI. Three bypass were patent on angiography and appeared occluded on MRI (2 mammary and 1 venous bypass). Nine bypasses were classed as occluded with both techniques. MRI demonstrated patency in one bypass for which selective catheterism was not possible. The sensitivity of MRI for the diagnosis of patency in aorto-coronary bypasses was 89% with a 92% specificity. MRI did not identify 1 out of 4 bypass stenoses. CONCLUSION: We conclude that the ultrarapid breath-hold magnetic resonance sequences can be used to determine patency of aorto-coronary bypasses with good sensitivity and specificity. Our results would suggest however that this method is inadequate for the diagnosis of bypass stenosis.

Aged↗
PubMed1996

Glucuronidation associated with intrinsic resistance to mycophenolic acid in human colorectal carcinoma cells.

The in vivo efficacy of the antitumor, immunosuppressive antibiotic mycophenolic acid is known to be limited by its rapid conversion to the biologically inactive 7-0-glucuronide, catalyzed by UDP-glucuronosyl transferase activity, which is widely distributed among normal tissues, including intestinal epithelium. We have found that mycophenolic acid is also converted to its glucuronide by several lines of human colorectal carcinoma cells, including HT29, Lovo, and Colo-205. In contrast, malignant cell lines not of colorectal origin, including EMT6, HeLa, and SKOV3, showed no ability to metabolize mycophenolic acid. The 7-amino derivative of mycophenolic acid was not metabolized by HT29 cells. This compound was less potent than mycophenolic acid versus EMT6 and HeLa cells but showed inhibitory activity against HT29 cells comparable with the parent antibiotic. The rapid metabolism of mycophenolic acid by HT29 cells was associated with a markedly lower sensitivity to both the antiproliferative activity of the drug and to its ability to inhibit GTP synthesis, compared with cells lacking the capacity for significant glucuronidation. After an initial decline in cellular GTP in HT29 cells induced by mycophenolic acid, there was a progressive recovery in GTP over 48 h, accompanying the metabolism of the antibiotic. This recovery process was not observed in EMT6 cells. It is suggested that glucuronosyl transferase activity may occur widely in colorectal cancer cells and could contribute to resistance to drugs that are susceptible to inactivation by glucuronide conjugation.

Animals↗
PubMed1995

Glucuronidation by human colorectal adenocarcinoma cells as a mechanism of resistance to mycophenolic acid.

Mycophenolic acid (MPA), a potent and specific inhibitor of IMP dehydrogenase, exerts its anti-mitotic action by a rapid depletion of the cellular content of guanine nucleotides. Although MPA is a potent inhibitor of GTP synthesis in the HT29 line of human colorectal adenocarcinoma cells in short-term culture, its ability to depress the cloning efficiency of these cells was found to be markedly less than against the mouse mammary carcinoma line, EMT6. In vivo, MPA is efficiently converted to the biologically inactive O-glucuronide derivative thereby limiting its effectiveness as an anti-tumor agent. Investigation of the fate of MPA incubated with monolayer cultures of HT29 and EMT6 cells revealed that the compound is rapidly converted to the O-glucuronide derivative by HT29 cells, but not by EMT6 cells. Confirmation of the identity of the glucuronide formed by HT29 cells was obtained by its conversion to MPA after incubation with beta-glucuronidase and by comparison of the mass spectrum of its HPLC peak with that of synthetic MPA O-glucuronide. Cultures of two other lines of human colorectal adenocarcinoma cells, Colo-205 and LoVo, also depleted their culture media of MPA although we have not yet established whether these cells also synthesize the glucuronide. The intrinsic partial resistance of HT29 cells to MPA appears to be associated with the ability of these cells to convert MPA to the biologically inactive glucuronide. These results, in conjunction with other reports of the capacity of colorectal cancer cells for Phase I and II metabolism of xenobiotics, may have implications for the design of drugs intended for the treatment of colorectal cancer.

Adenocarcinoma↗
PubMed1994

Conformational analysis of 5-lipoxygenase inhibitors: role of the substituents in chiral recognition and on the active conformations of the (methoxyalkyl)thiazole and methoxytetrahydropyran series.

The investigation of the SAR of 5-lipoxygenase (5-LO) inhibition of a series of racemic (methoxyalkyl)thiazoles, exemplified by compound 7 (ZM-211965), has led to other active, racemic derivatives in which the thiazole moiety has been replaced by an ester or an ether. Furthermore, the cyclization of the ethers has given a highly potent, but achiral series, the methoxytetrahydropyrans (methoxyTHP), exemplified by 41 (ZD-2138) presently under clinical evaluation. More recent structural investigations have led to chiral members of this series bearing a 2-methyl substituent in the tetrahydropyran ring. The potential for enantioselectivity in each of the three noncyclic, racemic series led us to synthesize the pure enantiomers ((R)-13c, (S)-13c, (R)-13d, (S)-13d, (R)-15c, (S)-15c, (R)-16b, (S)-16b, and (R)-16c, (S)-16c) and to determine their absolute configuration. The biological activity of each enantiomer was evaluated in intact mouse macrophages and in human whole blood and showed that, of these three series, only the thiazole is enantioselective and that the active configuration is (S) (being between 2 and 3 orders of magnitude more potent than the (R) isomer in mouse macrophages). Conformational analysis using systematic conformational searching, molecular mechanics, and semiempirical methods has been performed on the chiral compounds, and the results have helped to explain the enantioselectivity in the thiazole series and to define the role of the substituents around the quaternary carbon. Simultaneously in the achiral tetrahydropyran (THP) series, the critical role of the methoxy substituent has been examined through the synthesis of the ethyl (24b), ester (22b), methoxymethyl ether (26), hydroxymethyl (25b), aldehyde (27b), ketone (29b), hydroxy (31b), and methyl (23b) analogues and by analysis of their biological and conformational properties. This approach, complemented by the results of a similar study carried out on the Z and E isomers of the chiral ethyl-2-methylTHP derivative (39b and 40b), has also led to the characterization of the active conformation in this series. The whole study has identified new elements to clarify the 3D structural requirements of the 5-LO active site.

Animals↗
PubMed1993

[Evaluation of hypertrophic cardiomyopathy in treated essential hypertensive patients].

Assessment of left ventricular hypertrophy (LVH) in 231 essential hypertensive patients (61 year'old) treated in a department of internal medicine. Incidence of LVH defined by echocardiography: 34%. Better relationship between LVH and ambulatory blood pressure (BP) monitoring than with casual BP. Influence of age and obesity in the occurrence of LVH.

Aged↗
PubMed1993

[Prognostic value of thallium-201 myocardial scintigraphy in patients with hypertension, suspected of coronary disease].

This study was undertaken to determine the prognostic value of exercise myocardial scintigraphy in hypertension patients suspected of coronary disease. One hundred and thirty six hypertension patients (mean age: 59) suspected of coronary disease were monitored for 46 months after thallium 201 exercise myocardial scintigraphy (tomographic mode). Prognostic factors analysed were clinical (typical nature of pain, exercise blood pressure), electrocardiographic (presence of repolarisation abnormalities in resting ECG), ergometric (electrically positive test) and scintigraphic (existence or not of transitory hypofixation). Events sought were: death of coronary origin, non-fatal myocardial infarction, aorto-coronary bypass and coronary angioplasty. One-way analysis showed that the existence of transitory hypofixation by scintigraphy, positive exercise electrocardiogram and typical angina pain enabled the prediction of coronary events. Thus 14 of 36 patients (39%) with transitory or combined hypofixation had a coronary event as against 7 of the 100 patients without transitory hypofixation. Only the existence of transitory hypofixation retained a prognostic value for coronary events by multivariate analysis (relative risk = 5.4, p = 0.001). It was also found that the prognosis was good when scintigraphy did not reveal transitory hypofixation while exercise testing was positive (2 coronary events/27 patients). It is concluded that, despite the possibility of "false positives", linked in particular to myocardial hypertrophy, myocardial scintigraphy offers better prediction of coronary events in hypertension patients that other clinical or electrocardiographic parameters.

Adult↗
PubMed1992

Methoxytetrahydropyrans. A new series of selective and orally potent 5-lipoxygenase inhibitors.

Investigation of the SAR of the lead (methoxyalkyl)thiazole 1-[3-(naphth-2-ylmethoxy)phenyl]-1-thiazol-2-ylprop yl methyl ether (1, ICI 211965) led to the methoxytetrahydropyrans, a new series of 5-lipoxygenase (5-LPO) inhibitors exemplified by the parent compound 4-[3-(naphth-2-ylmethoxy)phenyl]-4- methoxy-3,4,5,6-tetrahydro-2H-pyran (4f). In vitro 4f inhibited leukotriene C4 (LTC4) synthesis in zymosan-stimulated plasma-free mouse macrophages and LTB4 synthesis in A-23187-stimulated human whole blood (IC50s 0.5 nM and 0.07 microM, respectively). In the rat 4f inhibited LTB4 synthesis in blood ex vivo and in zymosan-inflamed air pouch exudate with an ED50 3 h after oral dosing of 10 mg/kg in each system. In seeking more potent orally active compounds, strategies were explored in congeners of 4f for reducing lipophilicity without sacrificing potency. For example, replacement of 2-naphthyl of 4f by various aza- and oxoheterocycles afforded compounds in which log P is reduced by 1.7-2.3 units while potency in human whole blood in vitro was maintained or enhanced relative to 4f. In addition, the oxoheterocyclic replacements provided compounds with improved oral potency and the preferred compound from this group is 6-[[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4- yl)phenoxy]methyl]-1-methylquinol-2-one (4y). In the in vitro systems, 4y inhibited LT formation with IC50s in mouse macrophages and human whole blood of 3 nM and 0.02 microM, respectively. 4y did not inhibit the synthesis of cyclooxygenase (CO) products at concentrations up to 500 microM in human blood, a selectivity for 5-LPO over CO of greater than 20,000-fold. In the rat 4y inhibited the formation of LTB4 in blood ex vivo and in inflammatory exudate with ED50s 3 h after oral dosing of 0.9 and 0.3 mg/kg, respectively. 4y was more potent in vitro in human whole blood and in rat blood ex vivo at 3 h than either the 5-LPO inhibitor A-64077 or the FLAP antagonist MK-886. Based on these data 4y (ICI D2138) has been entered into development as an orally active, selective 5-LPO inhibitor for clinical evaluation in inflammatory conditions in which LTs are believed to play a role.

Administration, Oral↗
PubMed1991

Indazolinones, a new series of redox-active 5-lipoxygenase inhibitors with built-in selectivity and oral activity.

Since the hypothetical mechanisms of hydroperoxydation of arachidonic acid by, respectively, 5-lipoxygenase (5-LPO) and cyclooxygenase (CO) involve a redox cycle, a compound which reduces 5-LPO and CO to their inactive state would give a nonselective inhibitor of both enzymes. Structural modifications of such a compound could be expected to give improved potency and selectivity for 5-LPO and oral activity. Such an approach has led to the discovery of 1,2-dihydroindazol-3-ones which are potent 5-LPO inhibitors with various degrees of selectivity. Structure-activity relationship studies indicated that while N-1,N-2-unsubstituted and N-1-substituted derivatives are orally inactive, N-2-alkyl derivatives are orally active and inhibit both 5-LPO and CO. In contrast, N-2-benzyl derivatives are selective for 5-LPO but possess only weak oral activity. Further structural modifications have identified ICI 207968 [1,2-dihydro-2-(3-pyridylmethyl)-3H-indazol-3-one, 21a] which combines potent oral activity and high selectivity. Methemoglobin (MHb) induction by 21a in dog blood precluded its development for clinical use. Attempts at dissociating 5-LPO inhibitory properties and MHb formation showed that MHb formation in vitro seemed to be related to the redox potential of the compounds whereas 5-LPO inhibition was not. This study led to a series of 4-(N-n-pentylcarbamoyl)indazolinones which maintained in vitro 5-LPO potency but did not induce MHb.

Administration, Oral↗
PubMed1991

(Methoxyalkyl)thiazoles: a new series of potent, selective, and orally active 5-lipoxygenase inhibitors displaying high enantioselectivity.

(Methoxyalkyl)thiazoles are novel 5-lipoxygenase (5-LPO) inhibitors that are neither redox agents nor iron chelators. Consideration of a hypothetical model of the enzyme active site led to this series which is exemplified by 1-[3-(naphth-2-ylmethoxy)phenyl]-1-(thiazol-2-yl)propy l methyl ether (2d, ICI211965). 2d inhibits cell-free guinea pig 5-LPO activity, LTC4 synthesis in plasma free mouse macrophages, and LTB4 synthesis in rat and human blood (IC50s 0.1 microM, 8 nM, 0.5 microM, and 0.4 microM, respectively) but does not inhibit the synthesis of cyclooxygenase products at concentrations up to 50 microM in macrophages and 100 microM in blood. 2d is orally active in rat (ex vivo ED50 10 mg/kg in blood taken in 1 h after dosing). SAR studies show that high in vitro potency requires methoxy, thiazolyl, and naphthyl groups and depends critically on the substitution pattern. (Methoxyalkyl)thiazoles are chiral. Resolution of 1-methoxy-6-(naphth-2-ylmethoxy)-1-(thiazol-2-yl)indan (2j, ICI216800) shows that (+)-2j is 50-150-fold more potent than (-)-2j in in vitro assays. Thus, (methoxyalkyl)thiazoles are a new series of orally active, selective 5-LPO inhibitors and represent the first class of inhibitors in which inhibition is mediated by specific, enantioselective interactions with the enzyme.

Administration, Oral↗
PubMed1990

2-substituted indazolinones: orally active and selective 5-lipoxygenase inhibitors with anti-inflammatory activity.

1. This paper describes the pharmacological profile of ICI207968, a novel, orally-active and selective inhibitor of 5-lipoxygenase. 2. Inhibition of leukotriene B4 (LTB4) synthesis by 2-substituted indazolinones was not directly related to redox potential but was critically dependent on the nature of the N2 substituent. 2-(3-Pyridylmethyl)-indazolinone (ICI207968) combined selectivity and oral potency. 3. In several in vitro systems ICI207968 exhibited similar lipoxygenase inhibitory potency (IC50 values from 1.5 microM to 6.0 microM) and was approximately 300 times less potent against cyclo-oxygenase, as measured by inhibition of prostaglandin E2 (PGE2) synthesis. 4. ICI207968 also produced selective lipoxygenase inhibition following oral administration in the rat. ED50 values of 2.5, 10 and 25 mg kg-1 p.o. for inhibition of LTB4 release from A23187-stimulated blood were obtained 1, 3 and 5 h after dosing. The compound did not inhibit PGE2 synthesis at oral doses up to 300 mg kg-1. 5. Co-administration of ICI207968 with arachidonic acid, into rabbit dermis, potently inhibited both plasma extravasation and polymorphonuclear leucocyte (PMNL) infiltration induced by this inflammatory fatty acid. The anti-inflammatory potency of a number of intradermally administered indazolinones, with similar redox potentials, was related to their inhibitory potency against leukotriene generation in blood. Oral administration of ICI207968 (100 mg kg-1) in the rabbit inhibited ex vivo leukotriene generation in blood and arachidonic acid-induced skin inflammation. 6. These data demonstrate that ICI207968 is an orally active and selective inhibitor of 5-lipoxygenase which has anti-inflammatory properties. IC1207968 will be a valuable agent for clarifying the biological roles of leukotrienes and the therapeutic potential of 5-lipoxygenase inhibitors.

Administration, Oral↗
PubMed1990

[Medicine and archaeology: comparison of methods].

Medicine and archaeology are human sciences: their diagnostic claim consists of establishing the link between the singular case and the general model. Comparing and contrasting the two processes is not limited to a game of "similarities-differences". It makes possible a finer analysis of different methods of data collection, either with or without the help of instruments, and a comparison of different ways of handling and classifying symptoms observed and documentary evidence gathered. It shows that archaeology, in contrast to medicine (with physiology and health), has as a discipline, no real precisely defined reference. It is suggested that it is in the interest of medicine and archaeology to compare their own working methods...and their imperfections.

Archaeology↗
PubMed1984

The use of a monoclonal antibody and of DNA recombinant technology for the localization of a poliovirus neutralization epitope in viral capsid polypeptide VP1.

Poliovirus cDNA sequences encoding type 1 capsid polypeptide VP1 were fused in phase into the beta-lactamase sequence of pBR322. The resulting recombinant plasmid pSW119 expressed in E. coli a VP1-beta-lactamase fusion protein which reacted with antibodies raised against poliovirus capsid polypeptide VP1 and with a monoclonal poliovirus type 1 neutralizing antibody C3. Deletions of various length were introduced into the VP1 sequence. The truncated proteins expressed by the deleted plasmids did not react further with C3 when the region of VP1 amino acids 91-104 was deleted. A synthetic peptide corresponding to this region of VP1 (amino acids 93-104) was chemically synthesized. It was found to inhibit the seroneutralization of poliovirus by C3 antibodies and, once coupled to keyhole limpet hemocyanin, it was specifically immunoprecipitated with C3. Therefore, the C3 epitope recognized by the poliovirus neutralizing monoclonal antibody is located within the region of amino acids 93-104 of capsid polypeptide VP1.

Antibodies, Monoclonal↗
PubMed1983

A poliovirus type 1 neutralization epitope is located within amino acid residues 93 to 104 of viral capsid polypeptide VP1.

Using nuclease Bal31, deletions were generated within the poliovirus type 1 cDNA sequences, coding for capsid polypeptide VP1, within plasmid pCW119. The fusion proteins expressed in Escherichia coli by the deleted plasmids reacted with rabbit immune sera directed against poliovirus capsid polypeptide VP1 (alpha VP1 antibodies). They also reacted with a poliovirus type 1 neutralizing monoclonal antibody C3, but reactivity was lost when the deletion extended up to VP1 amino acids 90-104. Computer analysis of the protein revealed a high local density of hydrophilic amino acid residues in the region of VP1 amino acids 93-103. A peptide representing the sequence of this region was chemically synthesized. Once coupled to keyhole limpet hemocyanin, this peptide was specifically immunoprecipitated by C3 antibodies. The peptide also inhibited the neutralization of poliovirus type 1 by C3 antibodies. We thus conclude that the neutralization epitope recognized by C3 is located within the region of amino acids 93-104 of capsid polypeptide VP1.

Amino Acid Sequence↗
PubMed1983

Expression of poliovirus capsid polypeptide VP1 in Escherichia coli.

A recombinant plasmid (pPV1-958) carrying a poliovirus cDNA insert corresponding to nucleotides 1-5750 of the poliovirus RNA genome was constructed through in vitro recombination of two plasmids carrying overlapping poliovirus cDNA inserts (Van der Werf et al., Proc. Natl. Acad. Sci. USA 78 (1981) 5983-5987). pPV1-958 was then cleaved with PstI and the fragment carrying the sequence encoding capsid polypeptide VP1 was isolated and subcloned at the PstI site of pBR322. The VP1 sequence was successfully fused with the 5' sequence of the beta-lactamase gene by deleting 300-350 bp from each side of the PvuI site of the plasmid with nuclease BAL31. One of the resulting plasmids, pSW119, expressed an Mr 49 000 VP1-beta-lactamase-fusion protein, which was specifically immunoprecipitated with anti-VP1 immune serum but not by hyperimmune sera raised against native or heat-inactivated virus.

Capsid↗
PubMed1983

Localization of a poliovirus type 1 neutralization epitope in viral capsid polypeptide VP1.

Poliovirus type 1 cDNA sequences coding for viral capsid polypeptide VP1 were inserted into the beta-lactamase sequence of Escherichia coli plasmid pBR322. Resulting recombinant plasmid pSW119 expressed in Escherichia coli a VP1-beta-lactamase fusion protein that reacted with antibodies raised against poliovirus capsid polypeptide VP1 and with a monoclonal poliovirus type 1 neutralizing antibody, C3. Deletions of various lengths were generated within the VP1 sequence. The hybrid proteins expressed by the deleted plasmids did not react any more with C3 when the region of VP1 amino acids 95-110 (poliovirus nucleotides 2,754-2,806) was deleted. Therefore, the C3 epitope responsible for virus neutralization is most probably located in this region of the capsid polypeptide.

Amino Acid Sequence↗
PubMed1983

Beneficial effect of intravenous diltiazem in the acute management of paroxysmal supraventricular tachyarrhythmias.

We tested the effectiveness and safety of i.v. diltiazem in the management of paroxysmal supraventricular tachyarrhythmias in 39 patients, 21 with organic heart disease and seven in heart failure. Fifteen patients presented with supraventricular tachycardia, 12 with atrial fibrillation and 12 with atrial flutter. End points were conversion to sinus rhythm or slowing of the ventricular rate to 100 beats/min or less. Diltiazem was given as an i.v. bolus of either 150 or 300 micrograms/kg over 2 minutes. A second injection was administered to patients who received the lower dose and failed to reach either end point within 30 minutes. The overall success rate was 82% (32 of 39 patients). Time to end point was 5 minutes or less in 20 patients. Conversion to sinus rhythm occurred in 13 of 15 patients (87%) with supraventricular tachycardia and in two of 12 patients with atrial fibrillation. Treatment side effects included a slow ventricular rate in one patient who had a sick sinus syndrome and hypotension in two patients that rapidly responded to fluid administration. We conclude that i.v. diltiazem is effective and well tolerated and advocate its use in the management of paroxysmal supraventricular tachyarrhythmias.

Adult↗