Biomedical subjects

J Guay

Publications and source records attributed to J Guay.

At least 37 records · Page 2Linked to original sources

PubMed1998

Quinolines as potent 5-lipoxygenase inhibitors: synthesis and biological profile of L-746,530.

Leukotriene biosynthesis inhibitors have potential as new therapeutic agents for asthma and inflammatory diseases. A series of novel substituted 2-cyanoquinolines have been synthesized and the structure activity relationships were evaluated with respect to their ability to inhibit the formation of leukotrienes via the 5-lipoxygenase enzyme. [1S,5R]-2-Cyano-4-(3-furyl)-7-¿3-fluoro-5-[3-(3 alpha-hydroxy-6,8-dioxabicyclo[3.2.1]-octanyl)]phenoxymethyl ¿quinoline (L-746,530) 3 represents a distinct class of inhibitors and possesses in vitro and in vivo potency comparable or superior to naphthalenic analog (L-739,010) 2.

Bridged Bicyclo Compounds↗

PubMed1998

[Polytrauma and hemostatic anomalies].

OBJECTIVE: Polytraumatized patients present with defects of haemostasis that manifest clinically either by haemorrhage and/or thrombosis. During the initial, as well as during the later phases of treatment, clinicians should take into account the most recent developments in the understanding, in the evaluation of the risk, and in the prevention of haemorrhagic and thrombotic complications. SOURCE: A group of experts, convened by the "Groupe d'intérêt en hémostase périopératoire" (Perioperative Haemostasis Interest Group) during the Annual Meeting of the Association of Anaesthetists of Quebec, held a symposium to review and integrate recent developments on haemostatic complications associated with trauma. MAIN FINDINGS: The normal haemostatic balance is strongly compromised by trauma and shock. The percentage of patients with a coagulopathy and surgically uncontrollable haemorrhage varies between 18 and 40%. Abnormal coagulation after trauma is of multifactorial origin. Coagulopathy secondary to haemodilution is no longer considered the main cause of haemorrhage. Disseminated intravascular coagulation (DIC) is often manifest in the traumatic context. One out of every three polytraumatized patient will develop a deep vein thrombosis despite the preventive measures available at present. Clinical or laboratory detection of venous thrombosis either lacks sensitivity (physical examination or ultrasonography), or cannot be performed serially (phlebography). CONCLUSIONS: Prevention and treatment of disorders of haemostasis relies upon the rapid and effective treatment of shock associated with trauma. Prevention of thromboembolic complications is paramount, taking into account the evolving balance between the risk of haemorrhage and the risk of thrombosis.

Hemorrhage↗

PubMed1998

Cloning of a complementary DNA encoding an Ambystoma mexicanum metallothionein, AmMT, and expression of the gene during early development.

We have used a polymerase chain reaction strategy to isolate a metallothionein (MT) cDNA from the amphibian Ambystoma mexicanum (axolotl). This cDNA is 875-bp long and encodes a 60 amino acid protein, AmMT, typical for family 1 MTs. It contains 20 cysteine (Cys) residues that can be aligned with those of other vertebrate MTs. The overall structure of the protein is unique among vertebrates in having only two amino acid residues before the first Cys at the amino-terminal end. Northern analyses showed that AmMT is expressed throughout embryogenesis, giving rise to three mRNA species of 650, 750, and 1,600 nucleotides (nt). The 750 and 1,600 nt transcripts appear to result from differential use of polyadenylation signals, whereas the 650 nt RNA could arise from deadenylation of the 750-nt transcript. Both the 750- and 1,600-nt RNAs were presented in embryos before the mid-blastula transition (MBT). After the MBT, the 750-nt RNA was replaced by the 650-nt RNA which was gradually degraded to undetectable levels in post-neurulation embryos. Levels of the 1,600-nt transcript increased at gastrulation and reach a maximum in Stage 30 embryos. In adult animals, levels of the 750-nt RNA were high in liver and testes, and very low in lung, gut, skin, and oviducts, whereas levels of the 1,600-nt transcript were similar and moderately elevated in all tissues examined. In contrast, in Xenopus laevis, Northern analysis did not detect XIMT-A mRNA in embryos before late neurulation (Stage 24). XIMT-A mRNA levels then increased sharply in Stage 36 hatched embryos at levels similar to those found in adult livers. These results show that AmMT presents a unique expression pattern among metazoans being transcribed as two transcripts differing in the length of their 3' untranslated regions, the levels of which vary during embryogenesis and in adult tissues.

Ambystoma↗

PubMed1998

Clinical pharmacokinetics of neuromuscular relaxants in pregnancy.

Despite an increased in bodyweight, plasma volume by 45% and blood volume by 35% that might influence the volume of distribution of polar drugs, the apparent volume of distribution at steady state (Vss), volume of distribution (Vd) and the apparent volume of the central compartment (Vc) of atracurium, vecuronium and pancuronium are unchanged during pregnancy. With an elimination that is independent of renal, hepatic and enzymatic functions, the clearance of atracurium is also unchanged. This is corroborated by an unchanged clinical duration of atracurium during pregnancy. The clearance of pancuronium is increased by 27% during caesarean section. This may be explained by the increased glomerular filtration rate reported in pregnant women. The clinical duration of vecuronium in term and postpartum women is twice that reported in nonpregnant women. On the other hand, an increase in the clearance clearance of vecuronium during cesarean sections has been reported. The umbilical/maternal vein concentration ratio (UV/MV) of nondepolarising neuromuscular relaxants varies from 7 to 26% and clinical doses of these drugs may induce partial residual curarisation in neonates. Fetal concentrations of non-depolarising neuromuscular relaxants are proportional to the maternal dose injected as demonstrated for pancuronium and vecuronium. Increasing UV/MV with longer drug injection to delivery intervals have been demonstrated for drugs with a high molecular weight, such as atracurium, but not for those with a low molecular weight, such as vecuronium, while conflicting results have been reported for pancuronium. Despite decreased plasma pseudocholinesterases, the clinical duration of succinylcholine 1 mg/kg is unchanged in pregnant women, and only is slightly increased in postpartum women. On the other hand, larger doses of succinylcholine have induced prolonged apnoea and phase II block. The use of a pretreatment dose of a nondepolarising neuromuscular relaxant to decrease fasciculations and subsequent postoperative muscle pain is not only unnecessary in pregnant women but may be hazardous, since it may produce unexpected significant curarisation with respiratory distress. At clinical doses, transplacental passage of succinylcholine is insufficient to produce curarisation of neonates except in those born to mothers with abnormal plasma pseudocholinesterases. Magnesium sulfate, used in the treatment of pre-eclampsia, will enhance the blocking effects of nondepolarising neuromuscular relaxants but will have no effects on the characteristics of paralysis of succinylcholine. Histamine type 2 antagonists used to decrease the risk of aspiration during induction of anaesthesia do not influence the blocking properties of neuromuscular relaxants, while metoclopramide prolongs the block of succinylcholine.

Absorption↗

PubMed1997

Substituted (pyridylmethoxy)naphthalenes as potent and orally active 5-lipoxygenase inhibitors; synthesis, biological profile, and pharmacokinetics of L-739,010.

Dioxabicyclooctanyl naphthalenenitriles have been reported as a class of potent and nonredox 5-lipoxygenase (5-LO) inhibitors. These bicyclo derivatives were shown to be metabolically more stable than their tetrahydropyranyl counterparts but were not well orally absorbed. Replacement of the phenyl ring in the naphthalenenitrile 1 by a pyridine ring leads to the potent and orally absorbed inhibitor 3g (L-739,010, 2-cyano-4-(3-furyl)-7-[[6-[3-(3-hydroxy-6,8-dioxabicyclo[3.2.1] octanyl)]-2-pyridyl]methoxy]naphthalene). Compound 3g inhibits 5-HPETE production by human 5-LO and LTB4 biosynthesis by human PMN leukocytes and human whole blood (IC50S of 20, 1.6, and 42 nM, respectively). Derivative 3g is orally active in the rat pleurisy model (inhibition of LTB4, ED50 = 0.3 mg/kg) and in the anesthetized dog model (inhibition of ex vivo whole blood LTB4 and urinary LTE4, ED50 = 0.45 and 0.23 microgram/kg/min, respectively, i.v. infusion). In addition, 3g shows excellent functional activity against ovalbumin-induced dyspnea in rats (60% inhibition at 0.5 mg/kg, 4 h pretreatment) and Ascaris-induced bronchoconstriction in conscious sheep (50% and > 85% inhibition in early and late phases, respectively at 2.5 micrograms/kg/min, i.v. infusion) and, more particularly in the conscious antigen sensitive squirrel monkey model (53% inhibition of the increase in RL and 76% in the decrease of Cdyn, at 0.1 mg/kg, po). In rats and dogs, 3g presents excellent pharmacokinetics (estimated half-lives of 5 and 16 h, respectively) and bioavailabilities (26% and 73% when dosed as its hydrochloride salt at doses of 20 and 10 mg/kg, respectively, in methocel suspension). Based on its overall biological profile, compound 3g has been selected for preclinical animal toxicity studies.

Animals↗

PubMed1997

Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX-2 inhibitor.

1. DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furan one) was identified as a novel orally active and highly selective cyclo-oxygenase-2 (COX-2) inhibitor. 2. In CHO cells stably transfected with human COX isozymes, DFU inhibited the arachidonic acid-dependent production of prostaglandin E2 (PGE2) with at least a 1,000 fold selectivity for COX-2 (IC50 = 41 +/- 14 nM) over COX-1 (IC50 > 50 microM). Indomethacin was a potent inhibitor of both COX-1 (IC50 = 18 +/- 3 nM) and COX-2 (IC50 = 26 +/- 6 nM) under the same assay conditions. The large increase in selectivity of DFU over indomethacin was also observed in COX-1 mediated production of thromboxane B2 (TXB2) by Ca2+ ionophore-challenged human platelets (IC50 > 50 microM and 4.1 +/- 1.7 nM, respectively). 3. DFU caused a time-dependent inhibition of purified recombinant human COX-2 with a Ki, value of 140 +/- 68 microM for the initial reversible binding to enzyme and a kappa 2 value of 0.11 +/- 0.06 s-1 for the first order rate constant for formation of a tightly bound enzyme-inhibitor complex. Comparable values of 62 +/- 26 microM and 0.06 +/- 0.01 s-1, respectively, were obtained for indomethacin. The enzyme-inhibitor complex was found to have a 1:1 stoichiometry and to dissociate only very slowly (t1/2 = 1-3 h) with recovery of intact inhibitor and active enzyme. The time-dependent inhibition by DFU was decreased by co-incubation with arachidonic acid under non-turnover conditions, consistent with reversible competitive inhibition at the COX active site. 4. Inhibition of purified recombinant human COX-1 by DFU was very weak and observed only at low concentrations of substrate (IC50 = 63 +/- 5 microM at 0.1 microM arachidonic acid). In contrast to COX-2, inhibition was time-independent and rapidly reversible. These data are consistent with a reversible competitive inhibition of COX-1. 5. DFU inhibited lipopolysaccharide (LPS)-induced PGE2 production (COX-2) in a human whole blood assay with a potency (IC50 = 0.28 +/- 0.04 microM) similar to indomethacin (IC50 = 0.68 +/- 0.17 microM). In contrast, DFU was at least 500 times less potent (IC50 > 97 microM) than indomethacin at inhibiting coagulation-induced TXB2 production (COX-1) (IC50 = 0.19 +/- 0.02 microM). 6. In a sensitive assay with U937 cell microsomes at a low arachidonic acid concentration (0.1 microM), DFU inhibited COX-1 with an IC50 value of 13 +/- 2 microM as compared to 20 +/- 1 nM for indomethacin. CGP 28238, etodolac and SC-58125 were about 10 times more potent inhibitors of COX-1 than DFU. The order of potency of various inhibitors was diclofenac > indomethacin approximately naproxen > nimesulide approximately meloxicam approximately piroxicam > NS-398 approximately SC-57666 > SC-58125 > CGP 28238 approximately etodolac > L-745,337 > DFU. 7. DFU inhibited dose-dependently both the carrageenan-induced rat paw oedema (ED50 of 1.1 mg kg-1 vs 2.0 mg kg-1 for indomethacin) and hyperalgesia (ED50 of 0.95 mg kg-1 vs 1.5 mg kg-1 for indomethacin). The compound was also effective at reversing LPS-induced pyrexia in rats (ED50 = 0.76 mg kg-1 vs 1.1 mg kg-1 for indomethacin). 8. In a sensitive model in which 51Cr faecal excretion was used to assess the integrity of the gastrointestinal tract in rats, no significant effect was detected after oral administration of DFU (100 mg kg-1, b.i.d.) for 5 days, whereas chromium leakage was observed with lower doses of diclofenac (3 mg kg-1), meloxicam (3 mg kg-1) or etodolac (10-30 mg kg-1). A 5 day administration of DFU in squirrel monkeys (100 mg kg-1) did not affect chromium leakage in contrast to diclofenac (1 mg kg-1) or naproxen (5 mg kg-1). 9. The results indicate that COX-1 inhibitory effects can be detected for all selective COX-2 inhibitors tested by use of a sensitive assay at low substrate concentration. The novel inhibitor DFU shows the lowest inhibitory potency against COX-1, a consistent high selectivity of inhibition of COX-2 over COX-1 (>300 fold) with enzyme, whole cell and whole blood assays, with no detectable loss of integrity of the gastrointestinal tract at doses >200 fold higher than efficacious doses in models of inflammation, pyresis and hyperalgesia. These results provide further evidence that prostanoids derived from COX-1 activity are not important in acute inflammatory responses and that a high therapeutic index of anti-inflammatory effect to gastropathy can be achieved with a selective COX-2 inhibitor.

Administration, Oral↗

PubMed1997

Regulation of actin filament dynamics by p38 map kinase-mediated phosphorylation of heat shock protein 27.

We have studied the contribution of the individual kinases of the MAP (mitogen-activated protein) kinase family, including ERK (extracellular-signal regulated kinase), JNK/SAPK (c-JUN NH2-terminal kinase/stress-activated protein kinase) and p38, to activation of the HSP27 (heat shock protein 27) kinase MAPKAP kinase-2/3 and to HSP27 phosphorylation in Chinese hamster CCL39 cells stimulated by either growth factors, cytokines or stressing agents. In vitro assays using fractionated cell extracts or immunoprecipitates indicated that only fractions containing ERK or p38, and not those containing JNK/SAPK, had the capacity to activate MAPKAP kinase-2/3. In vivo, however, it appeared that only p38 is an upstream activator of HSP27 phosphorylation after both stress or growth factor stimulation: expression of an interfering mutant of ras, which blocked the activation of ERK by both types of inducers, had no effect on HSP27 phosphorylation and p38 activation; and the cell-permeant specific inhibitor of 038, SB203580, blocked MAPKAP-kinase2/3 activation and HSP27 phosphorylation. HSP27 has been suggested to have a phosphorylation-activated homeostatic function at the actin cytoskeleton level. This raises the possibility that p38 might be directly involved in mediating actin responses to external stimuli. Accordingly, we observed that a prior activation of p38 increased the stability of the actin microfilaments in cells exposed to cytochalasin D. The effect was dependent on the expression of HSP27 and was totally annihilated by blocking the p38 activity with SB203580. The results provide strong support to the idea that activation of p38 during adverse environmental conditions serves a homeostatic function aimed at regulating actin dynamics that would otherwise be destabilized during stress. Its activation during normal agonist stimulation may constitute an additional actin signaling pathway, the importance of which depends on the level of expression of HSP27.

Actin Cytoskeleton↗

PubMed1997

Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays.

Two forms of cyclooxygenase (COX) activity are involved in the synthesis of prostaglandins, prostacyclins, and thromboxanes in mammalian cells. There is now convincing evidence, obtained with a number of structurally distinct inhibitors, that selective COX-2 inhibitors possess anti-inflammatory effects with an improved gastrointestinal tolerability compared with conventional nonsteroidal anti-inflammatory drugs (NSAIDs) affecting both COX-1 and COX-2. As more selective COX-2 inhibitors are being developed, assays with a high degree of sensitivity to inhibition are needed to compare the relative effects of compounds on COX-1 activity. In the present report, we describe a sensitive assay for the inhibition of human COX-1 based on the production of prostaglandin E2 by microsomes from U937 cells incubated with a subsaturating concentration of arachidonic acid. More than 45 NSAIDs and selective COX-2 inhibitors were tested in this assay. IC50 values ranged from 1 nM for flunixin and flurbiprofen to about 200-500 microM for salicylate and acetaminophen. Potent and nonselective NSAIDs such as sulindac sulfide, diclofenac, and indomethacin showed IC50 values of < 20 nM. Among the compounds that have been reported to show selectivity for COX-2, the rank order of potency against COX-1 was DuP 697 > SC-58451 > celecoxib > nimesulide-meloxicam-piroxicam-NS-398-RS-57067 > SC-57666 > SC-58125 > flosulide > etodolac > L-745,337 > DFU-T-614, with IC50 values ranging from 7 nM to 17 microM. A good correlation was obtained between the IC50 values for the inhibition of microsomal COX-1 and both the inhibition of TXB2 production by Ca2+ ionophore challenged platelets and the inhibition of prostaglandin E2 production by CHO cells stably expressing human COX-1. However, the microsomal assay was more sensitive to inhibition than cell-based assays and allowed the detection of inhibitory effects on COX-1 for all NSAIDs and selective COX-2 inhibitors examined with discrimination of their potency under conditions of limited availability of arachidonic acid.

Animals↗

PubMed1996

Dioxabicyclooctanyl naphthalenenitriles as nonredox 5-lipoxygenase inhibitors: structure-activity relationship study directed toward the improvement of metabolic stability.

Naphthalenic lignan lactone 3a (L-702,539), a potent and selective 5-lipoxygenase (5-LO) inhibitor, is extensively metabolized at two different sites: the tetrahydropyran and the lactone rings. Early knowledge of the metabolic pathways triggered and directed a structure-activity relationship study aimed toward the improvement of metabolic stability in this series. The best modifications discovered, i.e., replacement of the lactone ring by a nitrile group, replacement of the tetrahydropyran ring by a 6,8-dioxabicyclo[3.2.1]octanyl moiety, and replacement of the pendant phenyl ring by a 3-furyl ring, were incorporated in a single molecule to produce inhibitor 9ac (L-708,780). Compound 9ac inhibits the oxidation of arachidonic acid to 5-hydroperoxy-eicosatetraenoic acid by 5-LO (IC50 = 190 nM) and the formation of leukotriene B4 in human polymorphonuclear leukocytes (IC50 = 3 nM) as well as in human whole blood (IC50 = 150 nM). The good inhibitory profile shown by naphthalenenitrile 9ac is accompanied by an improved resistance to oxidative metabolism. In addition, 9ac is orally active in the functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at 0.1 mg/kg).

Animals↗

PubMed1996

Mediastinal bleeding after cardiopulmonary bypass in pediatric patients.

BACKGROUND: The purpose of our review was to develop simple clinical recommendations to reduce the need for allogeneic blood transfusions in children undergoing cardiac operations. METHODS: The literature on hemostasis as it relates to children, cardiac disease in children, and pediatric heart surgery was reviewed. We also reexamined the efficacy of several strategies in this patient population: on-site monitoring of coagulation, transfusion of fresh whole blood, and administration of desmopressin, epsilon-aminocaproic acid, or aprotinin. RESULTS: Children with heart disease may present with preoperative thrombocytopenia, reduced platelet aggregation, and a decreased level of von Willebrand factor. Infants less than 6 months of age show a significant dilution of coagulation factors and decreased platelet counts during cardiopulmonary bypass. Fresh whole blood reduces blood loss in children younger than 2 years undergoing complex operations. Desmopressin does not reduce bleeding, whereas on-site monitoring, synthetic antifibrinolytics, and aprotinin require further evaluation in pediatric cardiac surgical patients. CONCLUSIONS: The use of fresh whole blood to reduce blood loss in children younger than 2 years undergoing complex heart operations is recommended. Therapy for excessive bleeding after cardiopulmonary bypass will vary according to the patient's age, platelet count, and activated partial thromboplastin and prothrombin times.

Blood Transfusion↗

PubMed1995

Involvement of cyclooxygenase 2 (COX-2) in intrinsic tone of isolated guinea pig trachea.

Indomethacin and related nonsteroidal anti-inflammatory drugs relax prostanoid-dependent intrinsic tone of isolated guinea pig trachea by inhibiting cyclooxygenase (COX). Recently, a second isoform of COX (COX-2) was discovered, which differed from COX-1 with respect to protein structure, transcriptional regulation, and susceptibility to inhibition by pharmacological agents. It is now known that indomethacin nonselectively inhibits COX-1 and COX-2, whereas NS-398 is a selective inhibitor of COX-2. In the present study we compared the activity of a selective (NS-398) and nonselective (indomethacin) COX-2 inhibitor on intrinsic tone of isolated guinea pig trachea. NS-398 > or = indomethacin produced a reversal of intrinsic tone with a similar concentration-dependent (10 nM to 1 microM) time course (Tmax approximately 20-45 min), potency (EC50 1.7 and 5.6 nM, respectively), and maximal response. Contractions to cholinergic nerve stimulation (45 V, 0.5 ms, 0.1-32 Hz) and histamine were similarly modulated in tissues relaxed with the selective or nonselective COX-2 inhibitors. Immunoblot analyses showed that COX-2 protein synthesis was induced in both the cartilage and smooth muscle portions of the trachea during changes in intrinsic tone. These findings are consistent with pharmacological results and provide the first demonstration that prostanoid tone in isolated guinea pig trachea is dependent on COX-2 activity. The results also suggest that the activity of indomethacin in this preparation is likely related to COX-2 inhibition.

Animals↗

PubMed1995

[Mutual aid as a complement to professional intervention].

This paper aims to illustrate and emphasize the relevance of Frank Riessman's futurist new paradigm for human services which proposes a restructuring that enables those who ordinarily receive help to function as providers of help. Some of the best known mutual-aid programs are briefly presented, followed by a more detailed description of pilot projects which have used the mutual-aid principle with multi-problematic clientele. Most of these pilot projects took place in the province of Québec and aimed at bridging the gap between public services and local communities by linking with informal support systems. Two specific modalities of mutual aid are discussed: pairings between clients and pairings between clients and natural helpers. The integration of mutual-aid strategies within clinical practice is not easy because of the important changes it requires of the professional both at the practical and the organizational level.

Adolescent↗

PubMed1994

Arachidonyl trifluoromethyl ketone, a potent inhibitor of 85-kDa phospholipase A2, blocks production of arachidonate and 12-hydroxyeicosatetraenoic acid by calcium ionophore-challenged platelets.

Arachidonyl trifluoromethyl ketone (AACOCF3) is a potent and selective slow binding inhibitor of the 85-kDa cytosolic phospholipase A2 (cPLA2) (Street, I. P., Lin, H.-K., Laliberté, F., Ghomashchi, F., Wang, Z., Perrier, H., Tremblay, N. M., Huang, Z., Weech, P. K., and Gelb, M. H. (1993) Biochemistry 32, 5935-5940). AACOCF3 and a number of its structural analogues have been used to investigate the role of cPLA2 in the cellular generation of free arachidonic acid (AA) and in eicosanoid biosynthesis. AACOCF3 inhibited the release of AA from calcium ionophore-challenged U937 cells (IC50 = 8 microM, 2 x 10(6) cells ml-1) and from platelets (IC50 = 2 microM, 4 x 10(7) cells ml-1). Arachidonyl methyl ketone (AACOCH3) and AACH(OH)CF3, both of which are noninhibitory to the purified cPLA2, did not inhibit the production of AA in the ionophore-challenged cells. In addition to the release of AA, AACOCF3 also inhibited the production of 12-hydroxyeicosatetraenoic acid (12-HETE) and thromboxane B2, two of the major metabolites of AA produced by platelets. The inhibition of 12-HETE biosynthesis showed a dose dependence similar to that of AA release in ionophore-challenged platelets; however, when platelet 12-HETE production was stimulated with 10 microM AA to circumvent the PLA2-dependent step, AACOCF3 no longer inhibited the production of 12-HETE. In contrast, AACOCF3 blocked thromboxane B2 formation by both calcium ionophore- and AA-challenged platelets, indicating that the compound affects the cyclooxygenase pathway in addition to AA release. The crude cytosol and membrane fractions from platelets were assayed for calcium-dependent and calcium-independent PLA2 activities and for the susceptibility of each to inhibition by AACOCF3. At AACOCF3 concentrations as high as 10 mol %, only one of the observed PLA2 activities was inhibited by more than 25%. The AACOCF3-susceptible PLA2 (77% inhibition at 1.6 mol %) was found in the cytosolic platelet fraction and showed the functional characteristics of the cPLA2. These results suggest that the cPLA2 plays an important role in the generation of free AA for 12-HETE biosynthesis in platelets.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed1994

Thiopyrano[2,3,4-cd]indoles as 5-lipoxygenase inhibitors: synthesis, biological profile, and resolution of 2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy]-4,5 -dihydro-1H-thiopyrano[2,3,4-cd]indol-2-yl]ethoxy]butanoic acid.

Leukotriene biosynthesis inhibitors have potential as new therapies for asthma and inflammatory diseases. The recently disclosed thiopyrano[2,3,4-cd]indole class of 5-lipoxygenase (5-LO) inhibitors has been investigated with particular emphasis on the side chain bearing the acidic functionality. The SAR studies have shown that the inclusion of a heteroatom (O or S) in conjunction with an alpha-ethyl substituted acid leads to inhibitors of improved potency. The most potent inhibitor prepared contains a 2-ethoxybutanoic acid side chain. This compound, 14d (2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methox y]- 4,5-dihydro-1H-thiopyrano[2,3,4-cd]indol-2-yl]ethoxy]-butanoic acid, L-699,333), inhibits 5-HPETE production by human 5-LO and LTB4 biosynthesis by human PMN leukocytes and human whole blood (IC50s of 22 nM, 7 nM and 3.8 microM, respectively). The racemic acid 14d has been shown to be functionally active in a rat pleurisy model (inhibition of LTB4, ED50 = 0.65 mg/kg, 6 h pretreatment) and in the hyperreactive rat model of antigen-induced dyspnea (50% inhibition at 2 and 4 h pretreatment; 0.5 mg/kg po). In addition, 14d shows excellent functional activity against antigen-induced bronchoconstriction in the conscious squirrel monkey [89% inhibition of the increase in RL and 68% inhibition in the decrease in Cdyn (0.1 mg/kg, n = 3)] and in the conscious sheep models of asthma (iv infusion at 2.5 micrograms/kg/min). Acid 14d is highly selective as an inhibitor of 5-LO activity when compared to the inhibition of human 15-LO, porcine 12-LO and ram seminal vesicle cyclooxygenase (IC50 > 5 microM) or competition in a FLAP binding assay (IC50 > 10 microM). Resolution of 14d affords 14g, the most potent diastereomer, which inhibits the 5-HPETE production of human 5-LO and LTB4 biosynthesis of human PMN leukocytes and human whole blood with IC50s of 8 nM, 4 nM, and 1 microM respectively. The in vitro and in vivo profile of 14d is comparable to that of MK-0591, which has showed biochemical efficacy in inhibiting ex vivo LTB4 biosynthesis and urinary LTE4 excretion in clinical trials.

Animals↗

PubMed1994

Naphthalenic lignan lactones as selective, nonredox 5-lipoxygenase inhibitors. Synthesis and biological activity of (methoxyalkyl)thiazole and methoxytetrahydropyran hybrids.

Combinations of structural elements found in (methoxyalkyl)thiazole 1a and methoxytetrahydropyran 2a with a naphthalenic lignan lactone produce the potent 5-lipoxygenase (5-LO) inhibitors 3 and 4. While the nature of link Y-Z has a major effect on the in vitro activity of compounds 1 and 2, inhibitors 3 and 4 retain their potencies with either an oxymethylene (Y = O, Z = CH2) or a methyleneoxy (Y = CH2, Z = O) link. Compound 4b inhibits the oxidation of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid by 5-LO (IC50 = 14 nM) and the formation of leukotriene B4 in human polymorphonuclear leukocytes (IC50 = 1.5 nM) as well as in human whole blood (IC50 = 50 nM). Compound 4b is a selective 5-LO inhibitor showing no significant inhibition of human 15-lipoxygenase or porcine 12-lipoxygenase or binding to human 5-lipoxygenase-activating protein up to 10 microM and inhibits leukotriene biosynthesis by a direct, nonredox interaction with 5-LO. Compound 15, the open form of lactone 4b, is well absorbed in the rat and is transformed into the active species 4b. In addition, 15 is orally active in the rat pleurisy model (ED50 = 0.6 mg/kg) and in the functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at 0.3 mg/kg).

Animals↗

PubMed1994

Predicting blood loss in surgery for idiopathic scoliosis.

The authors attempted to determine the relative importance of factors that influence bleeding during and after spinal fusion. Data from 30 ASA I patients with idiopathic scoliosis were prospectively collected and analyzed. Intraoperative bleeding was 1971 +/- 831 ml (mean +/- SD) (61.5 +/- 27% of estimated blood volume (EBV) and correlated with the number of fused vertebrae (r = 0.66, P < 0.0001) and the duration of surgery (r = 0.46, P = 0.0105). There was no correlation between intraoperative bleeding and the Cobb curve angle (43 to 86 degrees), the mean arterial blood pressure (MAP) (63 to 86 mmHg), the central venous pressure (CVP), the quantity of epinephrine infiltrated, muscle relaxants or opioids used, nor in the type of opioids used, the minimal body temperature or whether stored or autologous blood was used. Postoperative bleeding was 1383 +/- 369 ml (43.1 +/- 11.7% of EBV) and correlated with the length of time the Hemovac drain was in place (r = 0.40, P = 0.0285) and MAP (r = 0.40, P = 0.0285). There was no correlation between postoperative and intraoperative bleeding nor in the number of fused vertebrae. Six patients had greater postoperative than intraoperative bleeding. The total bleeding (intra- plus postoperative) was 3347 +/- 920 ml (104.2 +/- 30.6 of EBV) and correlated with the number of fused vertebrae (r = 0.63, P = 0.0001) and with the duration of surgery (r = 0.42, P = 0.0208). We conclude that the number of fused vertebrae is the key factor in predicting intraoperative and total bleeding. Postoperative bleeding is considerable (up to 76.9% of EBV).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1994

The paediatric chest tube.

Chest tubes are placed to empty the pleural space of air or fluid which prohibits full lung expansion. The function of these tubes is dependent on adequate placement, effective drainage and frequent re-evaluation of the patient and the chest drainage system. Knowledge of the principles of chest tube drainage is important to evaluate adequately the function of a tube thoracostomy.

Chest Tubes↗

PubMed1993

Substituted thiopyrano[2,3,4-c,d]indoles as potent, selective, and orally active inhibitors of 5-lipoxygenase. Synthesis and biological evaluation of L-691,816.

Thiopyrano[2,3,4-c,d]indoles are a new class of 5-lipoxygenase (5-LO) inhibitors. SAR studies have demonstrated that the thiopyran ring, the 5-phenylpyridine substituent, and an acidic functional group on a four-carbon C-2 side chain are all required for optimal inhibitor potency. In contrast, the indolic nitrogen may be substituted with a variety of lipophilic groups. As a result of the SAR investigation, 44 (L-691,816; 5-[3-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy ]- 4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]-2,2-dimethylpro pyl]-1H- tetrazole) has been identified as a potent inhibitor of the 5-LO reaction both in vitro and in a range of in vivo models. Compound 44 inhibits 5-HPETE production by both rat and human 5-LO and LTB4 synthesis in human PMN leukocytes (IC50s 16, 75, and 10 nM, respectively). The mechanism of inhibition of 5-LO activity by compound 44 appears to involve the formation of a reversible deadend complex with the enzyme and does not involve reduction of the nonheme iron of 5-LO. Compound 44 is highly selective for 5-LO when compared to the inhibition of human FLAP, porcine 12-LO, and also ram seminal vesicle cyclooxygenase. In addition, 44 is orally active in a rat pleurisy model (inhibition of LTB4, ED50 = 1.9 mg/kg; 8 h pretreatment) as well as in the hyperreactive rat model of antigen-induced dyspnea (ED50 = 0.1 mg/kg; 2-h pretreatment). Excellent functional activity was also observed in both the conscious allergic monkey and sheep models of asthma. In the latter case, the functional activity observed correlated with the inhibition of urinary LTE4 excretion.

Administration, Oral↗