Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Azetidines”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 505 records · Page 28Linked to original sources
PubMed1983

Involvement of collagen formation in the hormonally induced functional differentiation of mouse mammary gland in organ culture.

In mammary gland organ culture from midpregnant mice, synergistic actions of insulin, cortisol, and prolactin stimulate differentiation of mammary epithelium and induce the synthesis of the milk proteins casein and alpha-lactalbumin. In the present study we examined the production of collagen and its function in the hormone-dependent development of mammary gland in vitro. The measurement of collagen production by the hydroxyproline assay and by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that the accumulation of collagen type I and type III in cultured mammary explants increased with the addition of insulin, cortisol, and prolactin to a chemically defined medium. When an analog of proline, L-azetidine-2-carboxylic acid (LACA), was added at a concentration of 80 microgram/ml with insulin, cortisol, and prolactin at the beginning of culture, collagen production in cultured tissue was inhibited by 75% during a 3-day incubation period. This agent also inhibited the synthesis of casein and alpha-lactalbumin by about 77 and 70%, respectively. The inhibitory effect of LACA could be prevented by L-proline; concomitant addition of L-proline (80 microgram/ml) with LACA (80 microgram/ml) resulted in complete restoration of milk protein synthesis to normal levels. Measurement of the amount of milk protein mRNAs in mammary explants by a cell-free translation assay demonstrated that LACA reduced the hormone-stimulated accumulation of casein mRNA and alpha-lactalbumin mRNA by 79 and 76%, respectively. LACA, however, produced little inhibition of DNA synthesis in cultured tissue. These results suggest that collagen production may be involved in the phenotypic expression of milk protein genes during hormonal induction of mammary epithelial differentiation in vitro.

Animals↗
PubMed1984

Pharmacological inhibition of excessive collagen deposition in fibrotic diseases.

Excessive accumulation of collagen is a major pathological feature in diseases characterized by tissue fibrosis. Although several therapeutic approaches have been attempted in such patients, currently no treatment modality would specifically reduce collagen deposition in tissues. In this paper we discuss the mode of action of compounds that interfere with collagen production on the posttranslational level. First, structural analogs of proline, cis-4-hydroxy-L-proline and L-azetidine-2-carboxylic acid, which are incorporated into the newly synthesized polypeptides of procollagen during translation, prevent the polypeptides from folding into a stable triple-helical conformation. As a consequence, the nonhelical polypeptides are subject to degradation by proteases, thus leading to reduced deposition of collagen fibers. Second, several naturally occurring amino acids, polyamines, and their structural analogs prevent the removal of the carboxy-terminal extensions during the extracellular conversion of procollagen to collagen. Because the precursor molecules that contain the carboxy-terminal extensions are unable to assemble into functional fibers, collagen deposition is again reduced. Further development of these and related compounds, with appropriate tissue targeting, could potentially provide us with novel means to reduce the excessive deposition of collagen in fibrotic processes.

Animals↗
PubMed1982

Aortic endothelial cell migration. I. Matrix requirements and composition.

Endothelial cell migration was studied following a mechanical injury produced in cultured confluent monolayers of calf aortic endothelium with the use of a quantitative migration assay. In this method the cells were grown on glass coverslips coated with scarlet red-containing Formvar. At confluency, the cultures were cut in half with a blade; one half was removed with the pigmented Formvar, and the other was returned to culture. Migration was linear for a least 96 hours, and was due to cell motility, not proliferation. Since it was blocked in the presence of L-azetidine carboxylic acid or cis-hydroxyproline, inhibitors of collagen secretion, endothelial cell migration appeared to be dependent on the continual secretion of collagen. Furthermore, the types, apparent relative amounts, and localizations of the collagens as well as laminin changed during the migratory process. These studies support the notion that the aortic endothelial cell migratory response to injury is a dynamic one requiring the continual secretion and modulation of matrix molecules.

Animals↗
PubMed1982

Interaction of N-substituted ethanolamine analogs with ethanolamine ammonia-lyase, an adenosylcobalamin-requiring enzyme.

A number of N-substituted ethanolamine derivatives have been found to interact productively with ethanolamine ammonia-lyase, an adenosylcobalamin (AdoCbl) requiring enzyme that catalyzes the conversion of vicinal amino alcohols to oxo compounds. Inhibition, inactivation, cleavage of AdoCbl, and exchange of tritium out of [5'-3H]AdoCbl were all observed, the effects varying from analog to analog. The most striking effects were seen with azetidin-2-ol and pyrrolidin-3-ol, two aliphatic heterocycles composed of ethanolamine in which the nitrogen is tied back to the carbinol carbon by methylene bridges containing one and two carbon atoms, respectively. Incubation of azetidinol with the enzyme.AdoCbl complex resulted in extensive inactivation of the enzyme accompanied by cleavage of the cofactor; exchange of 3H from [5'-3H]AdoCbl into a nonbasic compound was also seen. Pyrrolidinol interacted with the enzyme.AdoCbl complex in a substrate-like way, causing exchange of 3H from labeled cofactor into a basic compound (perhaps the pyrrolidinol itself) together with a slight amount of C-Co bond cleavage. The interaction of the enzyme.AdoCbl complex with pyrrolidinol suggests that productively bound substrate is associated with the active site in such a way that the dihedral angle between the nitrogen and the oxygen is about 120 degrees, a configuration which maximizes bond-bond repulsions between the substituents on the adjacent carbon atoms.

Ammonia-Lyases↗
PubMed1982

Induction of bone by epithelial cell products.

The bones of the head and face of vertebrate embryos only form after their progenitor cells have undergone an inductive interaction with embryonic epithelia. We have investigated whether epithelial cell products can substitute for epithelia in allowing mandibular ectomesenchyme to form bone. Mandibular epithelia from embryonic chicks were cultured on Millipore filters for 28 days to allow them to deposit an extracellular matrix, shown by electron microscopy to be a basal lamina-like material. Mandibular ectomesenchymal cells formed bone when placed on to these epithelial extracellular products and grafted to chorioallantoic membranes of host embryos. Treatment of epithelial cultures with trypsin or L-azetidine-carboxylic acid removed both the extracellular products and their ability to induce bone formation. Hyaluronidase treatment did neither. We concluded that a proteinaceous component of epithelial basal lamina provides a sufficient inductive stimulus to initiate differentiation of bone within mandibular ectomesenchyme.

Animals↗
PubMed1989

Sites, mechanisms, and structural characteristics of the brain's nicotine receptor.

Studies are described dealing with the molecular features of nicotine, the receptor binding and psychotropic properties of nicotine agonists and antagonists, and the neuroanatomical locus of action of nicotine associated with its psychotropic action. Bridged analogues of nicotine have been developed to define the optimal conformation of the molecule for maximal receptor affinity and psychotropic action in rats. With another series of analogues, it was demonstrated that contraction of the pyrrolidine ring to a 4-member azetidine enhances potency while expansion diminishes it. A major site for nicotine's central action is the vestibular cerebellum as demonstrated by kainic acid lesioning studies and direct administration of nicotine into this region. Included among the antagonists to nicotine was alpha-lobeline, which appeared to be a mixed agonist-antagonist.

Animals↗
PubMed1994

Site-specific alteration of arginine 376, the unique positively charged amino acid residue in the mid-membrane-spanning regions of the proline carrier of Escherichia coli.

An alignment of 5 amino acids in the Escherichia coli proline carrier (G328-A366-L371-GR376) is common in the amino acid sequences of several Na+ symport carriers, and it has been proposed as the putative sodium binding motif (Deguchi, Y., Yamato, I., and Anraku, Y. (1990) J. Biol. Chem. 265, 21704-21708). To determine whether these amino acids are essential for Na+ symport activity as the Na+ binding site, one of the amino acids in this alignment, Arg-376, which is the only positively charged amino acid in the innermost part of the predicted membrane-spanning regions, was changed to either lysine, glutamine, or glutamic acid by oligonucleotide dependent site-specific mutagenesis. The transport and binding activities of the proline of the R376K mutant carrier were not detected at all. The activities of the other mutant carriers for uptake and binding of proline were as high as those of the wild-type carrier. These two mutant carriers were as sensitive to the proline analogue azetidine-2-carboxylate and to N-ethylmaleimide as the wild-type carrier, indicating that they have the same properties as the wild-type. The amounts of the carrier proteins expressed from these mutated putP genes were similar to that from the wild-type gene. These results imply that the Arg-376 in the proline carrier does not reside at the sodium binding site, suggesting that the similar alignment found in the amino acid sequences of several Na+ symport carriers is not essential for the transport or binding activities, although this similar alignment may have some relevance to the structure of the Na+ symporter. Furthermore, that the only Arg residue in the middle part of the predicted membrane-spanning regions is dispensable for the energy coupling activity indicates a unique difference of the coupling mechanism from the other secondary active transport systems, such as that of the lactose permease and the tetracycline/H+ antiporter.

Amino Acid Sequence↗
PubMed1993

70 kDa heat shock cognate protein is a transformation-associated antigen and a possible target for the host's anti-tumor immunity.

We previously investigated a novel heat-inducible transformation-associated cell surface Ag that is expressed on the activated H-ras oncogene-transformed rat fibrosarcoma W31, but not its parental nontransformed fibroblast WFB. This Ag was detected by mAb 067. Herein, we characterized the molecular nature of the Ag by using anti-heat shock protein (HSP) mAb. The accumulated data indicated that the cell surface expression of Ag was clearly enhanced by several stressors, such as TNF, L-azetidine-2-carboxylic acid, and sodium arsenite. The immunoprecipitate made with mAb 067 and W31 cell lysates reacted with anti-rat 70 kDa heat shock cognate (HSC) mAb, TG5E, indicating that 067-defined Ag may be a rat 70 kDa HSC. Because this Ag seemed to be one of the transformation-associated Ag of WFB, we further studied whether it could play an important role in the host's anti-tumor immunity. Peripheral T cells of rats primed with live BCG showed cytotoxicity to W31 but not to WFB. Because the possibility existed that HSP may interact with certain populations of T cells, we focused on the reactivity of CD4-CD8- double negative T (DNT) cells against 067-defined molecule. DNT cells from spleen and PBL of live BCG-primed rats showed the cytotoxicity against W31 cells. This cytotoxicity was completely blocked by mAb 067 and anti-CD3 mAb. However, it was not blocked by mAb R48B1 and 109, which detect the MHC class I nonpolymorphic determinant and a target molecule of the cytolysis by poly I:C-induced NK cells, respectively. Furthermore, brefeldin A was able to block the cytotoxicity against W31 targets by DNT cells, but not by NK cells. These data suggest that 70 kDa HSC may be a tumor Ag and may act as a presenting molecule perhaps complexed with cellular peptides to certain DNT cells.

Animals↗
PubMed1993

Chemotactic methylesterase promotes adaptation to high concentrations of attractant in Bacillus subtilis.

The Bacillus subtilis gene encoding CheB (cheBB), the chemotactic methylesterase, has been sequenced. The 39-kDa protein which resulted from the expression of cheBB, using a T7 expression system was consistent with the predicted open reading frame. CheBB shares 39.5% identity with Escherichia coli CheBE and can complement a cheBE null mutant. CheBB is required for removal of methyl groups from the receptors upon attractant stimulus and appears to play an important role in adaptation to the addition of attractants, whereas CheBE plays an important role in adaptation to the addition of repellents. Unlike the cheBE and cheRE mutants of E. coli, which show extreme flagellar rotational biases, the unstimulated cheBB mutant showed a normal (wild type) bias. Upon addition of attractant, the cheBB null mutant showed a counter-clockwise bias that was higher than for wild type and demonstrated only partial adaptation. In the capillary assay for the attractant azetidine-2-carboxylic acid, the mutant gave a wild type response at low concentrations but a very reduced response at high concentrations. We conclude that B. subtilis has an effective methylation-independent adaptation system but must utilize the methylation system for adaptation to high concentrations of attractant.

Amino Acid Sequence↗
PubMedDate not supplied

[Synthetic inhibitors targeting serine and aspartic acid proteases].

The interaction of novel series of synthetic inhibitors with various serine proteases (leukocyte elastase, thrombin, cathepsin G, chymotrypsin, plasminogen activators and plasmin) and an aspartic protease (HIV-1 protease) were studied. Various aspects were analyzed: mechanism of action, structure-activity relationships, and in some cases, molecular modelling and biological evaluation. Functionalized cyclopeptides and N-aryl azetidin-2-ones behaved as suicide substrates acting specifically on trypsin-like proteases (thrombin or urokinase) and elastases, respectively. Novel hydrazinopeptides acted as reversible inhibitors of elastases. Coumarin derivatives inactivated very efficiently chymotrypsin-like proteases (k(inact)/K(I) = 760,000 M(-1) .s(-1)). Inhibitors of HIV-1 protease acting either as inactivators or dimerization inhibitors are under investigation. The inhibitors described above are useful for elucidating the biological roles of the target enzymes and constitute potential drugs.

Animals↗
PubMed1997

Activation of the metabotropic glutamate receptor mGluR5 prevents glutamate toxicity in primary cultures of cerebellar neurons.

1-Aminocyclopentane-trans-1,3-dicarboxylic acid, an agonist of the metabotropic glutamate receptors 1, 2, 3 and 5, prevents neurotoxicity of glutamate and of N-methyl-D-aspartate in primary cultures of cerebellar neurons. The aim of this work was to assess which of the metabotropic glutamate receptors (mGluRs) is responsible for the protective effect. We tested the protective effects of selective agonists for each type of receptor. It is shown that glutamate and N-methyl-D-aspartate neurotoxicity are prevented by the following compounds: 1-amino-cyclo-pentane-trans-1,3-dicarboxylic acid, agonist of mGluR1, 2, 3 and 5; 3,5-dihydroxyphenylglycine, agonist of mGluR1 and 5; S-4-carboxy-3-hydroxyphenylglycine, agonist of mGluR5 and antagonist of mGluR1; trans-azetidine-2,4-dicarboxylic acid, agonist of mGluR5. Glutamate neurotoxicity is not prevented by (2S,1'S,2'S)-2(2'-carboxycyclopropyl)glycine, an agonist of mGluR2 and mGluR3. Moreover, the protective effect of 1-aminocyclo-pentane-trans-1,3-dicarboxylic acid is prevented by alpha-methyl-4-carboxyphenylglycine, an antagonist of mGluR1 and 5, but not by alpha-methyl-4-tetrazoylphenylglycine, an antagonist of mGluR2 and 3. A protective effect of activation of mGluR1 can not be ruled out because of the limitations imposed by the lack of specificity of the agonists and antagonists currently available. The results shown clearly indicate that activation of mGluR5 prevents glutamate and N-methyl-D-aspartate neurotoxicity in primary cultures of cerebellar neurons.

Animals↗
PubMed1976

Protein degradation in human fibroblasts (WI-38). Effects of aging, viral transformation, and amino acid analogs.

Protein degradation occurs more rapidly in senescent WI-38 cultures than in phase II cultures or in SV-40 transformed WI-38 cells (VA-13). The first differences are found in early phase III, when short lived but not long lived proteins are degraded more rapidly. At the end of phase III long lived proteins are also degraded more rapidly as shown by both intermittent perfusion and approach to equilibrium methods. By both methods the rates of protein degradation for the virally transformed derivative are the same as those for phase II WI-38, implying that transformation has not altered these characteristics of protein degradation. WI-38 cells incorporate canavanine, an analog of arginine, into protein. This analog, as well as p-fluorophenylalanine and azetidine carboxylic acid, accelerates the degradation of proteins labeled with [3H]leucine in their presence but does not alter the degradation rates of proteins prelabeled with [14C]leucine in the absence of the analogs. These results imply that the analogs increase the intracellular degradation rates of proteins because they render them more susceptible to the degradative system. Late phase III WI-38 cells may not selectively catabolize proteins containing canavanine as rapidly as do phase II and VA-13 cells. These results imply that the phase III protein degradative system becomes partially defective, thereby losing its ability to rapidly catabolize altered protein which leads to increased levels of abnormal proteins and decreased cell function.

Aging↗
PubMed1997

[Transfer of bacterial genes for proline synthesis in plants and their expression by various plant promotors].

Accumulation of free proline (Pro) by bacteria and plants serves as a mechanism protecting these organisms from abiotic stress. We introduced two E. coli genes, proBosm, encoding a mutant variant of the first enzyme of the Pro biosynthetic pathway, gamma-glutamyl kinase, and proA, encoding the second enzyme of the Pro pathway, glutamyl-gamma-semialdehyde dehydrogenase, into tobacco plants. The spontaneous proBosm mutation was selected for Pro overproduction and mapped to the N-terminus of a polypeptide chain; it was found to result from one amino-acid substitution. Two E. coli genes were simultaneously introduced into tobacco plants, each under the control of a strong constitutive CaMV 35S promoter, which contained a duplicated sequence of enhancer, or the root-specific Pmas promoter sequence. Transgenic plants were characterized by Pro overproduction, increased resistance to L-azetidine-2-carboxylic acid (a toxic analog of Pro), and tolerance to salt stress.

Agrobacterium tumefaciens↗
PubMed1997

Behavioural and electrophysiological evidence supporting a role for group I metabotropic glutamate receptors in the mediation of nociceptive inputs to the rat spinal cord.

A combined study of behavioural and electrophysiological tests was carried out in order to assess the role of metabotropic glutamate receptors (mGluRs) in mediating sensory inputs to the spinal cord of the rat. In the behavioural study the responses of conscious animals, with or without carrageenan-induced inflammation, to noxious mechanical and thermal stimuli were observed both before and after the intrathecal administration of mGluR antagonists L(+)-2-amino-3-phosphonopropionic acid (L-AP3) and (S)-4-carboxy-3-hydroxyphenylglycine (CHPG). It was found that the mGluR antagonist (S)-CHPG was capable of increasing both mechanical threshold and thermal latency in both groups of animals, and L-AP3 did so in those with inflammation induced in their hindpaw. Following this study, the responses of single lamina III-V dorsal horn neurons to an innocuous A beta fibre brush stimulus and a noxious C fibre (mustard oil) stimulus were extracellularly recorded and the effect of ionophoretically applied drugs was examined. Cyclothiazide (CTZ), a selective antagonist at mGluR1, markedly reduced the activity evoked by mustard oil, but not that elicited by brushing of the receptive field. Activity induced in dorsal horn neurons by ionophoresing various mGluR subgroup agonists was examined. CTZ successfully inhibited the activity evoked by group I mGluR agonist 3,5-dihydroxyphenylglycine (DHPG). In comparison to the neurons which responded to the ionophoresis of DHPG, less were activated by the selective mGluR5 agonist trans-azetidine dicarboxylic acid (t-ADA). Together these results indicate that group I mGlu receptors, in particular mGluR1, play a crucial role in mediating nociception, particularly following a sustained noxious input.

Alanine↗
PubMed1998

Antisense ablation of type I metabotropic glutamate receptor mGluR1 inhibits spinal nociceptive transmission.

Electrophysiological and behavioral studies point to a role of group I metabotropic glutamate receptors (mGluR1 and mGluR5) in mediating spinal nociceptive responses in rats. However, antagonists with a high degree of specificity for each of these sites are not yet available. We, therefore, examined the effects of antisense deletion of spinal mGluR1 expression in assays of behavioral analgesia and of electrophysiological responses of dorsal horn neurons. Rats treated with an mGluR1 antisense oligonucleotide reagent, delivered continuously to the intrathecal space of the lumbar spinal cord, developed marked analgesia as measured by an increase in the latency to tail-flick (55 degreesC) over a period of 4-7 d. This correlated with a selective reduction in mGluR1, but not mGluR5, immunoreactivity in the superficial dorsal horn compared with untreated control rats, in parallel with a significant reduction in the proportion of neurons activated by the mGluR group I agonist 3, 5-dihydroxyphenylglycine (DHPG), whereas the proportion of cells excited by the mGluR5 agonist, trans-azetidine-2,4-dicarboxylic acid (t-ADA) remained unaffected. In contrast, rats treated with mGluR1 sense or mismatch probes showed none of these changes compared with untreated, control rats. Furthermore, multireceptive dorsal horn neurons in mGluR1 antisense-treated rats were strongly excited by innocuous stimuli to their peripheral receptive fields, but showed severe reductions in their sustained excitatory responses to the selective C-fiber activator mustard oil and in responses to DHPG.

Animals↗
PubMed2001

Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase 2 dose-finding study.

BACKGROUND: Up to one third of patients who undergo total knee replacement develop deep vein thrombosis after surgery despite receiving low-molecular-weight heparin prophylaxis. Ximelagatran is a novel direct inhibitor of free and clot-bound thrombin. METHODS: We performed a randomized, parallel, dose-finding study of 600 adults undergoing elective total knee replacement at 68 North American hospitals to determine the optimum dose of ximelagatran to use as prophylaxis against venous thromboembolism after total knee replacement. Patients received either ximelagatran twice daily by mouth in blinded fixed doses of 8, 12, 18, or 24 mg or open-label enoxaparin sodium, 30 mg, subcutaneously twice daily, starting 12 to 24 hours after surgery and continuing for 6 to 12 days. We measured the 6- to 12-day cumulative incidence of symptomatic or venographic deep vein thrombosis, symptomatic pulmonary embolism, and bleeding. RESULTS: A total of 594 patients received at least 1 dose of the study drug; 443 patients were evaluable for efficacy. Rates of overall venous thromboembolism (and proximal deep vein thrombosis or pulmonary embolism) for the 8-, 12-, 18-, and 24-mg doses of ximelagatran were 27% (6.6%), 19.8% (2.0%), 28.7% (5.8%), and 15.8% (3.2%), respectively. Rates of overall venous thromboembolism (22.7%) and proximal deep vein thrombosis or pulmonary embolism (3.1%) for enoxaparin did not differ significantly compared with 24-mg ximelagatran (overall difference, -6.9%; 95% confidence interval, -18.0% to 4.2%; P=.3). There was no major bleeding with administration of 24 mg of ximelagatran twice daily. CONCLUSION: Fixed-dose, unmonitored ximelagatran, 24 mg twice daily, given after surgery appears to be safe and effective oral prophylaxis against venous thromboembolism after total knee replacement.

Administration, Oral↗
PubMed2006

Mixed comparison of stroke prevention treatments in individuals with nonrheumatic atrial fibrillation.

BACKGROUND: We aimed to identify different stroke prevention treatments for atrial fibrillation assessed in randomized controlled trials and to compare them within a single evidence synthesis framework. METHODS: We updated the Cochrane review on anticoagulants and antiplatelet therapy for nonrheumatic atrial fibrillation to include randomized controlled trials published between January 2000 and March 2005 identified via the CENTRAL database and MEDLINE. A mixed-treatment comparison method was used to combine direct within-trial, between-treatment comparisons with indirect trial evidence while maintaining randomization. RESULTS: Data were combined from 19 clinical trials that included 17 833 patients randomized to 9 treatment strategies, including placebo. For prevention of ischemic stroke, adjusted standard-dose warfarin sodium (relative rate [RR], 0.35; 95% credible interval [CrI], 0.24 to 0.52), adjusted low-dose warfarin (RR, 0.35; 95% CrI, 0.19 to 0.60), ximelagatran (RR, 0.34; 95% CrI, 0.18 to 0.61), and aspirin (RR, 0.64; 95% CrI, 0.44 to 0.88) were all associated with a significantly lower rate of ischemic stroke compared with placebo. For major and fatal bleeding episodes, there was some evidence of an increased risk for all treatments but none were statistically significant. Assuming a baseline risk of 51 ischemic stroke events per 1000 person-years, it can be estimated that adjusted standard-dose warfarin could prevent 28 (95% CrI, -37 to -19) ischemic strokes at the expense of 11 (95% CrI, -1 to +39) major or fatal bleeding episodes. In comparison, aspirin could prevent 16 (95% CrI, -26 to -5) ischemic strokes at the expense of 6 (95% CrI, -3 to +27) major or fatal bleeding episodes. CONCLUSIONS: A lower rate of ischemic stroke and a higher rate of major bleeding episodes were found to be associated with oral anticoagulants compared with aspirin, and both anticoagulants and aspirin were found to be associated with a reduction in the rate of stroke compared with placebo.

Anticoagulants↗
PubMed2006

Comparison of bleeding in patients with nonvalvular atrial fibrillation treated with ximelagatran or warfarin: assessment of incidence, case-fatality rate, time course and sites of bleeding, and risk factors for bleeding.

BACKGROUND: Ximelagatran is a novel direct thrombin inhibitor that can be administered as a fixed oral dose, without the need for anticoagulant monitoring. METHODS: We undertook a pooled analysis of 7329 patients with nonvalvular atrial fibrillation from the Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation III and V trials to compare bleeding outcomes in patients who received ximelagatran, 36 mg twice daily, or warfarin sodium (target international normalized ratio, 2.0-3.0). We determined annual risk of bleeding (any, major), case-fatality rate, time course and anatomic sites of major bleeding, and risk factors for major bleeding with ximelagatran and warfarin treatment. RESULTS: Annual incidence of any bleeding was 31.75% with ximelagatran and 38.82% with warfarin (relative risk reduction, 18.2%; 95% confidence interval [CI], 13.0-23.1; P<.001). Annual incidence of major bleeding was 2.01% with ximelagatran and 2.68% with warfarin (relative risk reduction, 25.1%; 95% CI, 3.2-42.1; P = .03). Case-fatality rate of bleeding was comparable in ximelagatran- and warfarin-treated patients (8.16% vs 8.09%; P = .98). Cumulative incidence of major bleeding was higher with warfarin than ximelagatran after 24 months of treatment (4.7% vs 3.7%; P = .04). Anatomic sites of bleeding were comparable with both treatments. Risk factors for bleeding with ximelagatran were as follows (hazard ratios and 95% CIs in parentheses): diabetes mellitus (1.81; 1.19-2.77; P = .006), previous stroke or transient ischemic attack (1.78; 1.16-2.73; P = .008), age 75 years or greater (1.70; 1.33-2.18; P<.001), and aspirin use (1.68; 1.08-2.59; P = .02). Risk factors for bleeding in warfarin-treated patients were previous liver disease (4.88; 1.55-15.39; P = .007); aspirin use (2.41; 1.69-3.43; P<.001); and age 75 years or greater (1.26; 1.03-1.52; P = .02). CONCLUSIONS: Treatment with ximelagatran, 36 mg twice daily, is associated with a lower risk of bleeding than warfarin in patients with nonvalvular atrial fibrillation. Aspirin use and increasing age were associated with an increased risk of bleeding in ximelagatran- and warfarin-treated patients.

Adolescent↗