Hemodynamic effects of phosphodiesterase III inhibitor in patients with a large ventricular left-to-right shunt.
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The hemodynamic effects of olprinone, a newly synthesized phosphodiesterase (PDE) III inhibitor, were assessed in patients with a large cardiac left-to-right shunt. Ten patients with a large ventricular septal defect (VSD) were evaluated during cardiac catheterization. Olprinone was administered as a bolus, 20 microg/kg body weight, and hemodynamic data were obtained before and after the administration. Heart rate and systemic flow increased significantly after administration. On the other hand, olprinone significantly reduced left and right atrial pressure, the systolic pulmonary/arterial pressure ratio, and systemic vascular resistance. However, pulmonary flow and pulmonary vascular resistance were not changed. These results suggested that olprinone had a positive inotropic effect and selective vasodilator effect on patients with a large ventricular left-to-right shunt. Thus, PDE inhibitors may be beneficial for the treatment of patients with a large VSD. (+info)
The pyrido[2,3-d]pyrimidine derivative PD180970 inhibits p210Bcr-Abl tyrosine kinase and induces apoptosis of K562 leukemic cells.
(18/814)
PD180970 is a novel pyrido[2,3-d]pyrimidine class of ATP-competitive inhibitor of protein tyrosine kinases. We found that PD180970 inhibited in vivo tyrosine phosphorylation of p210Bcr-Abl (IC50 = 170 nM) and the p210BcrAbl substrates Gab2 and CrkL (IC50 = 80 nM) in human K562 chronic myelogenous leukemic cells. In vitro, PD180970 potently inhibited autophosphorylation of p210Bcr-Abl (IC50 = 5 nM) and the kinase activity of purified recombinant Abl tyrosine kinase (IC50 = 2.2 nM). Incubation of K562 cells with PD180970 resulted in cell death. Results of nuclear staining, apoptotic-specific poly(ADP-ribose) polymerase cleavage, and annexin V binding assays indicated that PD180970 induced apoptosis of K562 cells. In contrast, PD180970 had no apparent effects on the growth and viability of p210Bcr-Abl-negative HL60 human leukemic cells. Thus, PD180970 is among the most potent inhibitors of the p210Bcr-Abl tyrosine kinase, which is present in almost all cases of human chronic myelogenous leukemia. These findings indicate that PD180970 is a promising candidate as a novel therapeutic agent for Bcr-Abl-positive leukemia. (+info)
An investigation of the uroselective properties of four novel alpha(1a)-adrenergic receptor subtype-selective antagonists.
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The development of alpha(1a)-adrenergic receptor (AR) subtype-selective antagonists is likely to result in uroselective agents that effectively treat benign prostatic hyperplasia (BPH) symptoms without causing undesirable side effects that may be due to vascular alpha(1)-AR blockade. The properties of four aryl piperazine compounds (RWJ-38063, RWJ-68141, RWJ-68157, and RWJ-69736) are described in this report and compared with the properties of tamsulosin, an alpha(1)-AR antagonist that is used in the treatment of BPH. Radioligand binding studies show that all four RWJ compounds have significantly higher affinity for the alpha(1a)-AR subtype than for the alpha(1b) or alpha(1d) subtype and display a higher level of receptor subtype selectivity than tamsulosin. The RWJ compounds were more potent in inhibiting (+/-)-norepinephrine-induced contractions of isolated rat prostate tissue than those of isolated rat aorta tissue, whereas tamsulosin had the reversed tissue selectivity. RWJ-38063 and RWJ-69736 had the highest potency in the isolated prostate tissue assays of the four RWJ compounds, with pK(B) values of 8.24 and 9.26, respectively, and were 319- and 100-fold more potent in their effects on isolated prostate tissue than aorta tissue. The in vivo uroselectivities of RWJ-38063, RWJ-69736, and tamsulosin were examined in anesthetized dogs. Both RWJ compounds suppressed the intraurethral pressure response to phenylephrine to a greater extent than the mean arterial pressure response; however, RWJ-69736 also caused a marked transient rise in heart rate. Although less potent, RWJ-38063 and RWJ-69736 were notably more uroselective than tamsulosin in this canine model. (+info)
Biliary and urinary metabolic profiles of 1,2-diethyl-3-hydroxypyridin-4-one (CP94) in the rat.
(20/814)
This study compares the biliary and urinary metabolic profiles of 1,2-diethyl-3-hydroxypyridin-4-one (CP94), an orally active iron chelator, in the normal rat. Surprisingly, CP94 was found to form two phase II metabolites, the 3-O- and 4-O-glucuronides. These glucuronides accounted for 38 and 28% of the administered CP94 dose, in bile and urine, respectively. Unchanged CP94 accounted for 5% of the CP94 dose in both bile and urine. The 2-(1'-hydroxy) metabolite of CP94 was found to be the dominant metabolite in urine. In addition, an unstable metabolite was detected in the bile although its structure remains unknown at the present stage. The excretion of iron in bile, after administration of CP94, was found to parallel the biliary elimination of CP94 together with its hydroxylated derivatives, indicating the importance of metabolites in iron excretion. (+info)
Epolones induce erythropoietin expression via hypoxia-inducible factor-1 alpha activation.
(21/814)
Induction of erythropoietin (Epo) expression under hypoxic conditions is mediated by the heterodimeric hypoxia-inducible factor (HIF)-1. Following binding to the 3' hypoxia-response element (HRE) of the Epo gene, HIF-1 markedly enhances Epo transcription. To facilitate the search for HIF-1 (ant)agonists, a hypoxia-reporter cell line (termed HRCHO5) was constructed containing a stably integrated luciferase gene under the control of triplicated heterologous HREs. Among various agents tested, we identified a class of substances called epolones, which induced HRE-dependent reporter gene activity in HRCHO5 cells. Epolones are fungal products known to induce Epo expression in hepatoma cells. We found that epolones (optimal concentration 4-8 micromol/L) potently induce HIF-1 alpha protein accumulation and nuclear translocation as well as HIF-1 DNA binding and reporter gene transactivation. Interestingly, the activity of a compound related to the fungal epolones, ciclopirox olamine (CPX), was blocked after addition of ferrous iron. This suggests that CPX might interfere with the putative heme oxygen sensor, as has been proposed for the iron chelator deferoxamine mesylate (DFX). However, about 10-fold higher concentrations of DFX (50-100 micromol/L) than CPX were required to maximally induce reporter gene activity in HRCHO5 cells. Moreover, structural, functional, and spectrophotometric data imply a chelator:iron stoichiometry of 1:1 for DFX but 3:1 for CPX. Because the iron concentration in the cell culture medium was determined to be 16 micromol/L, DFX but not CPX function can be explained by complete chelation of medium iron. These results suggest that the lipophilic epolones might induce HIF-1 alpha by intracellular iron chelation. (Blood. 2000;96:1558-1565) (+info)
Auxin-induced ethylene triggers abscisic acid biosynthesis and growth inhibition.
(22/814)
The growth-inhibiting effects of indole-3-acetic acid (IAA) at high concentration and the synthetic auxins 7-chloro-3-methyl-8-quinolinecarboxylic acid (quinmerac), 2-methoxy-3,6-dichlorobenzoic acid (dicamba), 4-amino-3,6, 6-trichloropicolinic acid (picloram), and naphthalene acetic acid, were investigated in cleavers (Galium aparine). When plants were root treated with 0.5 mM IAA, shoot epinasty and inhibition of root and shoot growth developed during 24 h. Concomitantly, 1-aminocyclopropane-1-carboxylic acid (ACC) synthase activity, and ACC and ethylene production were transiently stimulated in the shoot tissue within 2 h, followed by increases in immunoreactive (+)-abscisic acid (ABA) and its precursor xanthoxal (xanthoxin) after 5 h. After 24 h of treatment, levels of xanthoxal and ABA were elevated up to 2- and 24-fold, relative to control, respectively. In plants treated with IAA, 7-chloro-3-methyl-8-quinolinecarboxylic acid, naphthalene acetic acid, 2-methoxy-3,6-dichlorobenzoic acid, and 4-amino-3,6,6-trichloropicolinic acid, levels of ethylene, ACC, and ABA increased in close correlation with inhibition of shoot growth. Aminoethoxyvinyl-glycine and cobalt ions, which inhibit ethylene synthesis, decreased ABA accumulation and growth inhibition, whereas the ethylene-releasing ethephon promoted ABA levels and growth inhibition. In accordance, tomato mutants defective in ethylene perception (never ripe) did not produce the xanthoxal and ABA increases and growth inhibition induced by auxins in wild-type plants. This suggests that auxin-stimulated ethylene triggers ABA accumulation and the consequent growth inhibition. Reduced catabolism most probably did not contribute to ABA increase, as indicated by immunoanalyses of ABA degradation and conjugation products in shoot tissue and by pulse experiments with [(3)H]-ABA in cell suspensions of G. aparine. In contrast, studies using inhibitors of ABA biosynthesis (fluridone, naproxen, and tungstate), ABA-deficient tomato mutants (notabilis, flacca, and sitiens), and quantification of xanthophylls indicate that ABA biosynthesis is influenced, probably through stimulated cleavage of xanthophylls to xanthoxal in shoot tissue. (+info)
Reversal of multidrug resistance by 7-O-benzoylpyripyropene A in multidrug-resistant tumor cells.
(23/814)
7-O-Benzoylpyripyropene A (7-O-BzP), a semi-synthetic analog of pyripyropene, was investigated for its reversing effect on multidrug-resistant (MDR) tumor cells. 7-O-BzP (6.25 microg/ml) completely reversed resistance against vincristine and adriamycin in vincristine-resistant KB cells (VJ-300) and adriamycin-resistant P388 cells (P388/ADR), respectively. 7-O-BzP alone had no effect on the growth of drug sensitive and drug-resistant cells. 7-O-BzP (6.25 microg/ml) significantly enhanced accumulation of [3H]vincristine in VJ-300 cells and completely inhibited the binding of [3H]azidopine to the P-glycoprotein in VJ-300 cells and P388/ADR cells. The result suggests that 7-O-BzP effectively reverses P-glycoprotein-related MDR by interacting directly with P-glycoprotein in drug resistant VJ-300 and P388/ADR cells. (+info)
Desferrioxamine-chelatable iron, a component of serum non-transferrin-bound iron, used for assessing chelation therapy.
(24/814)
This study introduces a method for monitoring a component of serum non-transferrin-bound iron (NTBI), termed "desferrioxamine-chelatable iron" (DCI). It is measured with the probe fluorescein-desferrioxamine (Fl-DFO), whose fluorescence is stoichiometrically quenched by iron. DCI was found in the serum of most patients with thalassemia major (21 of 27 tested, range 1.5-8.6 microM), but only in a minority of patients with hereditary hemochromatosis (8 of 95 samples from 39 patients, range 0.4-1.1 microM) and in none of 48 controls. The method was applied to monitoring the appearance of iron in the serum of patients under chelation therapy. Short-term (2 hours) follow-up of patients immediately after oral administration of deferriprone (L1) showed substantial mobilization of DCI into the serum (up to 10 microM within 30-60 minutes). The transfer of DCI from L1 to Fl-DFO was observed in vitro with preformed L1-iron complexes, and occurred even at L1/iron ratios exceeding 3:1. Simultaneous administration of oral L1 and intravenous DFO to patients abrogated the L1-mediated rise in DCI, consistent with the shuttling of iron from L1 to DFO in vivo. A similar iron transfer from L1 to apo-transferrin was observed in vitro, lending experimental support to the notion that L1 can shuttle iron in vivo to other high-affinity ligands. These results provide a rationale for using chelator combinations, with the highly permeant L1 acting as an intracellular chelator-shuttle and the less permeant DFO serving as an extracellular iron sink. Potential applications of the DCI assay may be for studying chelator action and as an index of patient chelation status. (+info)