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Biomedical subjects

D H Albert

Publications and source records attributed to D H Albert.

At least 19 recordsLinked to original sources
PubMed1998

Discovery and evaluation of a series of 3-acylindole imidazopyridine platelet-activating factor antagonists.

Studies conducted with the goal of discovering a second-generation platelet-activating factor (PAF) antagonist have identified a novel class of potent and orally active antagonists which have high aqueous solubility and long duration of action in animal models. The compounds arose from the combination of the lipophilic indole portion of Abbott's first-generation PAF antagonist ABT-299 (2) with the methylimidazopyridine heterocycle moiety of British Biotechnology's BB-882 (1) and possess the positive attributes of both of these clinical candidates. Structure-activity relationship (SAR) studies indicated that modification of the indole and benzoyl spacer of lead compound 7b gave analogues that were more potent, longer-lived, and bioavailable and resulted in the identification of 1-(N, N-dimethylcarbamoyl)-4-ethynyl-3-[3-fluoro-4-[(1H-2-methylimidazo[4,5-c] pyrid-1-yl)methyl]benzoyl]indole hydrochloride (ABT-491, 22 m.HCl) which has been evaluated extensively and is currently in clinical development.

Animals↗
PubMed1998

The role of platelet-activating factor (PAF) and the efficacy of ABT-491, a highly potent and selective PAF antagonist, in experimental allergic rhinitis.

Platelet-activating factor (PAF) may be an important mediator of allergic rhinitis. In the present study we evaluated the effectiveness of a recently described PAF antagonist (ABT-491) in rat and guinea pig models of allergic rhinitis. PAF, when perfused through the nasal passages of anesthetized Brown Norway rats, provoked an acute increase, measured as dye leakage, in nasal vascular permeability evident within 15 min after exposure to PAF. ABT-491, given orally 1 hr before PAF challenge, inhibited the response in a dose-related manner (ED50 = 0.3 mg/kg). Intranasal perfusion with ovalbumin in rats sensitized to the antigen 18 to 21 days before challenge also induced an increase in vascular permeability. The antigen-induced leakage was inhibited a maximum of 74% (P < or = .001) by pretreatment with ABT-491 (3 mg/kg p.o.). An antihistamine (mepyramine, 10 mg/kg i.p.), a serotonin antagonist (methysergide) and a 5-lipoxygenase inhibitor (A-79175) also exhibited efficacy in this model (56%, 87% and 65% inhibition, respectively). Nearly complete inhibition (93%, P < or = .001) of the response was achieved by coadministration of ABT-491 and methysergide. In guinea pigs intranasal administration of PAF resulted in increased airway resistance that was inhibited in a dose-dependent manner by oral administration of ABT-491 (ED50 = 1 mg/kg). Antigen-induced nasal airway resistance, triggered by exposure of sensitized animals to aerosolized ovalbumin, was also inhibited by ABT-491 (maximum inhibition 64%, P < or = .05, 10 mg/kg p.o.). The effectiveness of the antagonist was increased to 80% protection by coadministration with either an antihistamine or a 5-lipoxygenase inhibitor, agents which were separately insignificant in blocking the response to antigen. These results suggest a therapeutic utility for ABT-491, perhaps in combination with other anti-inflammatory agents, in the treatment of allergic rhinitis.

Airway Resistance↗
PubMed1997

Pharmacology of ABT-491, a highly potent platelet-activating factor receptor antagonist.

ABT-491 (4-ethynyl-N, N-dimethyl-3-[3-fluoro-4-[(2-methyl-1H-imidazo-[4,5-c]pyridin-1-yl)methy l]benzoyl]-1H- indole-1-carboxamide hydrochloride) is a novel PAF (platelet-activating factor) receptor antagonist with a K(i) for inhibiting PAF binding to human platelets of 0.6 nM. Binding kinetics of ABT-491 to the PAF receptor is consistent with a relatively slow off-rate of the antagonist when compared to PAF. Inhibition of PAF binding is selective and is correlated with functional antagonism of PAF-mediated cellular responses (Ca2+ mobilization, priming, and degranulation). Administration of ABT-491 in vivo leads to potent inhibition of PAF-induced inflammatory responses (increased vascular permeability, hypotension, and edema) and PAF-induced lethality. Oral potency (ED50) was between 0.03 and 0.4 mg/kg in rat, mouse, and guinea-pig. When administered intravenously in these species, ABT-491 exhibited ED50 values between 0.005 and 0.016 mg/kg. An oral dose of 0.5 mg/kg in rat provided > 50% protection for 8 h against cutaneous PAF challenge. ABT-491 administered orally was also effective in inhibiting lipopolysaccharide-induced hypotension (ED50 = 0.04 mg/kg), gastrointestinal damage (0.05 mg/kg, 79% inhibition), and lethality (1 mg/kg, 85% vs. 57% survival). The potency of this novel antagonist suggests that ABT-491 will be useful in the treatment of PAF-mediated diseases.

Acute Disease↗
PubMed1997

Ex vivo inhibition of beta-thromboglobulin release following administration to man of ABT-299, a novel prodrug of a potent platelet activating factor antagonist.

OBJECTIVE AND DESIGN: ABT-299 is a prodrug that is converted by serum esterase to a potent platelet activating factor (PAF) antagonist (A-85783). In order to evaluate the pharmacological activity of this antagonist in man the effect of ABT-299 given to healthy volunteers on ex vivo PAF-induced beta-thromboglobulin (beta-TG) release in blood was assessed. SUBJECTS: 37 healthy male volunteers, age 18 to 40 (mean age of 23.6 years) and free of medication, participated in the study. TREATMENT: Subjects were administered intravenously 0.8 mg, 2 mg, or 70 mg doses of ABT-299 (6-7 subjects per group) or placebo (9 subjects, pooled). METHODS: Peripheral blood taken over 12 h after dosing was used for ex vivo beta-TG release and, in the case of the 70 mg dose, measurement of plasma drug concentration. Data were compared by Student's t-test. RESULTS: All three doses produced highly significant inhibition (p < 0.005 compared to predose values) of PAF-induced beta-TG release (units/ml plasma +/- SEM) 12 h after drug administration (54 +/- 14 vs. 405 +/- 51, n = 8; 79 +/- 23 vs. 480 +/- 127, n = 7; 21 +/- 10 vs. 327 +/- 72, n = 6, respectively) whereas there was no significant difference in beta-TG release in the placebo group (449 +/- 90 vs. 307 +/- 49, n = 9). Inhibition was associated with the rapid appearance in plasma of A-85783 and the pyridine N-oxide metabolite of A-85783. Within 2 h, the plasma concentration of the metabolite exceeded that of the parent drug. Both the parent drug and the metabolite exhibited potent in vitro inhibition of PAF-induced beta-TG release (A2 values of 4 and 1 nM respectively). CONCLUSIONS: These studies are the first to illustrate the utility of the beta-TG release assay for assessing ex vivo activity of PAF antagonists. These studies also demonstrate that the administration of ABT-299 to man results in potent, long lasting inhibition of PAF-mediated platelet activation, due in part to the pyridine-N-oxide metabolite, and support the potential therapeutic utility of this prodrug in treating PAF-mediated diseases.

Adolescent↗
PubMed1996

Attenuation of endotoxin-induced pathophysiology by a new potent PAF receptor antagonist.

The role of platelet-activating factor (PAF) as a mediator of endotoxin-induced pathophysiology has been studied in several animal models with conflicting results. We evaluated the effect of a new, potent, and specific PAF receptor antagonist, ABT-299 (Abbott Laboratories) against endotoxin (lipopolysaccharide; LPS)-induced cardiopulmonary dysfunction in a porcine model. In initial experiments, the potency of ABT-299 was confirmed in vitro by its ability to inhibit PAF-induced porcine platelet aggregation at an IC50 of .047 +/- .01 microM, and in vivo by the ability of low doses (.12 mg/kg + .03 mg/kg/h) to block the cardiopulmonary pathologic response to exogenous PAF infusion. To evaluate the effect of ABT-299 administration during endotoxemia, pigs were randomly assigned to one of three groups: controls (n = 7), LPS (n = 9), or ABT-299 + LPS (n =7). ABT-299 was given at 1.0 mg/kg from -0.5 to 0 h plus .3 mg/kg/h from 0 to 6 h. LPS was given at .5 micrograms/kg/hr from 0 to 6 h. ABT-299 reduced the early LPS-induced fall in cardiac index and stroke volume, pulmonary hypertension and vasoconstriction, bronchoconstriction, and hypoxemia. Administration of LPS resulted in 44% mortality (before 6 h), which was blocked by ABT-299. Results with this antagonist indicate that PAF contributes to endotoxin-induced cardiopulmonary dysfunction in the pig, and is associated with mortality in this model.

Animals↗
PubMed1996

ABT-299, a novel PAF antagonist, attenuates multiple effects of endotoxemia in conscious rats.

ABT-299, a highly potent and selective platelet activating factor (PAF) antagonist, was found to be effective in rat models of endotoxic shock. ABT-299 inhibited and reversed LPS-induced hypotension (ED50 of .008 mg/kg, intraarterially). When given prior to LPS challenge, ABT-299 (.1 mg/kg, intravenously) completely inhibited LPS-induced intestinal damage for as long as 8 h after the administration of the antagonist. Pretreatment of rats with ABT-299 (5 mg/kg, intravenously over 4 h) prevented by 85-95% symptoms of disseminated intravascular coagulation (DIC) induced by LPS, including thrombocytopenia, prolongation of prothrombin and partial thromboplastin time, decreased serum fibrinogen, and elevation of serum fibrinogen/fibrin degradation products. A .1 mg/kg dose of ABT-299 administered orally or intravenously improved long-term survival to 80% and 90%, respectively, following a lethal dose (LD65) of LPS. ABT-299 (.1 mg/kg) was also effective in preventing hypotension and gastrointestinal damage induced by lipoteichoic acid (LTA), a putative causative agent of shock in Gram-positive infections. These results illustrate the impressive potency and duration of action of ABT-299 and support the putative role of PAF in acute models of endotoxic shock.

Animals↗
PubMed1996

Properties of ABT-299, a prodrug of A-85783, a highly potent platelet activating factor receptor antagonist.

ABT-299 is an aqueous soluble prodrug that is converted rapidly in vivo to A-85783, a novel, highly potent, specific platelet activating factor (PAF) antagonist. The K, for inhibiting PAF binding to rabbit platelet membranes is 3.9 and 0.3 nM for human platelets. Inhibition is selective and reversible and is correlated with functional antagonism of PAF-mediated cellular responses (calcium mobilization, priming of superoxide generation, aggregation and degranulation). The in vivo generation of A-85783 from ABT-299 leads to potent inhibition of PAF-induced inflammatory responses (increased vascular permeability, hypotension and edema) and PAF-induced lethality. When administered i.v., the potency (ED50) of ABT-299 for inhibiting PAF responses was between 6 to 10 micrograms/kg in the rat and mouse and 100 micrograms/kg in the guinea pig. A dose of 100 micrograms/kg in the rat provided greater than 60% protection for 8 to 16 hr against cutaneous and systemic PAF challenge. This duration was also evidenced by ex vivo inhibition of platelet aggregation in guinea pig and sheep. In addition to being active parenterally, ABT-299 exhibited p.o. activity in the rat and mouse (ED50 = 100 micrograms/kg in both species). Pharmacokinetic studies in the rat revealed that ABT-299 was converted rapidly to A-85783 and, in turn, metabolized to the corresponding pyridine-N-oxide and sulfoxide metabolites. These metabolites exhibited significant potency in vitro and in vivo and thus may contribute to the activity observed after administration of ABT-299.

Animals↗
PubMed1994

N-(acyloxyalkyl)pyridinium salts as soluble prodrugs of a potent platelet activating factor antagonist.

Pyrrolothiazole 4 is a potent antagonist of platelet activating factor-mediated effects in a variety of in vitro and in vivo assays. Despite its positive activity in models of inflammation and septic shock, 4 lacks the aqueous solubility necessary for intravenous administration. This deficit was overcome by conversion of 4 to water-soluble pyridinium prodrugs. A two-step procedure was used to prepare a series of N-(acyloxyalkyl)pyridinium salts, all of which exhibited aqueous solubility of greater than 20 mg/mL. The rate of conversion of these prodrugs to 4 was faster in human plasma than in pH 7 aqueous buffer. This rate difference was shown to be due to serum enzymes since the conversion in plasma was significantly slower in the presence of a serine esterase inhibitor. A strong correlation between prodrug structure and buffer/plasma half-life was established. The N-(acetyloxymethyl)pyridinium prodrug 11 (ABT-299) is currently undergoing clinical evaluation for the treatment of sepsis.

Animals↗
PubMed1992

Synthesis and structure-activity relationships of a series of novel benzopyran-containing platelet activating factor antagonists.

A class of N-substituted tetrahydrobenzopyrano[3,4-c]pyridines, I, have been identified as antagonists of platelet activating factor (PAF). The structural features essential for PAF binding were determined by systematic modification of three sites in the molecule. While O-alkyl analogues had little effect on binding potency, N-alkyl analogues exhibited a wide range of activity. Structural changes in the core ring system generally resulted in a loss of binding activity. Optimization of the N- and O-substituents resulted in the analogues 25-27 which exhibited Ki values ranging between 131 and 167 nM in a [3H]PAF binding assay. Compound 23 was also active in a model of PAF-induced shock in the mouse following intravenous administration.

Alkylation↗
PubMed1991

5-lipoxygenase inhibitory activity of zileuton.

Zileuton [N-(1-benzo[b]thien-2-ylethyl)-N-hydroxyure] inhibited 5-hydroxyeicosatetraenoic acid synthesis by rat basophilic leukemia cell 20,000 x g supernatant and rat polymorphonuclear leukocytes (PMNL) (IC50 = 0.5 and 0.3 microM) respectively. It also inhibited leukotriene (LT)B4 biosynthesis by rat PMNL (IC50 = 0.4 microM), human PMNL (IC50 = 0.4 microM) and human whole blood (IC50 = 0.9 microM). Inhibition of human PMNL LTB4 biosynthesis was removed readily by a simple wash procedure. At concentrations up to 100 microM, the compound produced little or no inhibition of several related enzymes, such as platelet 12-lipoxygenase, soybean and rabbit reticulocyte 15-lipoxygenase and sheep seminal vesicle cyclooxygenase. At p.o. doses from 0.5 to 5 mg/kg in the dog, zileuton produced a rapid and sustained inhibition of ex vivo blood LTB4 biosynthesis which correlated with the pharmacokinetic behavior of the compound. In a similar ex vivo study in the rat, the compound displayed an p.o. ED50 of 2 mg/kg. Zileuton was highly effective in preventing 6-sulfidopeptide LT formation in the rat peritoneal cavity triggered by an antigen-antibody reaction with an ED50 of 3 mg/kg. In experimental models of inflammation, zileuton significantly reduced arachidonic-acid induced mouse ear edema (ED50 = 31 mg/kg) and also attenuated inflammatory cell accumulation in the rat pleural Arthus reaction. The effectiveness of this compound for preventing LT formation in vitro, ex vivo and in vivo suggests its utility for preventing the pathophysiological effects of the LTs and other 5-lipoxygenase products in animals and in humans.

Administration, Oral↗
PubMed1984

Release of arachidonic acid from 1-alkyl-2-acyl-sn-glycero-3-phosphocholine, a precursor of platelet-activating factor, in rat alveolar macrophages.

Platelet activating factor and the bioactive metabolites of arachidonic acid are secreted by alveolar macrophages in response to stimulation by phagocytic agents or calcium ionophore. We have previously shown a deacylation-acetylation sequence in the formation of 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF) from alkylacyl-(long chain)-GPC (Albert, D.H. and Snyder, F. (1983) J. Biol. Chem. 258, 97-102). This sequence may be an important source of 20:4 during inflammatory reactions since, in alveolar macrophages, the ether lipid precursor of PAF represents 35% of the choline glycerophospholipids and has a much higher content (35%) of 20:4 in the sn-2 position than does diacyl-GPC (17%). Alveolar macrophages prelabeled with 14C-labeled fatty acids (16:0, 18:1, 18:2 and 20:4) and [1-3H]alkyllyso-GPC were used to study the release of fatty acids from ether-linked and diacyl phospholipids. Each of these fatty acids was incorporated primarily into the choline glycerophospholipids of alveolar macrophages. The release of 20:4 from macrophage phospholipids was increased by treatment of the labeled cells with the calcium ionophore A23187 (2 microM) or zymosan (1 mg/ml), whereas the release of 16:0, 18:1 and 18:2 was not increased above control levels by either stimuli. Although more of the labeled 20:4 is released from the diacyl-GPC (50% of the total released), substantial amounts (44%) of 20:4 are derived from alkylacyl-GPC after incubating the stimulated cells for 60 min. The loss of 20:4 continued from the diacyl species throughout the incubation period studied, whereas a slower net release of 20:4 lost from the alkylacyl-GPC fraction was evident after 2 h. We conclude that the deacylation-reacylation cycle is an important aspect of the metabolism of 20:4 and alkylacyl-GPC during inflammatory stimulation of alveolar macrophages and that the deacylation of this ether-linked phospholipid (which is the first step in the formation of PAF) is responsible for a significant amount of the 20:4 released.

Animals↗
PubMed1983

Biosynthesis of 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine (platelet-activating factor) from 1-alkyl-2-acyl-sn-glycero-3-phosphocholine by rat alveolar macrophages. Phospholipase A2 and acetyltransferase activities during phagocytosis and ionophore stimulation.

1-Alkyl-2-acyl-sn-glycero-3-phosphocholine (alkyl-acyl-GPC) comprises 11% of the total phospholipids of rat alveolar macrophages. This endogenous pool of alkylacyl-GPC was prelabeled by incubating the macrophages with [1,2-3H]alkyllyso-GPC (54 Ci/mmol), which enters the cells and is acylated. The effect of various stimuli on the synthesis and release into the media of labeled alkylacetyl-GPC (platelet-activating factor) from the cells was used to establish the role of inactive alkylacyl-GPC as a precursor of the biologically active derivative. A phagocytic agent (zymosan, 100 micrograms/ml) and an ionophore (A23187, 2 microM) stimulated the release of both alkylacetyl-GPC and alkyllyso-GPC into the media at the expense of cellular alkylacyl-GPC. Phospholipase A2 activity (at pH 4.5 and in 1 mM EDTA) was also increased in the media. The stimulatory effect of zymosan and the ionophore on alkylacetyl-GPC release was prevented by mepacrine (0.1 mM), an agent that inhibits the release of fatty acids from phospholipids. These data indicate that phospholipase activity is required for the biosynthesis of alkylacetyl-GPC. However, since the inhibitory effect of mepacrine was not apparent when acetate was present, it appears that the acetylation step is rate limiting. Exposure of alveolar macrophages in culture to zymosan or A23187 stimulated acetyltransferase activity 250-300%. In contrast, phorbol myristate acetate (1.6 microM), which stimulated the accumulation of lysophospholipids but not the level of alkylacetyl-GPC in the media, did not substantially increase acetyltransferase activity. We conclude that alkylacyl-GPC serves as a precursor of alkylacetyl-GPC and that the production of this potent mediator by rat alveolar macrophages can be stimulated by agents that affect phospholipase A2 and acetyltransferase activities. The latter enzyme appears to have a regulatory function in the biosynthesis of alkylacetyl-GPC.

Acetyltransferases↗
PubMed1982

Cholesterol metabolism in human monocyte-derived macrophages: stimulation of cholesteryl ester formation and cholesterol excretion by serum lipoproteins.

The role of lipoproteins and serum in the formation and accumulation of cholesteryl esters in human monocyte-derived macrophages (HMD macrophages) was investigated; studies were also carried out with IC21 cells (a cell line derived from mouse peritoneal macrophages). Following preincubation of HMD macrophages with lipoprotein-depleted serum (LPDS), both native and acetylated low density lipoprotein (LDL and AcLDL, respectively) stimulated the formation of cholesteryl esters with a resultant increase in cellular cholesteryl ester content. Cholesteryl ester formation and accumulation was also stimulated in macrophages exposed continuously to 25-hydroxycholesterol. However, the stimulation of cholesterol esterification by either lipoproteins or 25-hydroxycholesterol was not inhibited by progesterone in HMD macrophages, but was in the IC21 cells. Cholesterol efflux and the hydrolysis of cellular cholesterol ester, promoted by serum components, were studied in HMD macrophages preloaded with cholesteryl ester by incubation with 25-hydroxy cholesterol. Replacement of the medium with one devoid of 25-hydroxycholesterol resulted within 24 hr in at least a 30% decrease in the cholesteryl ester content of the HMD macrophages; replacement with a medium high in cholesterol acceptor content (LPDS or high density lipoprotein) and incubation for three days led to the most marked decreases in cellular cholesterol content. Thus, hydrolysis of the cholesteryl esters by HMD macrophages was not dependent on the presence of cholesterol acceptors in the medium, but cellular cholesterol content was.

Cholesterol↗
PubMed1982

The conversion of progesterone into 5 alpha-pregnane-3,20-dione, 3 beta-hydroxy-5 alpha-pregnan-20-one, and its fatty acid esters by preparations of bovine corpora lutea.

Homogenates obtained from bovine corpora luteal tissue were found to catalyze the synthesis of 3 beta-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) from progesterone but not from pregnenolone. The major metabolites of progesterone included allopregnanolone, 5 alpha-pregnane-3,20-dione, and fatty acid esters of allopregnanolone. Incubation with labeled pregnenolone resulted in the formation of pregnenolone esters; however, neither allopregnanolone nor esterified derivatives of it were detected. The esterifying enzyme(s) leading to the formation of allopregnanolone esters was associated primarily with the microsome-enriched subcellular fraction and was stimulated by the addition of ATP and coenzyme A. With these added cofactors, the pH optimum was 6.0-6.5. The rate of steroid ester formation was enhanced by the addition to the homogenate fraction of oleic acid, which was incorporated into the steroid ester fraction. Thus, enzymatic activity, with characteristics similar to either cholesteryl ester hydrolase (EC 3.1.1.13) or acyl cholesterol acyltransferase (EC 2.3.1.26), catalyzed the esterification of allopregnanolone. The data suggest that the allopregnanolone esters found in vivo are derived from progesterone rather than from pregnenolone.

5-alpha-Dihydroprogesterone↗