The Experts below are selected from a list of 189 Experts worldwide ranked by ideXlab platform
Jacquelynn J. Cook - One of the best experts on this subject based on the ideXlab platform.
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Fibrinogen Receptor Antagonist induced thrombocytopenia in chimpanzee and rhesus monkey associated with preexisting drug dependent antibodies to platelet glycoprotein iib iiia
Blood, 1999Co-Authors: Bohumil Bednar, George D. Hartman, Jacquelynn J. Cook, Rodney A Bednar, Marie A Holahan, Michael E Cunningham, Patricia A Jumes, Robert J. GouldAbstract:Most clinical trials with Fibrinogen Receptor Antagonists (FRAs) have been associated with thrombocytopenia. This report describes the occurrence of thrombocytopenia in one chimpanzee and one rhesus monkey upon administration of potent FRAs. Chimpanzee A-264 experienced profound thrombocytopenia on two occasions immediately upon intravenous administration of two different potent FRAs, L-738,167 and L-739,758. However, an equally efficacious antiaggregatory dose of another potent Antagonist, L-734,217, caused no change in platelet count. These compounds did not affect platelet count in five other chimpanzees or numerous other nonhuman primates. Flow cytometric analysis showed drug-dependent antibodies (DDAbs) in the plasma of chimpanzee A-264 that bound to platelets of chimpanzees, humans, and all other primates tested only in the presence of the compounds that induced thrombocytopenia. Rhesus monkey 94-R021 experienced thrombocytopenia upon administration of a different Antagonist, L-767,679, and several prodrugs that are converted into the active form, L-767,679, in the blood. More than 20 other FRAs, including those that induced thrombocytopenia in chimpanzee A-264, had no effect on platelet count in this monkey. Flow cytometric measurements again identified DDAbs that reacted with platelets of all primates tested and required the presence of L-767,679. Screening for DDAbs in the plasma of 1,032 human subjects with L-738,167 and L-739,758 demonstrated that the incidence of these preexisting antibodies in this population was 0.8% ± 0.6% and 1.1% ± 0.6%, respectively.
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effects of pentobarbital on pharmacokinetics and pharmacodynamics of a potent Fibrinogen Receptor Antagonist l 734 217 in dogs
Biopharmaceutics & Drug Disposition, 1997Co-Authors: Thomayant Prueksaritanont, E. L. Hand, Joan D Ellis, Marie A Holahan, Maria T Stranieri, G R Sitko, Jacquelynn J. CookAbstract:Effects of pentobarbital on pharmacokinetics and pharmacodynamics of L-734,217, a potent Fibrinogen Receptor Antagonist, were studied in male dogs. L-734,217 was given intravenously at 0.01 mg kg-1, in a cross-over fashion, to conscious dogs or to dogs anesthetized with pentobarbital. Plasma concentrations of L-734,217 were measured using a radioimmunoassay and inhibitory effects on ex vivo platelet aggregation induced by ADP or collagen were determined. In pentobarbital-treated dogs, L-734,217 plasma concentrations during the first 3 h collection period were significantly higher than those in the control animals. Corresponding to the increased plasma levels, the mean ex vivo inhibitory effects on ADP- or collagen-induced platelet aggregation in dogs under anesthesia appeared greater than in those without the anesthetic treatment. Pharmacokinetic analysis revealed a modest, but significant (up to 40%) elevation in the area under the plasma concentration-time curve during 6 h of the drug administration, and a reduction in L-734,217 plasma clearance and volumes of distribution, in the anesthetized dogs. Analysis of pharmacodynamic data indicated that the EC50 and the Hill coefficient of the platelet aggregation response-plasma concentration curve were not altered by pentobarbital treatment. The results are in agreement with the findings that the administration of pentobarbital alone (in the absence of L-734,217) did not affect appreciably the ex vivo platelet aggregatory responses. In a separate group of dogs, L-734,217 was found to be metabolically stable, and was eliminated unchanged renally (64 +/- 4%) and hepatically (32 +/- 6%). In addition, L-734,217 did not bind substantially to canine plasma proteins or blood cellular components. It is possible that alterations of regional hemodynamics, reportedly mediated by pentobarbital, contributed to changes observed in the present study. That is, alterations occurred in L-734,217 elimination and distribution processes which resulted in an increase in drug plasma levels. Since pentobarbital anesthesia influenced only the pharmacokinetics, and not the pharmacodynamics, of L-734,217, the apparent increases in the inhibition of platelet aggregation responses observed following L-734,217 administration to the anesthetized dogs were probably sequential effects of the pharmacokinetic interactions.
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nonpeptide glycoprotein iib iiia inhibitors 13 design and synthesis of an orally active pyrazolopiperazinone nonpeptide Fibrinogen Receptor Antagonist
Bioorganic & Medicinal Chemistry Letters, 1997Co-Authors: B. C. Askew, Robert J. Gould, Paul S. Anderson, C.c. Chang, Charles J. Mcintyre, Cecilia A. Hunt, David A. Claremon, J. J. Baldwin, R. J. Lynch, Jacquelynn J. CookAbstract:Abstract The synthesis and antiplatelet activity of a series of pyrazolopiperazinone nonpeptide Fibrinogen Receptor Antagonists is reported. The sulfonamide analog 6 (L-734, 115), significantly inhibited ex vivo platelet aggregation 24 h after oral administration at doses of 1.0 and 2.0 mg/kg to dogs and rhesus monkeys, respectively.
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non peptide glycoprotein iib iiia inhibitors 17 design and synthesis of orally active long acting non peptide Fibrinogen Receptor Antagonists
Journal of Medicinal Chemistry, 1997Co-Authors: B. C. Askew, Robert J. Gould, Jacquelynn J. Cook, Charles J. Mcintyre, Cecilia A. Hunt, David A. Claremon, R. J. Lynch, Rodney A Bednar, Bohumil Bednar, Joseph J. LynchAbstract:The synthesis and pharmacological evaluation of 5 (L-738,167), a potent, selective non-peptide Fibrinogen Receptor Antagonist is reported. Compound 5 inhibited the aggregation of human gel-filtered platelets with an IC50 value of 8 nM and was found to be >33000-fold less effective at inhibiting the attachment of human endothelial cells to Fibrinogen, fibronectin, and vitronectin than it was at inhibiting platelet aggregation. Ex vivo platelet aggregation was inhibited by >85% 24 h after the oral administration of 5 to dogs at 100 μg/kg. The extended pharmacodynamic profile exhibited by 5 appears to be a consequence of its high-affinity binding to GPIIb/IIIa on circulating platelets and suggests that 5 is suitable for once-a-day dosing.
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non peptide glycoprotein iib iiia Antagonists 11 design and in vivo evaluation of 3 4 dihydro 1 1h isoquinolinone based Antagonists and ethyl ester prodrugs
Journal of Medicinal Chemistry, 1996Co-Authors: John H. Hutchinson, Robert J. Gould, Jacquelynn J. Cook, R. J. Lynch, Marie A Holahan, Michael J Breslin, Karen M. Brashear, Joan D. Glass, Wasyl Halczenko, Gary R. SitkoAbstract:The structure-activity relationship of a series of orally active glycoprotein IIb/IIIa Antagonists containing a nitrogen heterocycle grafted onto a 3,4-dihydro-1 (1H)-isoquinolinone core is described. These compounds are structurally novel analogs of the progenitor compound 1 (L-734,217,[[3(R)-[2-(piperidin-4-yl)ethyl]-2-oxopiperidinyl ]acetyl]-3(R)- methyl-beta-alanine) in which the lactam chiral center has been removed. The 4-piperazinyl- and 4-piperidinyl-substituted 3,4-dihydro-1(1H)-isoquinolinones were found to be optimal for in vitro potency. In addition, substitution at the 3-position of the beta-amino acid enhanced potency with the 3-pyridyl and 3-ethynyl analogs being the most potent prepared. Attempts to improve the in vivo profile of these compounds focused on modification of the physical properties. Ester prodrugs were prepared to increase the lipophilicity and remove the zwitterionic nature of the Antagonists. The prodrug approach, coupled with the arylpiperazine terminus (pKa = approximately 9.0), afforded moderately basic and relatively nonpolar compounds. The acid N-[[7-(piperazin-1-yl)-3,4-dihydro-1(1H)-oxoisoquinolin-2-yl ]acetyl]-3(S)- ethynyl-beta-alanine, 6d (L-767,679), is a potent Fibrinogen Receptor Antagonist able to inhibit the ADP-induced aggregation of human gel-filtered platelets with an IC50 of 12 nM. Although 6d is orally active based on the results of an ex vivo dog assay at 0.3 mg/kg, the ethyl ester prodrug of this compound, 19 (L-767,685), is better absorbed at this dose than 6d. Upon oral dosing, the ester 19 is converted to 6d in vivo in dog with an estimated oral systemic availability of > 17% (0-8 h, AUC19po/AUC6div). In addition, studies in monkey at an oral dose of 1 mg/kg show that 19 affects the complete inhibition of the ex vivo platelet aggregation in response to ADP between 2 and 8 h postdose with the level of inhibition remaining at 40% at 12 h postdose. This level of activity was superior to that observed for 6d and 1 at the same dose. Using ex vivo ADP-induced aggregation data from rhesus monkey (n = 2, 0-8 h using the AUC19po/AUC6div), the estimated systemic oral availability of 6d when dosed as 19 is 32%.
Robert J. Gould - One of the best experts on this subject based on the ideXlab platform.
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antiplatelet effects of mk 852 a platelet Fibrinogen Receptor Antagonist in healthy volunteers
The Journal of Clinical Pharmacology, 2000Co-Authors: Howard E Greenberg, Robert J. Gould, Paul Wissel, Jeffrey S Barrett, Aaron Barchowsky, Daniel Farrell, Deborah Panebianco, Elizabeth HandAbstract:MK-852, a cyclic heptapeptide, is a potent platelet Fibrinogen Receptor Antagonist. When administered to normal healthy male subjects by 1- and 4-hour constant rate intravenous infusions, it provides a generally well-tolerated and reversible means of inhibition of platelet function. At infusion rates of 1 microgram/kg/min for 1 hour and 0.44 microgram/kg/min for 4 hours, respectively, MK-852 extended baseline bleeding time by greater than 2.2-fold and 2.6-fold, inhibited ADP-induced platelet aggregation by 76% and 69%, and inhibited collagen-induced platelet aggregation by 65% and 67%, respectively. The pharmacokinetics of MK-852 include an elimination half-life of approximately 2 hours, total clearance of about 150 ml/min, and volume of distribution of about 18 liters. Examination of the relationship between MK-852 whole-blood concentration in vitro and inhibition of platelet aggregation showed an EC50 of about 55 ng/ml and a Hill coefficient of 1.55. The infusions were generally well tolerated, with no study drug-related changes in blood counts or biochemical profiles.
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Fibrinogen Receptor Antagonist induced thrombocytopenia in chimpanzee and rhesus monkey associated with preexisting drug dependent antibodies to platelet glycoprotein iib iiia
Blood, 1999Co-Authors: Bohumil Bednar, George D. Hartman, Jacquelynn J. Cook, Rodney A Bednar, Marie A Holahan, Michael E Cunningham, Patricia A Jumes, Robert J. GouldAbstract:Most clinical trials with Fibrinogen Receptor Antagonists (FRAs) have been associated with thrombocytopenia. This report describes the occurrence of thrombocytopenia in one chimpanzee and one rhesus monkey upon administration of potent FRAs. Chimpanzee A-264 experienced profound thrombocytopenia on two occasions immediately upon intravenous administration of two different potent FRAs, L-738,167 and L-739,758. However, an equally efficacious antiaggregatory dose of another potent Antagonist, L-734,217, caused no change in platelet count. These compounds did not affect platelet count in five other chimpanzees or numerous other nonhuman primates. Flow cytometric analysis showed drug-dependent antibodies (DDAbs) in the plasma of chimpanzee A-264 that bound to platelets of chimpanzees, humans, and all other primates tested only in the presence of the compounds that induced thrombocytopenia. Rhesus monkey 94-R021 experienced thrombocytopenia upon administration of a different Antagonist, L-767,679, and several prodrugs that are converted into the active form, L-767,679, in the blood. More than 20 other FRAs, including those that induced thrombocytopenia in chimpanzee A-264, had no effect on platelet count in this monkey. Flow cytometric measurements again identified DDAbs that reacted with platelets of all primates tested and required the presence of L-767,679. Screening for DDAbs in the plasma of 1,032 human subjects with L-738,167 and L-739,758 demonstrated that the incidence of these preexisting antibodies in this population was 0.8% ± 0.6% and 1.1% ± 0.6%, respectively.
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nonpeptide glycoprotein iib iiia inhibitors 13 design and synthesis of an orally active pyrazolopiperazinone nonpeptide Fibrinogen Receptor Antagonist
Bioorganic & Medicinal Chemistry Letters, 1997Co-Authors: B. C. Askew, Robert J. Gould, Paul S. Anderson, C.c. Chang, Charles J. Mcintyre, Cecilia A. Hunt, David A. Claremon, J. J. Baldwin, R. J. Lynch, Jacquelynn J. CookAbstract:Abstract The synthesis and antiplatelet activity of a series of pyrazolopiperazinone nonpeptide Fibrinogen Receptor Antagonists is reported. The sulfonamide analog 6 (L-734, 115), significantly inhibited ex vivo platelet aggregation 24 h after oral administration at doses of 1.0 and 2.0 mg/kg to dogs and rhesus monkeys, respectively.
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non peptide glycoprotein iib iiia inhibitors 17 design and synthesis of orally active long acting non peptide Fibrinogen Receptor Antagonists
Journal of Medicinal Chemistry, 1997Co-Authors: B. C. Askew, Robert J. Gould, Jacquelynn J. Cook, Charles J. Mcintyre, Cecilia A. Hunt, David A. Claremon, R. J. Lynch, Rodney A Bednar, Bohumil Bednar, Joseph J. LynchAbstract:The synthesis and pharmacological evaluation of 5 (L-738,167), a potent, selective non-peptide Fibrinogen Receptor Antagonist is reported. Compound 5 inhibited the aggregation of human gel-filtered platelets with an IC50 value of 8 nM and was found to be >33000-fold less effective at inhibiting the attachment of human endothelial cells to Fibrinogen, fibronectin, and vitronectin than it was at inhibiting platelet aggregation. Ex vivo platelet aggregation was inhibited by >85% 24 h after the oral administration of 5 to dogs at 100 μg/kg. The extended pharmacodynamic profile exhibited by 5 appears to be a consequence of its high-affinity binding to GPIIb/IIIa on circulating platelets and suggests that 5 is suitable for once-a-day dosing.
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non peptide glycoprotein iib iiia Antagonists 11 design and in vivo evaluation of 3 4 dihydro 1 1h isoquinolinone based Antagonists and ethyl ester prodrugs
Journal of Medicinal Chemistry, 1996Co-Authors: John H. Hutchinson, Robert J. Gould, Jacquelynn J. Cook, R. J. Lynch, Marie A Holahan, Michael J Breslin, Karen M. Brashear, Joan D. Glass, Wasyl Halczenko, Gary R. SitkoAbstract:The structure-activity relationship of a series of orally active glycoprotein IIb/IIIa Antagonists containing a nitrogen heterocycle grafted onto a 3,4-dihydro-1 (1H)-isoquinolinone core is described. These compounds are structurally novel analogs of the progenitor compound 1 (L-734,217,[[3(R)-[2-(piperidin-4-yl)ethyl]-2-oxopiperidinyl ]acetyl]-3(R)- methyl-beta-alanine) in which the lactam chiral center has been removed. The 4-piperazinyl- and 4-piperidinyl-substituted 3,4-dihydro-1(1H)-isoquinolinones were found to be optimal for in vitro potency. In addition, substitution at the 3-position of the beta-amino acid enhanced potency with the 3-pyridyl and 3-ethynyl analogs being the most potent prepared. Attempts to improve the in vivo profile of these compounds focused on modification of the physical properties. Ester prodrugs were prepared to increase the lipophilicity and remove the zwitterionic nature of the Antagonists. The prodrug approach, coupled with the arylpiperazine terminus (pKa = approximately 9.0), afforded moderately basic and relatively nonpolar compounds. The acid N-[[7-(piperazin-1-yl)-3,4-dihydro-1(1H)-oxoisoquinolin-2-yl ]acetyl]-3(S)- ethynyl-beta-alanine, 6d (L-767,679), is a potent Fibrinogen Receptor Antagonist able to inhibit the ADP-induced aggregation of human gel-filtered platelets with an IC50 of 12 nM. Although 6d is orally active based on the results of an ex vivo dog assay at 0.3 mg/kg, the ethyl ester prodrug of this compound, 19 (L-767,685), is better absorbed at this dose than 6d. Upon oral dosing, the ester 19 is converted to 6d in vivo in dog with an estimated oral systemic availability of > 17% (0-8 h, AUC19po/AUC6div). In addition, studies in monkey at an oral dose of 1 mg/kg show that 19 affects the complete inhibition of the ex vivo platelet aggregation in response to ADP between 2 and 8 h postdose with the level of inhibition remaining at 40% at 12 h postdose. This level of activity was superior to that observed for 6d and 1 at the same dose. Using ex vivo ADP-induced aggregation data from rhesus monkey (n = 2, 0-8 h using the AUC19po/AUC6div), the estimated systemic oral availability of 6d when dosed as 19 is 32%.
Cheming Teng - One of the best experts on this subject based on the ideXlab platform.
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halysin an antiplatelet arg gly asp containing snake venom peptide as Fibrinogen Receptor Antagonist
Biochemical Pharmacology, 1991Co-Authors: Turfu Huang, Chaozon Liu, Chaoho Ouyang, Cheming TengAbstract:Abstract By means of Sephadex G-75 and CM-Sephadex C-50 column chromatography and reversephase HPLC, a low molecular weight ( M r = 7500), cysteine-rich peptide, halysin, was purified from Agkistrodon halys (mamushi) snake venom. Halysin is a potent platelet aggregation inhibitor that concentration-dependently inhibited human platelet aggregation stimulated by ADP, thrombin and collagen ( ic 50 = 0.16 to 0.36 μM) without affecting platelet secretion. It was active in inhibiting platelet aggregation of platelet-rich plasma and whole blood. Halysin had no effect on thromboxane B 2 formation of platelets or intracellular Ca 2+ mobilization of Quin 2-AM loaded platelets stimulated by thrombin. It inhibited the Fibrinogen-induced aggregation of elastase-treated platelets. Halysin concentration-dependently inhibited the 125 I-Fibrinogen binding to ADP-stimulated platelets in a competitive manner (IC 50 = 0.16 μM). 125 I-Halysin bound to resting platelets ( K d = 1.6 × 10 −7 M) and to ADP-stimulated platelets ( K d = 3.4 × 10 −8 M) in a saturable manner. EDTA, the Arg-Gly-Asp (RGD)-containing snake venom peptides trigamin and rhodostomin, Arg-Gly-Asp-Ser (RODS), and Gly-Gln-Gln-His-His-Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val blocked both 125 I-Fibrinogen binding and 125 I-halysin binding to ADP-stimulated platelets. The monoclonal antibody, 7E 3 , raised against glycoprotein IIb-IIIa complex blocked both 125 I-Fibrinogen and 125 I-halysin binding, whereas 10E 5 had no significant effect on halysin binding to ADP-stimulated platelets, indicating that 7E 3 and halysin bind to an epitope which is different from that of 10E 5 . RODS concentration-dependently inhibited 125 I-halysin binding in a competitive manner. We determined the primary structure of halysin which is a single peptide chain of 71 amino acid residues. An RGD sequence appeared in the carboxy-terminal domain of halysin. Halysin showed about an 85% identical sequence with trigamin which is a specific Antagonist of Fibrinogen Receptor associated with glycoprotein IIb-IIIa complex. In conclusion, halysin inhibited platelet aggregation by interfering with Fibrinogen binding to the Fibrinogen Receptor of the activated platelets. The RGD sequence of halysin plays an important role in the expression of its biological activity.
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a potent antiplatelet peptide triflavin from trimeresurus flavoviridis snake venom
Biochemical Journal, 1991Co-Authors: Turfu Huang, Jeonrong Sheu, Cheming TengAbstract:The interaction of Fibrinogen with its Receptors on platelet surfaces leads to platelet aggregation. A snake-venom peptide, trigramin, has previously been demonstrated to inhibit platelet aggregation by acting as a Fibrinogen-Receptor Antagonist. By means of gel filtration, ionic-exchange chromatography and reverse-phase h.p.l.c., a potent platelet-aggregation inhibitor, triflavin, has now been purified from the venom of Trimeresurus flavoviridis. The purified triflavin is a single-chain polypeptide, consisting of about 71 amino acid residues with a molecular mass of 7600 Da, and its N-terminal sequence is Gly-Glu-Glu-Cys-Asp. Triflavin dose-dependently inhibited human platelet aggregation stimulated by ADP, adrenaline, collagen, thrombin or prostaglandin endoperoxide analogue U46619 in preparations of platelet-rich plasma, platelet suspension and whole blood. Its IC50 ranged from 38 to 84 nM, depending on the aggregation inducer used and the platelet preparation. However, triflavin apparently did not affect the platelet shape change and ATP-release reactions caused by these agonists. Triflavin inhibited Fibrinogen-induced aggregation of human elastase-treated platelets in a dose-dependent manner, indicating that it directly interferes with the binding of Fibrinogen to its Receptors on platelet membranes exposed by elastase treatment. Additionally, triflavin dose-dependently blocked 125I-labelled Fibrinogen binding to ADP-activated platelets. In conclusion, triflavin inhibits platelet aggregation through the blockade of Fibrinogen binding to Fibrinogen Receptors on platelet membranes.
Thomayant Prueksaritanont - One of the best experts on this subject based on the ideXlab platform.
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analysis of metabolite kinetics by deconvolution and in vivo in vitro correlations of metabolite formation rates studies of Fibrinogen Receptor Antagonist ester prodrugs
Journal of Pharmaceutical Sciences, 1997Co-Authors: Thomayant Prueksaritanont, Lynn M Gorham, Kuang C YehAbstract:The pharmacokinetics of L-767,679, a potent Fibrinogen Receptor Antagonist, were characterized following administration of its ethyl ester prodrug to dogs and monkeys. Deconvolution analysis was performed to determine the rate and extent of (1) the formation of L-767,679 from the prodrug in the systemic circulation, (2) the composite input (systemic and presystemic) of L-767,679 to the general circulation after oral administration of the prodrug, (3) the oral input of the prodrug, and (4) the input of the presystemically formed L-767,679 following oral administration of the prodrug. The results indicated that there were species differences in the kinetics of the disposition of L-767,679 and its prodrug. In dogs, the prodrug was absorbed faster than it was converted to the active drug, and the presystemic formation of L-767,679 contributed to about one-half of the total input of L-767,679 following oral administration of the prodrug. In monkeys, the low input of L-767,679 following oral administration of the prodrug was not due to an inefficient formation of L-767,679 in the systemic circulation but rather to the low oral bioavailability of the prodrug. Virtually all of the total oral input of L-767,679 following administration of its prodrug to monkeys resulted from the presystemic metabolism of the prodrug. These results were consistent with the finding in monkeys that the ester prodrug underwent extensive transformation to metabolites other than L-767,679. In addition, the present study also demonstrated a correlation between in vivo formation rates of L-767,679 determined using deconvolution analysis following its ethyl, methyl, and isopropyl esters in dogs and the ethyl ester in monkeys and in vitro formation rates of L-767,679 obtained following incubations of the corresponding esters with dog and monkey liver microsomes. The results suggested that deconvolution and/or convolution analysis together with in vitro metabolism results could potentially be used to predict in vivo formation rates of other ester prodrugs of L-767,679 and also plasma concentrations of L-767,679 as a function of time, following administration of its prodrugs.
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effects of pentobarbital on pharmacokinetics and pharmacodynamics of a potent Fibrinogen Receptor Antagonist l 734 217 in dogs
Biopharmaceutics & Drug Disposition, 1997Co-Authors: Thomayant Prueksaritanont, E. L. Hand, Joan D Ellis, Marie A Holahan, Maria T Stranieri, G R Sitko, Jacquelynn J. CookAbstract:Effects of pentobarbital on pharmacokinetics and pharmacodynamics of L-734,217, a potent Fibrinogen Receptor Antagonist, were studied in male dogs. L-734,217 was given intravenously at 0.01 mg kg-1, in a cross-over fashion, to conscious dogs or to dogs anesthetized with pentobarbital. Plasma concentrations of L-734,217 were measured using a radioimmunoassay and inhibitory effects on ex vivo platelet aggregation induced by ADP or collagen were determined. In pentobarbital-treated dogs, L-734,217 plasma concentrations during the first 3 h collection period were significantly higher than those in the control animals. Corresponding to the increased plasma levels, the mean ex vivo inhibitory effects on ADP- or collagen-induced platelet aggregation in dogs under anesthesia appeared greater than in those without the anesthetic treatment. Pharmacokinetic analysis revealed a modest, but significant (up to 40%) elevation in the area under the plasma concentration-time curve during 6 h of the drug administration, and a reduction in L-734,217 plasma clearance and volumes of distribution, in the anesthetized dogs. Analysis of pharmacodynamic data indicated that the EC50 and the Hill coefficient of the platelet aggregation response-plasma concentration curve were not altered by pentobarbital treatment. The results are in agreement with the findings that the administration of pentobarbital alone (in the absence of L-734,217) did not affect appreciably the ex vivo platelet aggregatory responses. In a separate group of dogs, L-734,217 was found to be metabolically stable, and was eliminated unchanged renally (64 +/- 4%) and hepatically (32 +/- 6%). In addition, L-734,217 did not bind substantially to canine plasma proteins or blood cellular components. It is possible that alterations of regional hemodynamics, reportedly mediated by pentobarbital, contributed to changes observed in the present study. That is, alterations occurred in L-734,217 elimination and distribution processes which resulted in an increase in drug plasma levels. Since pentobarbital anesthesia influenced only the pharmacokinetics, and not the pharmacodynamics, of L-734,217, the apparent increases in the inhibition of platelet aggregation responses observed following L-734,217 administration to the anesthetized dogs were probably sequential effects of the pharmacokinetic interactions.
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in vitro and in vivo evaluations of the metabolism pharmacokinetics and bioavailability of ester prodrugs of l 767 679 a potent Fibrinogen Receptor Antagonist an approach for the selection of a prodrug candidate
Drug Metabolism and Disposition, 1997Co-Authors: Thomayant Prueksaritanont, George D. Hartman, John H. Hutchinson, Lynn M Gorham, Michael J Breslin, Kamlesh P Vyas, Thomas A BaillieAbstract:The present study demonstrates the utility of an in vitro-in vivo correlative approach in the selection of an optimum prodrug candidate of L-767,679 (N-([7-(piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl]acetyl)-3(S)-(ethynyl)-beta-alanine), a potent Fibrinogen Receptor Antagonist. As an initial screening step, a comparative in vitro hepatic metabolism study was conducted for L-767,679 and a series of aliphatic and aromatic ester prodrugs in dogs, monkeys, and humans. In all species, the active acid L-767,679, but not the ester prodrugs, was resistant to metabolism. Only the methyl, ethyl, and isopropyl esters were converted exclusively to the active acid in liver microsomal preparations from dogs and humans, and thus were selected for further studies. In the preparations from monkeys, all of the esters investigated were metabolized efficiently to both the active acid and several other products. The absolute formation rates of L-767,679 from the esters followed the rank order: methyl approximately ethyl > isopropyl in all species, and in humans > dogs for the three esters. The three ester prodrugs did not undergo appreciable hydrolysis in blood or upon incubation with intestinal S9 from any of the studied species. In vivo evaluation of the previous three aliphatic esters in dogs and monkeys supported the in vitro findings. L-767,679 was metabolically stable in both dogs and monkeys. After intravenous administration of the prodrugs to either species, the extent of acid formation was higher in dogs than in monkeys. In addition, the extent of L-767,679 formed from these prodrugs followed the rank order: methyl approximately ethyl > isopropyl. Similar results were obtained after oral dosing of the prodrugs, such that the bioavailability of L-767,679 was higher in dogs than in monkeys, and the bioavailability was higher after the ethyl ester than after the isopropyl prodrug in both species. In either species, both ethyl and isopropyl ester prodrugs were better absorbed than L-767,679. Overall, the results suggested that the bioavailability of the active acid after administration of an ester prodrug was dictated primarily by two factors, viz.:1) the relative rates of ester hydrolysis versus competing metabolic reactions and 2) the absolute rates of ester hydrolysis. In the case of L-767,679 prodrugs, absorption was not a limiting factor. Consequently, the bioavailability of L-767,679 after oral administration of the ester prodrugs would likely be greater in humans than in dogs, and in humans would be higher with the ethyl ester than with the isopropyl ester. On this basis, the ethyl ester was considered as a promising candidate for clinical evaluation as a Fibrinogen Receptor Antagonist prodrug.
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disposition of l 738 167 a potent and long acting Fibrinogen Receptor Antagonist in dogs dose dependent pharmacokinetics
Drug Metabolism and Disposition, 1997Co-Authors: Thomayant Prueksaritanont, Lynn M Gorham, Jeanne A Naue, Terrence Hamill, Ben Askew, Kamlesh P VyasAbstract:L-738,167 is a potent and long-acting Fibrinogen Receptor Antagonist and may be useful for treatment of chronic thrombotic occlusive disorders. The purposes of this study were to characterize the metabolism and disposition of L-738,167, and to investigate factors affecting its pharmacokinetic behaviors in dogs, one of the animal models used in pharmacological and toxicological studies. In vitro and in vivo experiments indicated that L-738,167 was not metabolized to any appreciable extent in dogs. Biliary excretion was found to be the major route (approximately 75%) of drug elimination. Following 1 and 3 micrograms/kg iv doses, blood pharmacokinetics of L-738,167 were linear. Total blood clearance (CLB) was much lower than hepatic blood flow, and the apparent volume of distribution at steady-state (Vdss,B) was comparable with blood volume. Blood pharmacokinetics in the dose range of 3-250 micrograms/kg were dose-dependent; both CLB and Vdss,B for L-738,167 increased markedly with increasing doses. However, the terminal half-life (t1/2) was dose-independent, with a mean value of approximately 4 days. L-738,167 was found to bind negligibly to dog plasma proteins. Determinations of whole blood (WB), platelet-rich plasma, and platelet-poor plasma concentrations after several intravenous doses of [3H]L-738,167 revealed significant concentration-dependent binding of the compound to platelets. Kinetic analysis of the platelet binding indicated that L-738,167 was bound to dog platelets with high affinity (apparent Kd approximately 1 nM platelet-poor plasma concentration) and relatively low capacity (approximately 70 nM WB concentration). Findings are consistent with the binding kinetics of L-738,167 to glycoprotein IIb/IIIa (GP IIb/IIIa) Receptor, supporting that GP IIb/IIIa was the primary binding component on the platelets. It was concluded that the dose-dependent pharmacokinetics of L-738,167 were the consequence of the concentration-dependent drug-platelet binding. Due to this extensive platelet binding, L-738,167, when given in therapeutic doses or lower, resided primarily in the vascular compartment-the site of pharmacological action. At doses exceeding the Receptor binding capacity, the excess amount or the unbound drug was eliminated rapidly. In all cases, the equally long t1/2 of L-738,167 was also a consequence of the high-affinity binding to platelets, in good agreement with its prolonged pharmacodynamic profile.
E. L. Hand - One of the best experts on this subject based on the ideXlab platform.
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effects of pentobarbital on pharmacokinetics and pharmacodynamics of a potent Fibrinogen Receptor Antagonist l 734 217 in dogs
Biopharmaceutics & Drug Disposition, 1997Co-Authors: Thomayant Prueksaritanont, E. L. Hand, Joan D Ellis, Marie A Holahan, Maria T Stranieri, G R Sitko, Jacquelynn J. CookAbstract:Effects of pentobarbital on pharmacokinetics and pharmacodynamics of L-734,217, a potent Fibrinogen Receptor Antagonist, were studied in male dogs. L-734,217 was given intravenously at 0.01 mg kg-1, in a cross-over fashion, to conscious dogs or to dogs anesthetized with pentobarbital. Plasma concentrations of L-734,217 were measured using a radioimmunoassay and inhibitory effects on ex vivo platelet aggregation induced by ADP or collagen were determined. In pentobarbital-treated dogs, L-734,217 plasma concentrations during the first 3 h collection period were significantly higher than those in the control animals. Corresponding to the increased plasma levels, the mean ex vivo inhibitory effects on ADP- or collagen-induced platelet aggregation in dogs under anesthesia appeared greater than in those without the anesthetic treatment. Pharmacokinetic analysis revealed a modest, but significant (up to 40%) elevation in the area under the plasma concentration-time curve during 6 h of the drug administration, and a reduction in L-734,217 plasma clearance and volumes of distribution, in the anesthetized dogs. Analysis of pharmacodynamic data indicated that the EC50 and the Hill coefficient of the platelet aggregation response-plasma concentration curve were not altered by pentobarbital treatment. The results are in agreement with the findings that the administration of pentobarbital alone (in the absence of L-734,217) did not affect appreciably the ex vivo platelet aggregatory responses. In a separate group of dogs, L-734,217 was found to be metabolically stable, and was eliminated unchanged renally (64 +/- 4%) and hepatically (32 +/- 6%). In addition, L-734,217 did not bind substantially to canine plasma proteins or blood cellular components. It is possible that alterations of regional hemodynamics, reportedly mediated by pentobarbital, contributed to changes observed in the present study. That is, alterations occurred in L-734,217 elimination and distribution processes which resulted in an increase in drug plasma levels. Since pentobarbital anesthesia influenced only the pharmacokinetics, and not the pharmacodynamics, of L-734,217, the apparent increases in the inhibition of platelet aggregation responses observed following L-734,217 administration to the anesthetized dogs were probably sequential effects of the pharmacokinetic interactions.
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use of lc ms ms to cross validate a radioimmunoassay for the Fibrinogen Receptor Antagonist aggrastat tirofiban hydrochloride in human plasma
Journal of Pharmaceutical and Biomedical Analysis, 1997Co-Authors: Joan D Ellis, E. L. Hand, J.d. GilbertAbstract:A method based on LC-MS/MS was developed for the determination of the Fibrinogen-Receptor Antagonist Aggrastat in human plasma. The drug is isolated from plasma by liquid extraction and converted into its N-trifluoroacetyl derivative prior to analysis by HPLC with atmospheric pressure negative chemical ionization MS/MS detection. A structural analog is used as the internal standard and the lower quantifiable limit of the assay is 0.4 ng ml-1 with a relative standard deviation of 7%. This assay was used to cross-validate the existing immunoassay by analysis of plasma from patients receiving the drug. The specificity of the immunoassay was thereby confirmed.
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Determination of MK-383, a non-peptide Fibrinogen Receptor Antagonist, in human plasma and urine by radioimmunoassay.
Journal of pharmaceutical and biomedical analysis, 1994Co-Authors: E. L. Hand, A.s. Yuan, Timothy V. Olah, J.d. Gilbert, M. HichensAbstract:Abstract MK-383 is a novel, non-peptide Fibrinogen Receptor Antagonist. A sensitive and specific radioimmunoassay has been developed for the determination of this drug candidate in plasma and urine. The immunogen was prepared by coupling to albumin via the N-hydroxysuccinimide ester from which the radioligand was also prepared by reaction with [I 125 ]iodotyrosine. The method was specific and no immunoreactive material other than the parent drug was detectable in plasma and urine from dosed volunteers. This direct assay, using 5 μl of plasma or 0.5 μl of urine, is sensitive to 1 and 10 ng ml −1 , respectively, without matrix interference and has sufficient sensitivity, specificity, accuracy, and precision for the analysis of clinical samples.
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Determination of MK-852, a new Fibrinogen Receptor Antagonist, in plasma and urine by radioimmunoassay
Journal of pharmaceutical and biomedical analysis, 1993Co-Authors: A.s. Yuan, E. L. Hand, M. Hichens, Timothy V. Olah, A. Barrish, Carmen Fernandez-metzler, J.d. GilbertAbstract:Abstract MK-852 is a novel Fibrinogen Receptor Antagonist. A sensitive and specific radioimmunoassay has been developed for the determination of this drug candidate in plasma and urine. The immunogen was prepared by coupling to albumin via a dinitrophenylene bridge and the radioligand by reaction of the drug with the 125I-labelled Bolton—Hunter reagent. The method was specific and no immunoreactive material other than parent drug was detectable in plasma from dosed volunteers. The direct assay using 0.05 ml of plasma is sensitive to 0.2 ng ml−1 without matrix interference and has sufficient sensitivity, precision, accuracy, and selectivity for the analysis of clinical samples. The lower quantifiable limit in (diluted) urine is 50 ng ml−1.