The Experts below are selected from a list of 60 Experts worldwide ranked by ideXlab platform
Richard Greil - One of the best experts on this subject based on the ideXlab platform.
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The Cochrane Library - Purine Antagonists for Chronic Lymphocytic Leukaemia
The Cochrane database of systematic reviews, 2006Co-Authors: Michael Steurer, Georg Pall, Sue Richards, Guido Schwarzer, Julia Bohlius, Richard GreilAbstract:BACKGROUND Recent trials suggest improved response rates for Purine Antagonists compared to alkylator-based regimens in the treatment of B-CLL. However, none was able to show a survival advantage. OBJECTIVES To determine if there is any advantage of Purine Antagonists compared to alkylating agents (alone or in combination) in the treatment of patients with previously untreated B-CLL. SEARCH STRATEGY Medical databases (Cochrane Library, MEDLINE, EMBASE), conference proceedings and internet-based trial registers were searched electronically and/or by hand (1990-2003). All references were checked for further trial information. We also contacted experts in the field and pharmaceutical companies. SELECTION CRITERIA Randomised controlled trials comparing Purine Antagonists as single agents with alkylator-based regimens in patients with previously untreated B-CLL were included. We included full-text and abstract publications as well as unpublished data. DATA COLLECTION AND ANALYSIS Data extraction and quality assessment were done in duplicate by two independent reviewers. Missing data were obtained from original authors. Endpoints included overall survival, overall response rate, rate of complete remissions, progression-free survival, treatment-related morbidity and mortality. MAIN RESULTS Five trials with 1838 randomised patients were included. There is some evidence for improved overall survival after treatment with Purine Antagonists compared to alkylators, but statistical significance was not reached (HR 0.89 [95% CI 0.78-1.01], 4 trials, n=1638). However, the relative risk for achieving an overall response (RR 1.22 [95% CI 1.13-1.31], 5 trials, n=1751) and complete remission (RR 1.94 [95% CI 1.65-2.28], 5 trials, n=1751) was significantly higher, resulting in a longer progression-free survival (HR 0.70 [95% CI 0.61-0.82], 4 trials, n=1638). Incidence of grade III/IV infections was significantly higher in patients receiving treatment with Purine Antagonists (RR 1.83 [95% 1.30-2.58], 4 trials, n=1620). There was no significant difference concerning the relative risk for grade III/IV neutropenia (RR 1.14 [95% CI 0.98-1.34], 4 trials, n=1620) and therapy-related mortality (RR 0.94 [95% CI 0.45-1.95]). Overall incidence of hemolytic anemia was low, but significantly increased in the Purine Antagonist group (RR 3.36 [95% CI 1.27-8.91], 3 trials, n=1258). AUTHORS' CONCLUSIONS Despite significantly increased overall response and complete remission rates and longer progression-free survival with first-line treatment of B-CLL patients with single-agent Purine Antagonists, we were not able to detect a statistically significant improvement of overall survival compared to alkylator-based regimens. Furthermore, the use of Purine Antagonists also augments the risk for grade III/IV infections and hemolytic anemia.
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2′,2′‐Difluorodeoxycytidine (Gemcitabine) Induces Apoptosis in Myeloma Cell Lines Resistant to Steroids and 2‐Chlorodeoxyadenosine (2‐CdA)
Stem cells (Dayton Ohio), 1996Co-Authors: Johann Gruber, Francoise Geisen, Roswitha Sgonc, Alexander Egle, Andreas Villunger, Guenther Boeck, Günther Konwalinka, Richard GreilAbstract:The paucity of effective cytotoxic agents for the treatment of steroid resistant multiple myeloma explains the ongoing search for alternative substances for chemotherapy of this disease. In the present study, the Purine Antagonist 2-chlorodeoxyadenosine (2-CdA, cladribine) and the pyrimidine Antagonist 2',2'-difluorodeoxycytidine (gemcitabine) were tested on four myeloma cell lines (i.e., U 266, OPM 2, RPMI 8226, IM 9), one plasma cell leukemia cell line (HS Sultan) and a myeloid control cell line (HL 60), all of which are resistant to 10-6 M dexamethasone. Gemcitabine has been found to be promising in the chemotherapy of other tumors with low proliferative activity, but its effectiveness against myeloma cells has not been analyzed so far. In our tests, gemcitabine induced a significant degree of apoptosis in all cell lines investigated. After incubation for 48 h with 10 microM gemcitabine, the median numbers of apoptotic cells were in the range of 45% in the OPM 2 and 79% in the U 266 cell line. All of the investigated cell lines were responsive to concentrations of 10 microM gemcitabine even after an exposure of only 30 min, three of them (U 266, HS Sultan, IM 9) also responded to a concentration of 10 nM. Higher concentrations and longer exposure times were necessary to suppress the growth of normal hematopoietic bone marrow progenitor cells. In contrast to gemcitabine, standard concentrations of 2-CdA (i.e., 30 and 300 nM) failed to induce a significant degree of apoptosis in the cell lines investigated but inhibited the growth of myeloid progenitor cells. The results suggest that gemcitabine induces apoptosis in myeloma and plasma cell leukemia lines resistant to steroids and 2-CdA. The fact that tumor cell apoptosis was achieved at concentrations clinically achievable and tolerable, which at the same time do not inhibit the growth of normal CFU-GM progenitor cells, favors the initiation of phase I trials with this drug for the treatment of multiple myeloma.
Rangan Maitra - One of the best experts on this subject based on the ideXlab platform.
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Peripherally selective diphenyl Purine Antagonist of the CB1 receptor.
Journal of medicinal chemistry, 2013Co-Authors: Alan Fulp, Katherine Bortoff, Yanan Zhang, Rodney W. Snyder, Timothy R. Fennell, Julie A. Marusich, Jenny L. Wiley, Herbert H. Seltzman, Rangan MaitraAbstract:Antagonists of the CB1 receptor can be useful in the treatment of several important disorders. However, to date, the only clinically approved CB1 receptor Antagonist, rimonabant, was withdrawn because of adverse central nervous system (CNS)-related side effects. Since rimonabant’s withdrawal, several groups are pursuing peripherally selective CB1 Antagonists. These compounds are expected to be devoid of undesirable CNS-related effects but maintain efficacy through antagonism of peripherally expressed CB1 receptors. Reported here are our latest results toward the development of a peripherally selective analog of the diphenyl Purine CB1 Antagonist otenabant 1. Compound 9 (N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}pentanamide) is a potent, orally absorbed Antagonist of the CB1 receptor that is >50-fold selective for CB1 over CB2, highly selective for the periphery in a rodent model, and without efficacy in a series of in vivo assays designed to evaluate its ability to mitigate ...
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Peripherally Selective Diphenyl Purine Antagonist of the CB1 Receptor
2013Co-Authors: Alan Fulp, Katherine Bortoff, Yanan Zhang, Julie A. Marusich, Jenny L. Wiley, Herbert H. Seltzman, Rodney Snyder, Tim Fennell, Rangan MaitraAbstract:Antagonists of the CB1 receptor can be useful in the treatment of several important disorders. However, to date, the only clinically approved CB1 receptor Antagonist, rimonabant, was withdrawn because of adverse central nervous system (CNS)-related side effects. Since rimonabant’s withdrawal, several groups are pursuing peripherally selective CB1 Antagonists. These compounds are expected to be devoid of undesirable CNS-related effects but maintain efficacy through antagonism of peripherally expressed CB1 receptors. Reported here are our latest results toward the development of a peripherally selective analog of the diphenyl Purine CB1 Antagonist otenabant 1. Compound 9 (N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}pentanamide) is a potent, orally absorbed Antagonist of the CB1 receptor that is >50-fold selective for CB1 over CB2, highly selective for the periphery in a rodent model, and without efficacy in a series of in vivo assays designed to evaluate its ability to mitigate the central effects of Δ9-tetrahydrocannabinol through the CB1 receptor
Yanan Zhang - One of the best experts on this subject based on the ideXlab platform.
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Blocking alcoholic steatosis in mice with a peripherally restricted Purine Antagonist of the type 1 cannabinoid receptor
Journal of medicinal chemistry, 2018Co-Authors: George S. Amato, Yanan Zhang, Rodney W. Snyder, Amruta Manke, Danni L. Harris, Robert W. Wiethe, Vineetha Vasukuttan, Timothy W. Lefever, Ricardo A. Cortes, Shaobin WangAbstract:Type 1 cannabinoid receptor (CB1) Antagonists have demonstrated promise for the treatment of obesity, liver disease, metabolic syndrome, and dyslipidemias. However, the inhibition of CB1 receptors in the central nervous system can produce adverse effects, including depression, anxiety, and suicidal ideation. Efforts are now underway to produce peripherally restricted CB1 Antagonists to circumvent CNS-associated undesirable effects. In this study, a series of analogues were explored in which the 4-aminopiperidine group of compound 2 was replaced with aryl- and heteroaryl-substituted piperazine groups both with and without a spacer. This resulted in mildly basic, potent Antagonists of human CB1 (hCB1). The 2-chlorobenzyl piperazine, 25, was found to be potent (Ki = 8 nM); to be >1000-fold selective for hCB1 over hCB2; to have no hERG liability; and to possess favorable ADME properties including high oral absorption and negligible CNS penetration. Compound 25 was tested in a mouse model of alcohol-induced li...
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Peripherally selective diphenyl Purine Antagonist of the CB1 receptor.
Journal of medicinal chemistry, 2013Co-Authors: Alan Fulp, Katherine Bortoff, Yanan Zhang, Rodney W. Snyder, Timothy R. Fennell, Julie A. Marusich, Jenny L. Wiley, Herbert H. Seltzman, Rangan MaitraAbstract:Antagonists of the CB1 receptor can be useful in the treatment of several important disorders. However, to date, the only clinically approved CB1 receptor Antagonist, rimonabant, was withdrawn because of adverse central nervous system (CNS)-related side effects. Since rimonabant’s withdrawal, several groups are pursuing peripherally selective CB1 Antagonists. These compounds are expected to be devoid of undesirable CNS-related effects but maintain efficacy through antagonism of peripherally expressed CB1 receptors. Reported here are our latest results toward the development of a peripherally selective analog of the diphenyl Purine CB1 Antagonist otenabant 1. Compound 9 (N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}pentanamide) is a potent, orally absorbed Antagonist of the CB1 receptor that is >50-fold selective for CB1 over CB2, highly selective for the periphery in a rodent model, and without efficacy in a series of in vivo assays designed to evaluate its ability to mitigate ...
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Peripherally Selective Diphenyl Purine Antagonist of the CB1 Receptor
2013Co-Authors: Alan Fulp, Katherine Bortoff, Yanan Zhang, Julie A. Marusich, Jenny L. Wiley, Herbert H. Seltzman, Rodney Snyder, Tim Fennell, Rangan MaitraAbstract:Antagonists of the CB1 receptor can be useful in the treatment of several important disorders. However, to date, the only clinically approved CB1 receptor Antagonist, rimonabant, was withdrawn because of adverse central nervous system (CNS)-related side effects. Since rimonabant’s withdrawal, several groups are pursuing peripherally selective CB1 Antagonists. These compounds are expected to be devoid of undesirable CNS-related effects but maintain efficacy through antagonism of peripherally expressed CB1 receptors. Reported here are our latest results toward the development of a peripherally selective analog of the diphenyl Purine CB1 Antagonist otenabant 1. Compound 9 (N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}pentanamide) is a potent, orally absorbed Antagonist of the CB1 receptor that is >50-fold selective for CB1 over CB2, highly selective for the periphery in a rodent model, and without efficacy in a series of in vivo assays designed to evaluate its ability to mitigate the central effects of Δ9-tetrahydrocannabinol through the CB1 receptor
Rodney W. Snyder - One of the best experts on this subject based on the ideXlab platform.
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Blocking alcoholic steatosis in mice with a peripherally restricted Purine Antagonist of the type 1 cannabinoid receptor
Journal of medicinal chemistry, 2018Co-Authors: George S. Amato, Yanan Zhang, Rodney W. Snyder, Amruta Manke, Danni L. Harris, Robert W. Wiethe, Vineetha Vasukuttan, Timothy W. Lefever, Ricardo A. Cortes, Shaobin WangAbstract:Type 1 cannabinoid receptor (CB1) Antagonists have demonstrated promise for the treatment of obesity, liver disease, metabolic syndrome, and dyslipidemias. However, the inhibition of CB1 receptors in the central nervous system can produce adverse effects, including depression, anxiety, and suicidal ideation. Efforts are now underway to produce peripherally restricted CB1 Antagonists to circumvent CNS-associated undesirable effects. In this study, a series of analogues were explored in which the 4-aminopiperidine group of compound 2 was replaced with aryl- and heteroaryl-substituted piperazine groups both with and without a spacer. This resulted in mildly basic, potent Antagonists of human CB1 (hCB1). The 2-chlorobenzyl piperazine, 25, was found to be potent (Ki = 8 nM); to be >1000-fold selective for hCB1 over hCB2; to have no hERG liability; and to possess favorable ADME properties including high oral absorption and negligible CNS penetration. Compound 25 was tested in a mouse model of alcohol-induced li...
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Peripherally selective diphenyl Purine Antagonist of the CB1 receptor.
Journal of medicinal chemistry, 2013Co-Authors: Alan Fulp, Katherine Bortoff, Yanan Zhang, Rodney W. Snyder, Timothy R. Fennell, Julie A. Marusich, Jenny L. Wiley, Herbert H. Seltzman, Rangan MaitraAbstract:Antagonists of the CB1 receptor can be useful in the treatment of several important disorders. However, to date, the only clinically approved CB1 receptor Antagonist, rimonabant, was withdrawn because of adverse central nervous system (CNS)-related side effects. Since rimonabant’s withdrawal, several groups are pursuing peripherally selective CB1 Antagonists. These compounds are expected to be devoid of undesirable CNS-related effects but maintain efficacy through antagonism of peripherally expressed CB1 receptors. Reported here are our latest results toward the development of a peripherally selective analog of the diphenyl Purine CB1 Antagonist otenabant 1. Compound 9 (N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}pentanamide) is a potent, orally absorbed Antagonist of the CB1 receptor that is >50-fold selective for CB1 over CB2, highly selective for the periphery in a rodent model, and without efficacy in a series of in vivo assays designed to evaluate its ability to mitigate ...
Alan Fulp - One of the best experts on this subject based on the ideXlab platform.
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Peripherally selective diphenyl Purine Antagonist of the CB1 receptor.
Journal of medicinal chemistry, 2013Co-Authors: Alan Fulp, Katherine Bortoff, Yanan Zhang, Rodney W. Snyder, Timothy R. Fennell, Julie A. Marusich, Jenny L. Wiley, Herbert H. Seltzman, Rangan MaitraAbstract:Antagonists of the CB1 receptor can be useful in the treatment of several important disorders. However, to date, the only clinically approved CB1 receptor Antagonist, rimonabant, was withdrawn because of adverse central nervous system (CNS)-related side effects. Since rimonabant’s withdrawal, several groups are pursuing peripherally selective CB1 Antagonists. These compounds are expected to be devoid of undesirable CNS-related effects but maintain efficacy through antagonism of peripherally expressed CB1 receptors. Reported here are our latest results toward the development of a peripherally selective analog of the diphenyl Purine CB1 Antagonist otenabant 1. Compound 9 (N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}pentanamide) is a potent, orally absorbed Antagonist of the CB1 receptor that is >50-fold selective for CB1 over CB2, highly selective for the periphery in a rodent model, and without efficacy in a series of in vivo assays designed to evaluate its ability to mitigate ...
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Peripherally Selective Diphenyl Purine Antagonist of the CB1 Receptor
2013Co-Authors: Alan Fulp, Katherine Bortoff, Yanan Zhang, Julie A. Marusich, Jenny L. Wiley, Herbert H. Seltzman, Rodney Snyder, Tim Fennell, Rangan MaitraAbstract:Antagonists of the CB1 receptor can be useful in the treatment of several important disorders. However, to date, the only clinically approved CB1 receptor Antagonist, rimonabant, was withdrawn because of adverse central nervous system (CNS)-related side effects. Since rimonabant’s withdrawal, several groups are pursuing peripherally selective CB1 Antagonists. These compounds are expected to be devoid of undesirable CNS-related effects but maintain efficacy through antagonism of peripherally expressed CB1 receptors. Reported here are our latest results toward the development of a peripherally selective analog of the diphenyl Purine CB1 Antagonist otenabant 1. Compound 9 (N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}pentanamide) is a potent, orally absorbed Antagonist of the CB1 receptor that is >50-fold selective for CB1 over CB2, highly selective for the periphery in a rodent model, and without efficacy in a series of in vivo assays designed to evaluate its ability to mitigate the central effects of Δ9-tetrahydrocannabinol through the CB1 receptor
