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N A Minton - One of the best experts on this subject based on the ideXlab platform.
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volunteer models for predicting antiemetic activity of 5 ht3 Receptor Antagonists
British Journal of Clinical Pharmacology, 1994Co-Authors: N A MintonAbstract:Abstract 1. Selective 5-HT3-Receptor Antagonists are highly effective in preventing nausea and vomiting associated with chemotherapy, radiotherapy and surgery. Their pharmacological activity may be determined in vitro and in animal models of emesis. However, these methods may not give an accurate indication of the antiemetic dose range of 5-HT3-Receptor Antagonists in patients. Two volunteer models have been used to predict more accurately clinically effective antiemetic doses of 5-HT3-Receptor Antagonists. 2. The flare response to intradermal 5-HT is thought to be mediated by excitation of 5-HT3-Receptors on cutaneous afferents, with release of substance P and subsequent vasodilation. Antagonism of the flare response appears to provide an indication of the effective antiemetic dose of 5-HT3-Receptor Antagonists but data on duration of action are conflicting. 3. Ipecacuanha-induced emesis is thought to be mediated through both peripheral and central 5-HT3-Receptors. Antagonism of this response has demonstrated a close correlation with clinically effective antiemetic doses of the specific 5-HT3-Receptor antagonist, ondansetron, and has the advantage of being more conceptually relevant than the flare model. 4. Further work, with newer 5-HT3-Receptor Antagonists, will clarify the role of these models as predictive of the use of these drugs in clinical practice.
Holger Stark - One of the best experts on this subject based on the ideXlab platform.
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histamine h3 Receptor Antagonists inverse agonists where do they go
Pharmacology & Therapeutics, 2019Co-Authors: Nakisa Ghamari, Holger Stark, Omid Zarei, Joseantonio Ariasmontano, David Reiner, Siavoush Dastmalchi, Maryam HamzehmivehroudAbstract:Since the discovery of the histamine H3 Receptor in 1983, tremendous advances in the pharmacological aspects of H3 Receptor Antagonists/inverse agonists have been accomplished in preclinical studies. At present, there are several drug candidates that reached clinical trial studies for various indications. However, entrance of these candidates to the pharmaceutical market is not free from challenges, and a variety of difficulties is engaged with their developmental process. In this review, the potential role of H3 Receptors in the pathophysiology of various central nervous system, metabolic and allergic diseases is discussed. Thereafter, the current status for H3 Receptor Antagonists/inverse agonists in ongoing clinical trial studies is reviewed and obstacles in developing these agents are emphasized.
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Multiple Targeting Approaches on Histamine H3 Receptor Antagonists
Frontiers in Neuroscience, 2016Co-Authors: Mohammad A. Khanfar, Anna Affini, Kiril Lutsenko, Katarina Nikolic, Stefania Butini, Holger StarkAbstract:With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 Receptor Antagonists has clearly increased. Since histamine H3 Receptor Antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 Receptor Antagonists on different G-protein coupled Receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.
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Histamine H3 Receptor Antagonists Go to Clinics
Biological & Pharmaceutical Bulletin, 2008Co-Authors: Kerstin Sander, Tim Kottke, Holger StarkAbstract:Within the recent years novel lead optimisations for histamine H3 Receptor Antagonists made their way from bench to bedside. Structure–activity relationships, cross-affinities and side effects as well as pharmacokinetic profiling will be discussed on selected promising compound series. Due to diversity in potential therapeutic applications and in some cases a controversial debate, different indications will be highlighted with the potential and the problems of the test compounds, e.g. sleep-wake disorders, attention-deficient hyperactivity disorder, epilepsy, cognitive impairment, schizophrenia, obesity and neuropathic pain. First data published on clinical trials phase II (IIb) are presented showing proof of concept of H3 Receptor Antagonists in narcolepsy and photo-induced epilepsy.
Christof Schaefer - One of the best experts on this subject based on the ideXlab platform.
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angiotensin ii Receptor Antagonists further evidence of fetotoxicity but not teratogenicity
Birth Defects Research Part A-clinical and Molecular Teratology, 2003Co-Authors: Christof SchaeferAbstract:BACKGROUND: Like angiotensin converting enzyme (ACE) inhibitors angiotensin II (AT II)-Receptor-Antagonists may cause persistent or even lethal fetotoxic defects when used during the late second or third trimester. There are insufficient data on first-trimester exposure to these substances in terms of teratogenicity. The two databases of the Berlin Teratology Information Service (TIS) were evaluated for pregnancy outcome following exposure to AT II-Receptor-Antagonists. One database covers case reports on newborns with congenital abnormalities identified after birth, in which drug-effect associations can be evaluated retrospectively. The other enrolls women prospectively according to exposure to particular drugs during pregnancy, with follow-up of pregnancy outcome. CASES: Five cases (four retrospective and one prospective) involving late-pregnancy use of AT II-Receptor-Antagonists were recently reported to us, each of which included one or more of the following abnormalities: oligohydramnios/anhydramnios, anuria, hypoplastic skull bones, limb contractions, lung hypoplasia, and neonatal death. Among 37 prospectively enrolled first-trimester-exposed pregnancies there were 30 live births including one with a major malformation (cleft palate). One pregnancy was electively terminated after exencephaly had been diagnosed. CONCLUSIONS: AT II-Receptor-Antagonists may induce fetotoxic effects when used in the second and third trimesters. The available data on first-trimester use do not strongly support a teratogenic potential. AT II-Receptor-Antagonists should not be used by pregnant women. In case of inadvertent exposure, therapy should be changed to the known antihypertensives of choice (e.g., metoprolol, methyldopa, and hydralazine) and fetotoxic effects should be ruled out by ultrasound. Treatment with AT II-Receptor-Antagonists during early pregnancy is not in itself an indication for termination of a wanted pregnancy.
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angiotensin ii Receptor Antagonists further evidence of fetotoxicity but not teratogenicity
Birth Defects Research Part A-clinical and Molecular Teratology, 2003Co-Authors: Christof SchaeferAbstract:BACKGROUND: Like angiotensin converting enzyme (ACE) inhibitors angiotensin II (AT II)-Receptor-Antagonists may cause persistent or even lethal fetotoxic defects when used during the late second or third trimester. There are insufficient data on first-trimester exposure to these substances in terms of teratogenicity. The two databases of the Berlin Teratology Information Service (TIS) were evaluated for pregnancy outcome following exposure to AT II-Receptor-Antagonists. One database covers case reports on newborns with congenital abnormalities identified after birth, in which drug-effect associations can be evaluated retrospectively. The other enrolls women prospectively according to exposure to particular drugs during pregnancy, with follow-up of pregnancy outcome. CASES: Five cases (four retrospective and one prospective) involving late-pregnancy use of AT II-Receptor-Antagonists were recently reported to us, each of which included one or more of the following abnormalities: oligohydramnios/anhydramnios, anuria, hypoplastic skull bones, limb contractions, lung hypoplasia, and neonatal death. Among 37 prospectively enrolled first-trimester-exposed pregnancies there were 30 live births including one with a major malformation (cleft palate). One pregnancy was electively terminated after exencephaly had been diagnosed. CONCLUSIONS: AT II-Receptor-Antagonists may induce fetotoxic effects when used in the second and third trimesters. The available data on first-trimester use do not strongly support a teratogenic potential. AT II-Receptor-Antagonists should not be used by pregnant women. In case of inadvertent exposure, therapy should be changed to the known antihypertensives of choice (e.g., metoprolol, methyldopa, and hydralazine) and fetotoxic effects should be ruled out by ultrasound. Treatment with AT II-Receptor-Antagonists during early pregnancy is not in itself an indication for termination of a wanted pregnancy.
Michael P. Curtis - One of the best experts on this subject based on the ideXlab platform.
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Tricyclic aminopyrimidine histamine H4 Receptor Antagonists.
Bioorganic & medicinal chemistry letters, 2011Co-Authors: Savall Brad M, Laurent Gomez, Frank Chavez, Michael P. Curtis, Meduna Steven P, Kearney Aaron M, Paul J. Dunford, Jeffery M. Cowden, Robin L. Thurmond, Cheryl A. GriceAbstract:This report discloses the development of a series of tricyclic histamine H4 Receptor Antagonists. Starting with a low nanomolar benzofuranopyrimidine HTS hit devoid of pharmaceutically acceptable properties, we navigated issues with metabolism and solubility to furnish a potent, stable and water soluble tricyclic histamine H4 Receptor antagonist with desirable physiochemical parameters which demonstrated efficacy a mouse ova model.
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structure activity relationships of arylbenzofuran h3 Receptor Antagonists
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Gregory A. Gfesser, Timothy A Esbenshade, Michael P. Curtis, Ramin Faghih, Youssef L Bennani, Arthur A Hancock, Marlon D CowartAbstract:An SAR study of histamine H3 Receptor Antagonists based on substituted (R)-2-methyl-1-[2-(5-phenyl-benzofuran-2-yl)-ethyl]-pyrrolidines is presented.
Stephen E Ullrich - One of the best experts on this subject based on the ideXlab platform.
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inhibition of photocarcinogenesis by platelet activating factor or serotonin Receptor Antagonists
Cancer Research, 2008Co-Authors: Coimbatore S Sreevidya, Noor M Khaskhely, Atsushi Fukunaga, Polina Khaskina, Stephen E UllrichAbstract:The UV radiation in sunlight is the primary cause of nonmelanoma skin cancer. Moreover, UV exposure induces immune suppression. Early steps in the cascade of events leading to immune suppression are the binding of UV-induced platelet-activating factor (PAF) to its Receptor and the binding of cis -urocanic acid, a photoReceptor for UVB radiation, to the serotonin (5-HT 2A ) Receptor. Here, we tested the hypothesis that blocking the binding of PAF and 5-HT 2A to their Receptors would also block skin cancer induction. Hairless mice were injected with PAF or serotonin Receptor Antagonists and then exposed to solar-simulated UV radiation. We noted a significant and substantial decrease in skin cancer incidence in mice treated with the PAF or 5-HT 2A Receptor Antagonists. Also, the PAF and/or serotonin Receptor Antagonists blocked skin cancer progression. The PAF and serotonin Receptor Antagonists worked in a synergistic fashion to block skin cancer induction. We also measured the effect that injecting PAF and 5-HT 2A Receptor Antagonists had on UV-induced skin damage after a single UV exposure. We noted a significant decrease in UV-induced hypertrophy, sunburn cell formation, and apoptosis when the mice were injected with PAF and/or 5-HT 2A Receptor Antagonists. These data indicate that treating UV-irradiated mice with PAF and 5-HT 2A Receptor Antagonists blocks skin cancer induction in vivo , in part by reversing UV-induced damage to the skin and by preventing the induction of immune suppression. [Cancer Res 2008;68(10):3978–84]
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inhibition of photocarcinogenesis by platelet activating factor or serotonin Receptor Antagonists
Cancer Research, 2008Co-Authors: Coimbatore S Sreevidya, Noor M Khaskhely, Atsushi Fukunaga, Polina Khaskina, Stephen E UllrichAbstract:The UV radiation in sunlight is the primary cause of nonmelanoma skin cancer. Moreover, UV exposure induces immune suppression. Early steps in the cascade of events leading to immune suppression are the binding of UV-induced platelet-activating factor (PAF) to its Receptor and the binding of cis-urocanic acid, a photoReceptor for UVB radiation, to the serotonin (5-HT(2A)) Receptor. Here, we tested the hypothesis that blocking the binding of PAF and 5-HT(2A) to their Receptors would also block skin cancer induction. Hairless mice were injected with PAF or serotonin Receptor Antagonists and then exposed to solar-simulated UV radiation. We noted a significant and substantial decrease in skin cancer incidence in mice treated with the PAF or 5-HT(2A) Receptor Antagonists. Also, the PAF and/or serotonin Receptor Antagonists blocked skin cancer progression. The PAF and serotonin Receptor Antagonists worked in a synergistic fashion to block skin cancer induction. We also measured the effect that injecting PAF and 5-HT(2A) Receptor Antagonists had on UV-induced skin damage after a single UV exposure. We noted a significant decrease in UV-induced hypertrophy, sunburn cell formation, and apoptosis when the mice were injected with PAF and/or 5-HT(2A) Receptor Antagonists. These data indicate that treating UV-irradiated mice with PAF and 5-HT(2A) Receptor Antagonists blocks skin cancer induction in vivo, in part by reversing UV-induced damage to the skin and by preventing the induction of immune suppression.
