The Experts below are selected from a list of 1479 Experts worldwide ranked by ideXlab platform
Ralph R Weichselbaum - One of the best experts on this subject based on the ideXlab platform.
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tnferade biologic Preclinical Toxicology of a novel adenovector with a radiation inducible promoter carrying the human tumor necrosis factor alpha gene
Cancer Gene Therapy, 2002Co-Authors: Henrik S Rasmussen, Camilla S Rasmussen, Maria Lempicki, Rebecca G Durham, Douglas E Brough, Richter C King, Ralph R WeichselbaumAbstract:TNFerade Biologic: Preclinical Toxicology of a novel adenovector with a radiation-inducible promoter, carrying the human tumor necrosis factor alpha gene
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tnferade biologic Preclinical Toxicology of a novel adenovector with a radiation inducible promoter carrying the human tumor necrosis factor alpha gene
Cancer Gene Therapy, 2002Co-Authors: Henrik S Rasmussen, Camilla S Rasmussen, Maria Lempicki, Rebecca G Durham, Douglas E Brough, Richter C King, Ralph R WeichselbaumAbstract:TNFerade Biologic (TNFerade) is a second-generation (E1-, E3-, and E4-deleted) replication-deficient adenovector carrying the transgene encoding for human tumor necrosis factor alpha (TNFalpha), regulated by the radiation-sensitive promoter Early Growth Response (Egr-1). We hypothesized that intratumoral injection of TNFerade followed by radiation would result in potentially therapeutic levels of TNFalpha with minimal toxicity. Three Preclinical studies were conducted, the purpose of which was to characterize the toxicity and pharmacokinetics of TNFerade in conjunction with radiation in nude as well as immune-competent (Balb/c) mice. A total of 80 mice in the nude mouse Toxicology study, all bearing human squamous cell carcinoma xenografts, 120 mice in the Balb/c study, and 33 nude mice in the pharmacokinetic study were used. Doses ranging from 4x10(9) to 4x10(10) particle units (pu) (4x10(11) pu in the Balb/c study) were explored, with and without radiation. In the nude mice studies, TNFerade was injected intratumorally, whereas in the Balb/c study, TNFerade was administered by subcutaneous injection. TNFerade was well tolerated. In the nude mice studies, no significant toxicity occurred in any dose group. In the Balb/c study, 6/40 mice at the top dose (4x10(11) pu) were sacrificed in moribund condition (5/20 in the TNFerade+radiation group, 1/20 in the TNFerade alone group). Necropsy showed local necrosis and ulceration at the site of the injection. No deaths or significant toxicity were observed at the lower dose levels (4x10(9) and 4x10(10) pu), indicating a large safety margin for initial studies in humans. The pharmacokinetic study demonstrated high sustained levels of TNFalpha in the tumor homogenate with no "spillover" to plasma, where TNFalpha levels were below the level of detection. Radiation increased intratumoral levels of TNFalpha by a factor of 12 (from 0.998 to 11.55 ng/g). In conclusion, a gene therapy approach with TNFerade, in combination with radiation, represents a potential way to utilize the potent anticancer activity of TNFalpha without systemic toxicity.
Matthew R Kaller - One of the best experts on this subject based on the ideXlab platform.
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discovery of trpm8 antagonist s 6 3 fluoro 4 trifluoromethoxy phenyl 3 fluoropyridin 2 yl methyl carbamoyl nicotinic acid amg 333 a clinical candidate for the treatment of migraine
Journal of Medicinal Chemistry, 2018Co-Authors: Daniel B Horne, Kaustav Biswas, James Brown, Michael D Bartberger, Jeffrey Clarine, Carl Davis, Vijay Keshav Gore, Scott Harried, Michelle Horner, Matthew R KallerAbstract:Transient-receptor-potential melastatin 8 (TRPM8), the predominant mammalian cold-temperature thermosensor, is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system, including nerve circuitry implicated in migraine pathogenesis: the trigeminal and pterygopalatine ganglia. Genomewide association studies have identified an association between TRPM8 and reduced risk of migraine. This disclosure focuses on medicinal-chemistry efforts to improve the druglike properties of initial leads, particularly removal of CYP3A4-induction liability and improvement of pharmacokinetic properties. A novel series of biarylmethanamide TRPM8 antagonists was developed, and a subset of leads were evaluated in Preclinical Toxicology studies to identify a clinical candidate with an acceptable Preclinical safety profile leading to clinical candidate AMG 333, a potent and highly selective antagonist of TRPM8 that was evaluated in human clinical trials.
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Discovery of TRPM8 Antagonist (S)‑6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic Acid (AMG 333), a Clinical Candidate for the Treatment of Migraine
2018Co-Authors: Daniel B Horne, Kaustav Biswas, James Brown, Michael D Bartberger, Jeffrey Clarine, Vijay Keshav Gore, Scott Harried, Michelle Horner, Carl D. Davis, Matthew R KallerAbstract:Transient-receptor-potential melastatin 8 (TRPM8), the predominant mammalian cold-temperature thermosensor, is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system, including nerve circuitry implicated in migraine pathogenesis: the trigeminal and pterygopalatine ganglia. Genomewide association studies have identified an association between TRPM8 and reduced risk of migraine. This disclosure focuses on medicinal-chemistry efforts to improve the druglike properties of initial leads, particularly removal of CYP3A4-induction liability and improvement of pharmacokinetic properties. A novel series of biarylmethanamide TRPM8 antagonists was developed, and a subset of leads were evaluated in Preclinical Toxicology studies to identify a clinical candidate with an acceptable Preclinical safety profile leading to clinical candidate AMG 333, a potent and highly selective antagonist of TRPM8 that was evaluated in human clinical trials
Henrik S Rasmussen - One of the best experts on this subject based on the ideXlab platform.
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tnferade biologic Preclinical Toxicology of a novel adenovector with a radiation inducible promoter carrying the human tumor necrosis factor alpha gene
Cancer Gene Therapy, 2002Co-Authors: Henrik S Rasmussen, Camilla S Rasmussen, Maria Lempicki, Rebecca G Durham, Douglas E Brough, Richter C King, Ralph R WeichselbaumAbstract:TNFerade Biologic: Preclinical Toxicology of a novel adenovector with a radiation-inducible promoter, carrying the human tumor necrosis factor alpha gene
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tnferade biologic Preclinical Toxicology of a novel adenovector with a radiation inducible promoter carrying the human tumor necrosis factor alpha gene
Cancer Gene Therapy, 2002Co-Authors: Henrik S Rasmussen, Camilla S Rasmussen, Maria Lempicki, Rebecca G Durham, Douglas E Brough, Richter C King, Ralph R WeichselbaumAbstract:TNFerade Biologic (TNFerade) is a second-generation (E1-, E3-, and E4-deleted) replication-deficient adenovector carrying the transgene encoding for human tumor necrosis factor alpha (TNFalpha), regulated by the radiation-sensitive promoter Early Growth Response (Egr-1). We hypothesized that intratumoral injection of TNFerade followed by radiation would result in potentially therapeutic levels of TNFalpha with minimal toxicity. Three Preclinical studies were conducted, the purpose of which was to characterize the toxicity and pharmacokinetics of TNFerade in conjunction with radiation in nude as well as immune-competent (Balb/c) mice. A total of 80 mice in the nude mouse Toxicology study, all bearing human squamous cell carcinoma xenografts, 120 mice in the Balb/c study, and 33 nude mice in the pharmacokinetic study were used. Doses ranging from 4x10(9) to 4x10(10) particle units (pu) (4x10(11) pu in the Balb/c study) were explored, with and without radiation. In the nude mice studies, TNFerade was injected intratumorally, whereas in the Balb/c study, TNFerade was administered by subcutaneous injection. TNFerade was well tolerated. In the nude mice studies, no significant toxicity occurred in any dose group. In the Balb/c study, 6/40 mice at the top dose (4x10(11) pu) were sacrificed in moribund condition (5/20 in the TNFerade+radiation group, 1/20 in the TNFerade alone group). Necropsy showed local necrosis and ulceration at the site of the injection. No deaths or significant toxicity were observed at the lower dose levels (4x10(9) and 4x10(10) pu), indicating a large safety margin for initial studies in humans. The pharmacokinetic study demonstrated high sustained levels of TNFalpha in the tumor homogenate with no "spillover" to plasma, where TNFalpha levels were below the level of detection. Radiation increased intratumoral levels of TNFalpha by a factor of 12 (from 0.998 to 11.55 ng/g). In conclusion, a gene therapy approach with TNFerade, in combination with radiation, represents a potential way to utilize the potent anticancer activity of TNFalpha without systemic toxicity.
Maria Lempicki - One of the best experts on this subject based on the ideXlab platform.
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tnferade biologic Preclinical Toxicology of a novel adenovector with a radiation inducible promoter carrying the human tumor necrosis factor alpha gene
Cancer Gene Therapy, 2002Co-Authors: Henrik S Rasmussen, Camilla S Rasmussen, Maria Lempicki, Rebecca G Durham, Douglas E Brough, Richter C King, Ralph R WeichselbaumAbstract:TNFerade Biologic: Preclinical Toxicology of a novel adenovector with a radiation-inducible promoter, carrying the human tumor necrosis factor alpha gene
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tnferade biologic Preclinical Toxicology of a novel adenovector with a radiation inducible promoter carrying the human tumor necrosis factor alpha gene
Cancer Gene Therapy, 2002Co-Authors: Henrik S Rasmussen, Camilla S Rasmussen, Maria Lempicki, Rebecca G Durham, Douglas E Brough, Richter C King, Ralph R WeichselbaumAbstract:TNFerade Biologic (TNFerade) is a second-generation (E1-, E3-, and E4-deleted) replication-deficient adenovector carrying the transgene encoding for human tumor necrosis factor alpha (TNFalpha), regulated by the radiation-sensitive promoter Early Growth Response (Egr-1). We hypothesized that intratumoral injection of TNFerade followed by radiation would result in potentially therapeutic levels of TNFalpha with minimal toxicity. Three Preclinical studies were conducted, the purpose of which was to characterize the toxicity and pharmacokinetics of TNFerade in conjunction with radiation in nude as well as immune-competent (Balb/c) mice. A total of 80 mice in the nude mouse Toxicology study, all bearing human squamous cell carcinoma xenografts, 120 mice in the Balb/c study, and 33 nude mice in the pharmacokinetic study were used. Doses ranging from 4x10(9) to 4x10(10) particle units (pu) (4x10(11) pu in the Balb/c study) were explored, with and without radiation. In the nude mice studies, TNFerade was injected intratumorally, whereas in the Balb/c study, TNFerade was administered by subcutaneous injection. TNFerade was well tolerated. In the nude mice studies, no significant toxicity occurred in any dose group. In the Balb/c study, 6/40 mice at the top dose (4x10(11) pu) were sacrificed in moribund condition (5/20 in the TNFerade+radiation group, 1/20 in the TNFerade alone group). Necropsy showed local necrosis and ulceration at the site of the injection. No deaths or significant toxicity were observed at the lower dose levels (4x10(9) and 4x10(10) pu), indicating a large safety margin for initial studies in humans. The pharmacokinetic study demonstrated high sustained levels of TNFalpha in the tumor homogenate with no "spillover" to plasma, where TNFalpha levels were below the level of detection. Radiation increased intratumoral levels of TNFalpha by a factor of 12 (from 0.998 to 11.55 ng/g). In conclusion, a gene therapy approach with TNFerade, in combination with radiation, represents a potential way to utilize the potent anticancer activity of TNFalpha without systemic toxicity.
Rebecca G Durham - One of the best experts on this subject based on the ideXlab platform.
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tnferade biologic Preclinical Toxicology of a novel adenovector with a radiation inducible promoter carrying the human tumor necrosis factor alpha gene
Cancer Gene Therapy, 2002Co-Authors: Henrik S Rasmussen, Camilla S Rasmussen, Maria Lempicki, Rebecca G Durham, Douglas E Brough, Richter C King, Ralph R WeichselbaumAbstract:TNFerade Biologic: Preclinical Toxicology of a novel adenovector with a radiation-inducible promoter, carrying the human tumor necrosis factor alpha gene
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tnferade biologic Preclinical Toxicology of a novel adenovector with a radiation inducible promoter carrying the human tumor necrosis factor alpha gene
Cancer Gene Therapy, 2002Co-Authors: Henrik S Rasmussen, Camilla S Rasmussen, Maria Lempicki, Rebecca G Durham, Douglas E Brough, Richter C King, Ralph R WeichselbaumAbstract:TNFerade Biologic (TNFerade) is a second-generation (E1-, E3-, and E4-deleted) replication-deficient adenovector carrying the transgene encoding for human tumor necrosis factor alpha (TNFalpha), regulated by the radiation-sensitive promoter Early Growth Response (Egr-1). We hypothesized that intratumoral injection of TNFerade followed by radiation would result in potentially therapeutic levels of TNFalpha with minimal toxicity. Three Preclinical studies were conducted, the purpose of which was to characterize the toxicity and pharmacokinetics of TNFerade in conjunction with radiation in nude as well as immune-competent (Balb/c) mice. A total of 80 mice in the nude mouse Toxicology study, all bearing human squamous cell carcinoma xenografts, 120 mice in the Balb/c study, and 33 nude mice in the pharmacokinetic study were used. Doses ranging from 4x10(9) to 4x10(10) particle units (pu) (4x10(11) pu in the Balb/c study) were explored, with and without radiation. In the nude mice studies, TNFerade was injected intratumorally, whereas in the Balb/c study, TNFerade was administered by subcutaneous injection. TNFerade was well tolerated. In the nude mice studies, no significant toxicity occurred in any dose group. In the Balb/c study, 6/40 mice at the top dose (4x10(11) pu) were sacrificed in moribund condition (5/20 in the TNFerade+radiation group, 1/20 in the TNFerade alone group). Necropsy showed local necrosis and ulceration at the site of the injection. No deaths or significant toxicity were observed at the lower dose levels (4x10(9) and 4x10(10) pu), indicating a large safety margin for initial studies in humans. The pharmacokinetic study demonstrated high sustained levels of TNFalpha in the tumor homogenate with no "spillover" to plasma, where TNFalpha levels were below the level of detection. Radiation increased intratumoral levels of TNFalpha by a factor of 12 (from 0.998 to 11.55 ng/g). In conclusion, a gene therapy approach with TNFerade, in combination with radiation, represents a potential way to utilize the potent anticancer activity of TNFalpha without systemic toxicity.