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Peter J. Goadsby - One of the best experts on this subject based on the ideXlab platform.
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Rimegepant, an Oral Calcitonin Gene–Related Peptide Receptor Antagonist, for Migraine
The New England Journal of Medicine, 2019Co-Authors: Richard B Lipton, Robert Croop, E Stock, David A Stock, Beth A Morris, Marianne Frost, Gene M Dubowchik, Charles M Conway, Vladimir Coric, Peter J. GoadsbyAbstract:Abstract Background Calcitonin gene–related Peptide Receptor has been implicated in the pathogenesis of migraine. Rimegepant is an orally administered, small-molecule, calcitonin gene–related pepti...
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rimegepant an oral calcitonin gene related Peptide Receptor antagonist for migraine
The New England Journal of Medicine, 2019Co-Authors: Richard B Lipton, Robert Croop, E Stock, David A Stock, Beth A Morris, Marianne Frost, Gene M Dubowchik, Charles M Conway, Vladimir Coric, Peter J. GoadsbyAbstract:Abstract Background Calcitonin gene–related Peptide Receptor has been implicated in the pathogenesis of migraine. Rimegepant is an orally administered, small-molecule, calcitonin gene–related pepti...
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Modulation of nocioceptive transmission with calcitonin gene-related Peptide Receptor antagonists in the thalamus
Brain, 2010Co-Authors: O. Summ, Annabelle R. Charbit, Anna P. Andreou, Peter J. GoadsbyAbstract:Calcitonin gene-related Peptide Receptor antagonists are effective acute migraine treatments without the vascular contraindications associated with triptans. While it has been demonstrated that calcitonin gene-related Peptide Receptor antagonists act in the central nervous system, their effects in preclinical migraine models have been investigated in only the trigeminocervical complex. Migraine is a complex neurological disorder; sites in the brainstem and forebrain are clearly involved in its expression. We have performed electrophysiological recordings in thalamic neurons of rats responding to nocioceptive trigeminovascular inputs and tested the effect of olcegepant, a calcitonin gene-related Peptide Receptor antagonist (1 mg/kg, intravenously), on cell firing. We further tested the effect of microiontophoresed calcitonin gene-related Peptide and the Receptor antagonists calcitonin gene-related Peptide 8-37 and olcegepant on thalamic cell firing, elicited by stimulation of the superior sagittal sinus or by microiontophoretic application of L -glutamate. Additionally, we used immunofluorescent staining to demonstrate the presence of functional calcitonin gene-related Peptide Receptors in the ventroposteromedial thalamic nucleus by specifically co-staining for the calcitonin gene-related Peptide Receptor subunits calcitonin Receptor-like Receptor and Receptor activity modifying protein 1. Intravenously administered olcegepant significantly inhibited cell firing evoked by stimulation of the superior sagittal sinus as well as the background activity. Microiontophoresis of calcitonin gene-related Peptide 8-37 also showed a significant inhibition of L -glutamate-evoked cell firing and firing evoked by stimulation of the superior sagittal sinus. Immunofluorescent staining confirmed the presence of the components of a functional calcitonin gene-related Peptide Receptor, the calcitonin Receptor-like Receptor and the Receptor activity modifying protein 1, within the area of the ventroposteromedial thalamic nucleus. This is the first report on the efficacy of calcitonin gene-related Peptide Receptor antagonists at the level of third-order neurons in the migraine pathway, showing that the central effects of calcitonin gene-related Peptide Receptor antagonists extend beyond the trigeminocervical complex at least to the sensory thalamus.
Lisa Bodei - One of the best experts on this subject based on the ideXlab platform.
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Peptide Receptor therapies in neuroendocrine tumors
Journal of Endocrinological Investigation, 2020Co-Authors: Lisa Bodei, Chiara Grana, Marta Cremonesi, Diego Ferone, Alberto Signore, Rudi Dierckx, Giovanni PaganelliAbstract:Neuroendocrine tumors (NETs) are relatively rare tumors, mainly originating from the digestive system, able to produce bioactive amines and hormones. NETs tend to be slow growing and are often diagnosed when metastatic. The localization of a NETs and the assessment of the extent of disease are crucial for management. Commonly used diagnostic techniques include morphological imaging (ultrasound, computerized tomography, magnetic resonance), and functional imaging (somatostatin Receptor scintigraphy, positron emission tomography techniques). Treatment is multidisciplinary and should be individualized according to the tumor type, burden, and symptoms. Therapeutic tools include surgery, interventional radiology, and medical treatments such as somatostatin analogues, interferon, chemotherapy, new targeted drugs and Peptide Receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues. NETs usually over-express somatostatin Receptors, thus enabling the therapeutic use of somatostatin analogues, one of the basic tools, able to reduce signs and symptoms of hormone hypersecretion, improve quality of life, and slow tumor growth. PRRT with somatostatin analogues 90Y-DOTATOC and 177Lu-DOTATATE has been explored in NETs for more than a decade. Present knowledge and clinical studies indicate that it is possible to deliver high-absorbed doses to tumors expressing sst2 Receptors, with partial and complete objective responses in up to 30% of patients. Side effects, involving the kidney and the bone marrow, are mild if adequate renal protection is used. Moreover, a consistent survival benefit is reported. As NETs may also express cholecystokinin 2, bombesin, neuroPeptide Y or vasoactive intestinal Peptide Receptors even simultaneously, the potential availability and biological stability of radio-analogues will improve the multiReceptor targeting of NETs.
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Peptide Receptor Radionuclide Therapy of Neuroendocrine Tumors
Frontiers of Hormone Research, 2015Co-Authors: Lisa Bodei, Mark Kidd, Vikas Prasad, Irvin M. ModlinAbstract:Peptide Receptor radionuclide therapy (PRRT) has been a well-accepted and effective therapeutic modality for inoperable or metastatic gastroenteropancreatic, bronchopulmonary and other neuroendocrine
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the joint iaea eanm and snmmi practical guidance on Peptide Receptor radionuclide therapy prrnt in neuroendocrine tumours
European Journal of Nuclear Medicine and Molecular Imaging, 2013Co-Authors: John J Zaknun, Dieter Horsch, Lisa Bodei, Jan Muellerbrand, Marianne Pavel, R P Baum, M Odorisio, T M Odorisiol, James R Howe, Marta CremonesiAbstract:Peptide Receptor radionuclide therapy (PRRNT) is a molecularly targeted radiation therapy involving the systemic administration of a radiolabelled Peptide designed to target with high affinity and specificity Receptors overexpressed on tumours. PRRNT employing the radiotagged somatostatin Receptor agonists 90Y-DOTATOC ([90Y-DOTA0,Tyr3]-octreotide) or 177Lu-DOTATATE ([177Lu-DOTA0,Tyr3,Thr8]-octreotide or [177Lu-DOTA0,Tyr3]-octreotate) have been successfully used for the past 15 years to target metastatic or inoperable neuroendocrine tumours expressing the somatostatin Receptor subtype 2. Accumulated evidence from clinical experience indicates that these tumours can be subjected to a high absorbed dose which leads to partial or complete objective responses in up to 30 % of treated patients. Survival analyses indicate that patients presenting with high tumour Receptor expression at study entry and receiving 177Lu-DOTATATE or 90Y-DOTATOC treatment show significantly higher objective responses, leading to longer survival and improved quality of life. Side effects of PRRNT are typically seen in the kidneys and bone marrow. These, however, are usually mild provided adequate protective measures are undertaken. Despite the large body of evidence regarding efficacy and clinical safety, PRRNT is still considered an investigational treatment and its implementation must comply with national legislation, and ethical guidelines concerning human therapeutic investigations. This guidance was formulated based on recent literature and leading experts’ opinions. It covers the rationale, indications and contraindications for PRRNT, assessment of treatment response and patient follow-up. This document is aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRNT and to deliver the treatment in a safe and effective manner. This document is largely based on the book published through a joint international effort under the auspices of the Nuclear Medicine Section of the International Atomic Energy Agency.
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Peptide Receptor radionuclide therapy with 177lu dotatate the ieo phase i ii study
European Journal of Nuclear Medicine and Molecular Imaging, 2011Co-Authors: Lisa Bodei, Mirco Bartolomei, Chiara Grana, Nicola Fazio, Marta Cremonesi, Simona Iodice, Silvia M Baio, Dario Lombardo, Mahila Ferrari, Maddalena SansoviniAbstract:Purpose Peptide Receptor radionuclide therapy (PRRT) is used in tumours expressing type 2 somatostatin Receptors (sst2), mainly neuroendocrine. The aim of this prospective phase I-II study was to evaluate the toxicity and efficacy of 177Lu-DOTATATE in multiple cycles.
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long term evaluation of renal toxicity after Peptide Receptor radionuclide therapy with 90y dotatoc and 177lu dotatate the role of associated risk factors
European Journal of Nuclear Medicine and Molecular Imaging, 2008Co-Authors: Lisa Bodei, Mirco Bartolomei, Chiara Grana, Marta Cremonesi, Silvia M Baio, Mahila Ferrari, Maddalena Sansovini, Monica Pacifici, Giovanni PaganelliAbstract:Purpose Peptide Receptor radionuclide therapy (PRRT) of neuroendocrine tumours with 90Y-DOTATOC and 177Lu-DOTATATE is promising. The kidney is the critical organ and despite renal protection, function loss may become evident years later. The aim of this study was to analyse renal parameters in patients who had undergone dosimetry before PRRT.
Dik J. Kwekkeboom - One of the best experts on this subject based on the ideXlab platform.
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Peptide Receptor Radionuclide Therapy in the Treatment of Neuroendocrine Tumors
Hematology-oncology Clinics of North America, 2016Co-Authors: Dik J. Kwekkeboom, Eric P. KrenningAbstract:Peptide Receptor radionuclide therapy (PRRT) is a promising new treatment modality for inoperable or metastasized gastroenteropancreatic neuroendocrine tumors patients. Most studies report objective response rates in 15% to 35% of patients. Progression-free (PFS) and overall survival (OS) compare favorably with that for somatostatin analogues, chemotherapy, or newer, "targeted" therapies. Prospective, randomized data regarding the potential PFS and OS benefit of PRRT compared with standard therapies is anticipated.
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Peptide Receptor radionuclide therapy in patients with gastroenteropancreatic neuroendocrine tumors
Seminars in Nuclear Medicine, 2010Co-Authors: Dik J. Kwekkeboom, Martijn Van Essen, Wouter W De Herder, Casper H J Van Eijck, Jaap J M Teunissen, Eric P. KrenningAbstract:Somatostatin Receptor imaging with [ 111 In-DTPA 0 )octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic neuroendocrine tumors. Treatment with radiolabeled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized, well-differentiated neuroendocrine tumors. Symptomatic improvement may occur with all 111 In, 90 Y, or 177 Lu-labeled somatostatin analogues that have been used for Peptide Receptor radionuclide therapy. The results that were obtained with [ 90 Y-DOTA 0 , Tyr 3 ]octreotide and [ 177 Lu-DOTA 0 , Tyr 3 ]octreotate are very encouraging in terms of tumor regression. Also, if kidney protective agents are used, the side effects of this therapy are few and mild, and the median duration of the therapy response for these radiopharmaceuticals is 30 and 40 months, respectively. The patients' self-assessed quality of life increases significantly after treatment with [ 177 Lu-DOTA 0 , Tyr 3 ]octreotate. Finally, compared with historical controls, there is a benefit in overall survival of several years from time of diagnosis in patients treated with [ 177 Lu-DOTA 0 , Tyr 3 ]octreotate. These data compare favorably with the limited number of alternative treatment approaches. If more widespread use of Peptide Receptor radionuclide therapy can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable gastroenteropancreatic neuroendocrine tumors.
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enets consensus guidelines for the standards of care in neuroendocrine tumors Peptide Receptor radionuclide therapy with radiolabeled somatostatin analogs
Neuroendocrinology, 2009Co-Authors: Dik J. Kwekkeboom, Eric P. Krenning, Wouter W De Herder, Rachida Lebtahi, Paul Komminoth, Beata Koskudla, Ursula PlockingerAbstract:The purpose of this guideline is to assist physicians caring for patients with neuroendocrine tumors in considering eligibility criteria for Peptide Receptor radionuclide therapy (PRRT), and in defining the minimum requirements for PRRT. This guideline also makes recommendations on what minimal patient, tumor, and treatment outcome characteristics should be reported for PRRT in order to make comparisons between studies possible. It is not this guideline's aim to give specific recommendations on the use of specific radiolabeled somatostatin analogs for PRRT because different analogs are being used, and their availability depends on national law and local permissions.
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Peptide-Receptor radionuclide therapy for endocrine tumors
Nature Reviews Endocrinology, 2009Co-Authors: Martijn Van Essen, Eric P. Krenning, Marion De Jong, Roelf Valkema, Dik J. KwekkeboomAbstract:Peptide-Receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs, such as octreotide, is a promising option for the treatment of somatostatin-Receptor-positive endocrine tumors. Here, van Essen et al. evaluate data from preliminary studies of PRRT, and discuss the pros and cons of this approach. The authors propose that PRRT might soon become the treatment of choice for patients with metastatic or inoperable endocrine tumors.
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overview of results of Peptide Receptor radionuclide therapy with 3 radiolabeled somatostatin analogs
The Journal of Nuclear Medicine, 2005Co-Authors: Dik J. Kwekkeboom, Lisa Bodei, Roelf Valkema, Giovanni Paganelli, Jan Muellerbrand, Lowell Anthony, Stanislas Pauwels, Larry K Kvols, Thomas M Odorisio, Marco ChinolAbstract:A new treatment modality for inoperable or metastasized gastroenteropancreatic tumors is the use of radiolabeled somatostatin analogs. Initial studies with high doses of [(111)In-diethylenetriaminepentaacetic acid (DTPA)(0)]octreotide in patients with metastasized neuroendocrine tumors were encouraging, although partial remissions were uncommon. Another radiolabeled somatostatin analog that is used for Peptide Receptor radionuclide therapy (PRRT) is [(90)Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)(0),Tyr(3)]octreotide. Various phase 1 and phase 2 PRRT trials have been performed with this compound. Despite differences in the protocols used, complete and partial remissions in most of the studies with [(90)Y-DOTA(0),Tyr(3)]octreotide were in the same ranges, 10%-30%; these ranges were higher than those obtained with [(111)In-DTPA(0)]octreotide. Treatment with the newest radiolabeled somatostatin analog, [(177)Lu-DOTA(0),Tyr(3)]octreotate, which has a higher affinity for the subtype 2 somatostatin Receptor, resulted in complete or partial remissions in 30% of 76 patients. Tumor regression was positively correlated with a high level of uptake on OctreoScan imaging, a limited hepatic tumor mass, and a high Karnofsky performance score. Treatment with radiolabeled somatostatin analogs is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumors. Symptomatic improvement may occur with all (111)In-, (90)Y-, or (177)Lu-labeled somatostatin analogs that have been used for PRRT. The results obtained with [(90)Y-DOTA(0),Tyr(3)]octreotide and [(177)Lu-DOTA(0),Tyr(3)]octreotate are very encouraging in terms of tumor regression. Also, if kidney protective agents are used, the side effects of this therapy are few and mild, and the duration of the therapy response for both radiopharmaceuticals is more than 2 y. These data compare favorably with those for the limited number of alternative treatment approaches.
Franco O Ranelletti - One of the best experts on this subject based on the ideXlab platform.
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parathyroid hormone related Peptide hpthrp and parathyroid hormone related Peptide Receptor type 1 pthr1 expression in human thymus
Journal of Histochemistry and Cytochemistry, 2005Co-Authors: Marco Gessi, Giovanni Monego, Libero Lauriola, Nicola Maggiano, Franco O RanellettiAbstract:Parathyroid hormone-related Peptide (hPTHrP) is expressed in human tissues and regulates cellular proliferation, differentiation, and apoptosis by an autocrine/paracrine loop. In rodent thymus, both parathormone and parathyroid hormone-related Peptide (PTHrP) are expressed by thymic epithelial cells (TECs). The present study demonstrated by RT-PCR and immunohistochemistry that hPTHrP and parathyroid hormone-related Peptide Receptor type 1 (PTHR1) were expressed in human thymus at both RNA and protein levels. hPTHrP was expressed mainly in the thymic medulla by epithelial (cytokeratin-positive), mature dendritic (CD40+/86+) and plasmacytoid interleukin (IL)-3Rα+ cells. This protein was also present in some cells forming Hassall's bodies and a few subcapsular and cortical TECs. PTHR1 was expressed by scattered subcapsular and cortical TECs and by rare TECs in the medulla. Thymocytes did not express either hPTHrP or PTHR1. Primary cultures of human TECs revealed the presence of both hPTHrP and PTHR1 mRNAs, c...
Richard D Ye - One of the best experts on this subject based on the ideXlab platform.
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serum amyloid a1 isoforms display different efficacy at toll like Receptor 2 and formyl Peptide Receptor 2
Immunobiology, 2014Co-Authors: Mingjie Chen, Richard D Ye, Huibing Zhou, Ni Cheng, Feng QianAbstract:Serum amyloid A (SAA) is a major acute-phase protein and a precursor of amyloid A, the deposit of which leads to amyloidosis. Different alleles exist in SAA1, a predominant form of the human SAA gene family. Emerging evidence has shown correlations between these alleles and diseases including familiar Mediterranean fever and amyloidosis. However, it remains unclear how the proteins encoded by these SAA1 alleles act differently. Here we report the characterization of proteins encoded by SAA1.1, SAA1.3, and SAA1.5, in comparison to that encoded by SAA2.2, for their preference of the SAA Receptors including formyl Peptide Receptor 2 (FPR2) and Toll-like Receptor 2 (TLR2). SAA1.1 was more efficacious than SAA1.3 and SAA1.5 but equally efficacious to SAA2.2 in calcium mobilization and chemotaxis assays, which measure the activation of the G protein-coupled FPR2. In agreement with this, SAA1.1 and SAA2.2 induced more robust phosphorylation of ERK than SAA1.3 and SAA1.5. Only small differences were observed between the SAA1 proteins tested and SAA2.2 in TLR2-dependent NF-κB luciferase reporter assay. In comparison, SAA1.3 was most effective in stimulating ERK and p38 MAPK phosphorylation. Using bone marrow-derived macrophages from C57BL/10ScN (Tlr4lps-del) mice, we examined the SAA isoforms for their induction of selected pro- and anti-inflammatory cytokines. SAA1.3 was most potent in the induction of TNFα and IL-1rn, whereas SAA1.5 induced robust IL-10 expression. These results show differences of the SAA1 isoforms in their selectivity for the SAA Receptors, which may affect their roles in modulating inflammation and immunity.
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Reconstitution of recombinant N-formyl chemotactic Peptide Receptor with G protein
Journal of Leukocyte Biology, 1993Co-Authors: Ronda E. Schreiber, Richard D Ye, Eric R. Prossnitz, Charles G. Cochrane, Algirdas J. Jesaitis, Gary M. BokochAbstract:A recombinant human neutrophil N-forinyl Peptide Receptor (rFPR) expressed in transfected mouse fIbroblasts (TX2 cells) was analyzed for its ability to couple physically with the heterotrimeric C protein, G�. Im- munoprecipitation of photoaffinity-labeled rFPR and en- dogenous neutrophil formyl Peptide Receptor (nFPR) with an anti-FPR Peptide antibody demonstrated that the Receptors were identical in both size and extent of glycosylation. Coupling of rFPR with endogenous TX2 Gwas demonstrated by coimmunoprecipitation of the two proteins with an anti-G1 antibody. Moreover, rFPR was able to form a physical complex with purified G1 in a soluble reconstitution system. We observed similar affinities of rFPR and nFPR for G1. This report provides the first direct evidence that rFPR associates physically with G1 and provides a foundation for analysis of the G protein coupling capacity of mutant rFPRs. J. Leukoc. Rio!. 53: 470-474; 1993.
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Transmembrane signalling by the N-formyl Peptide Receptor in stably transfected fibroblasts
Biochemical and Biophysical Research Communications, 1991Co-Authors: Eric R. Prossnitz, Charles G. Cochrane, Oswald Quehenberger, Richard D YeAbstract:Abstract We investigated the requirement for N-formyl Peptide Receptor-mediated transmembrane signalling in transfected mouse fibroblasts that express the Receptor. Stably transfected cells displayed specific binding for N-formyl-Met-Leu-[3H]Phe with a dissociation constant of 3 nM. The cells responded to ligand stimulation with mobilization of calcium from intracellular stores. Calcium mobilization was ligand dose-dependent (EC50=3 nM fMet-Leu-Phe) and could be inhibited by pertussis toxin treatment. These results provide the first demonstration that expression of the single-chain N-formyl Peptide Receptor in mouse fibroblasts is sufficient for mediating ligand-induced early transmembrane signalling events, which do not appear to require other neutrophil-specific cellular components.