Author: Miyara, Santiago J. ; Watt, Stacey ; Shoaib, Muhammad ; Grande, Daniel A. ; Shore-Lesserson, Linda ; Guevara, Sara ; Morales, Luis F. ; Metz, Christine N. ; Alsalmay, Yaser M. ; Molmenti, Ernesto P. ; Kressel, Adam M. ; McCann-Molmenti, Alexia ; Aranalde, Gabriel I. ; Cho, Young Min ; Takegawa, Ryosuke ; Becker, Lance B. ; Shinozaki, Koichiro ; Nishikimi, Mitsuaki ; Zafeiropoulos, Stefanos ; Choudhary, Rishabh C. ; Zanos, Stavros ; Brindley, Elena C. ; Hayashida, Kei ; Mazzotta, Elvio A.

AbstractWe describe the clinical course of a 65-year-old male patient who suffered from hydrocarbon-induced myelodysplasia and was successfully treated with the thrombopoietin receptor agonist (TPO-RA), romiplostim. Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, cytopenias, and increased risk of leukemic transformation. Here, we present a clinical vignette of MDS-associated thrombocytopenia refractory to first-line drugs as well as the TPO-RA, eltrombopag. To date, romiplostim is an U.S. Food and Drug Administration (FDA)-approved drug for idiopathic thrombocytopenic purpura and thrombocytopenia secondary to liver disease. Of note, currently the FDA advises against its use in MDS based on previous long-term safety concerns. Since the therapeutic options for thrombocytopenia in MDS patients are sparse, repurposing and reassessing romiplostim in this setting have been the focus of recent studies. At the time of writing, no published double-blind randomized clinical trials have conducted a head-to-head comparison between romiplostim and eltrombopag in thrombocytopenic MDS patients. To the best of our knowledge, for a thrombocytopenic patient in the setting of MDS, this is the first documented report of refractory clinical response after a 2-year use of eltrombopag in which replacement of treatment with romiplostim resulted in sustained physiological counts of thrombocytes within four weeks.

01 Nov 2024·Molecular Psychiatry

Reduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders

Article

Author: Hashimoto-Torii, Kazue ; Ito, Mariko ; Foroud, Tatiana ; Mohammad, Shahid ; Schwantes-An, Tae-Hwi ; Sasaki, Junko ; Chambers, Christina ; Wetherill, Leah ; Edwards, Alex ; Miranda, Rajesh C ; Yamashita, Chiho ; Mahnke, Amanda H ; Matsumoto, Yu ; Torii, Masaaki ; Mattson, Sarah N ; Dutta, Dipankar J ; Hwang, Hye M ; Yamashita, Satoshi ; Abreu, Marco

AbstractA hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.

13 Oct 2024·Cureus

The Establishment of a Novel Murine Model of Immune Thrombocytopenia in Pregnancy and the Impacts of Thrombopoietin Receptor Agonist on Platelet Production

Article

Author: Shibata, Satoshi ; Nakano, Akemi ; Tachibana, Daisuke ; Nakai, Kensaku ; Kurihara, Yasushi ; Uemura, Ryo ; Hamuro, Akihiro ; Kitada, Kohei ; Tahara, Mie ; Misugi, Takuya

Objective Immune thrombocytopenia (ITP) is frequently associated with pregnancy. However, treatment options for ITP in pregnancy are limited, and there are few animal models available for the establishment of treatments. Here, we aimed to establish a novel murine pregnant model of ITP and to investigate the impacts of thrombopoietin receptor agonist (TPO-RA) on platelet production and reproductive outcomes. Methods Anti-glycoprotein Ib-alpha (GPIbα) antibody, which binds to megakaryocytes and platelets, was subcutaneously administered to pregnant mice in order to develop an ITP model (ITP group). TPO-RA was given in doses of 1 µg/kg, 10 µg/kg, and 100 µg/kg (low-dose group, mid-dose group, and high-dose group, respectively) for the treatment of ITP in pregnancy. Results The ITP group showed a significant reduction of platelet counts of less than 15% of healthy pregnant mice (control group) and also showed a significant increase in miscarriage rate (control group, 3.8%; ITP group, 44.4%; p < 0.05). Striking increases in platelet counts were observed in every TPO-RA group without any negative effects on fetal growth and placental pathology. No abnormality was noted in the external examination of fetal mice. Interestingly, a significant recovery of miscarriage rate was observed in the mid-dose group (23.5%) compared with the ITP group (p < 0.05). Conclusion A novel ITP model in pregnant mice was induced by injection of an anti-GPIbα antibody, and sufficient effects of TPO-RA on platelet production were observed in the present study. Furthermore, the positive impacts of TPO-RA on reproductive outcomes were revealed in the ITP model.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus	Phase 1	-	vTv Therapeutics, Inc.	-
Diabetes Mellitus, Type 1	Preclinical	US	vTv Therapeutics, Inc.	02 Nov 2023

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