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Tyrosine kinase inhibitors and pregnancy

Hiroko Tanaka, Keiichi Kumasawa, Aiko Kakigano, Kazuya Mimura, Masayuki Endo, Takuji Tomimatsu, Tadashi Kimura
Excessive soluble fms-like tyrosine kinase-1 (sFlt-1) has been strongly implicated in preeclampsia. An increase in the serum sFlt-1 level occurs before the onset of preeclampsia, and the sFlt-1 level is already higher in women who are predisposed to preeclampsia than in normotensive pregnant women. This study aimed to investigate the relation between arginase and sFlt-1 in the plasma of preeclamptic women and normotensive pregnant women. We suggested that a regulatory mechanism exists that suppresses the level of sFlt-1...
March 13, 2018: Biochemical and Biophysical Research Communications
Dorien Reijnders, Chin-Chi Liu, Xinjing Xu, Anna Zhao, Kelsey Olson, Scott D Butler, Nataki C Douglas, Jenny L Sones
Preeclampsia (PE), a hypertensive disease of pregnancy, is a leading cause of fetal and maternal morbidity/mortality. Early angiogenic and inflammatory disturbances within the placenta are thought to underlie the development of the maternal PE syndrome and poor pregnancy outcomes. However, the exact etiology remains largely unknown. Here, we use the BPH/5 mouse model of PE to elucidate the way in which inflammation early in pregnancy contributes to abnormal expression of angiogenic factors at the maternal-fetal interface...
March 9, 2018: Physiological Genomics
Nicholas Thomas, John Glod, Claudia Derse-Anthony, Emma L Baple, Nigel Obsborne, Rachel Sturley, Bijay Vaidya, Kate Newbold, Antonia Brooke
Vandetanib is a tyrosine kinase inhibitor (TKI) used in the treatment of medullary thyroid carcinoma occurring in >95% of patients with multiple endocrine neoplasia type 2b (MEN 2b). Pregnancy in women with MEN 2b on vandetanib is previously unreported and has multiple potential implications for both the mother and developing fetus [1]. We describe the case of a 22 year old woman with a background of MEN 2b who was first diagnosed aged 6 presenting with marfanoid habitus, and oral mucosal neuromas. This article is protected by copyright...
February 19, 2018: Clinical Endocrinology
Ellin Berman, Brian J Druker, Richard Burwick
No abstract text is available yet for this article.
February 15, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Chunhua Zhang, Yong Zhu, Yan Shen, Changting Zuo
Reduced expression of peroxisome proliferator-activated receptor γ (PPARγ) in the placenta was found in women with severe preeclampsia. Aspirin is currently used as the only recommended intervention in pregnancies for prevention of preeclampsia. In this study, we aimed to investigate whether aspirin could attenuate PPARγ inhibitor (T0070907)-induced preeclampsia and its impact on expression of PPARγ. Sixty Sprague-Dawley rats were used and treated with different doses of aspirin (0, 1, and 1.5 mg/kg) in presence or absence of PPARγ antagonist, T0070907...
January 1, 2018: Reproductive Sciences
Theodora Barkoulas, Philip D Hall
Pregnancy in a patient with chronic myeloid leukemia presents a therapeutic challenge. Both dasatinib and nilotinib are indicated for first-line treatment as well as for treatment-resistant chronic myeloid leukemia. Animal studies with dasatinib or nilotinib demonstrate fetal skeletal malformations as well as significant mortality during organogenesis. The goal of this article is to review the experience to date of dasatinib and nilotinib in human pregnancy, specifically dasatinib and nilotinib dose, length of exposure, trimester of use, as well as patient and fetal outcomes...
January 1, 2017: Journal of Oncology Pharmacy Practice
Ana Correia-Branco, Elisa Keating, Fátima Martel
We previously described a negative effect of xanthohumol (XN) upon placentation-related processes. We aimed to better characterize this effect by investigating the effect of XN upon the uptake of arachidonic acid (ARA), a crucial nutrient during pregnancy, by the HTR-8/SVneo human first-trimester extravillous trophoblast cell line and its relationship with the negative effect of XN upon placentation-related processes. Uptake of14 C-ARA (100 nM) was time dependent and inhibited by short-term (26 minutes) or long-term (24 hours) exposure to XN...
January 1, 2017: Reproductive Sciences
David J Hermel, Victor Chiu, Melody H Hermel, Anil Tulpule, Mojtaba Akhtari
Preclinical animal studies have demonstrated an association between maternal use of tyrosine kinase inhibitors and embryofetal toxicity; yet, multiple clinical case series have reported normal pregnancy outcomes and healthy infants in women on these medications during the course of their pregnancy. We describe a case of a woman with chronic myeloid leukemia who had taken the second-generation tyrosine kinase inhibitor dasatinib during the first 12 weeks of her dichorionic diamniotic twin pregnancy and subsequently delivered two low-birth weight infants, one with severe cardiac malformations and the other without apparent birth abnormalities...
January 1, 2017: Journal of Oncology Pharmacy Practice
Sasha Mikhael, Ashlee Pascoe, Joseph Prezzato
The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) in reproductive-aged women poses major dilemmas concerning its associated teratogenicity as observed in many animal studies. Much controversy exists regarding continuation versus discontinuation of its use in pregnancy with some studies suggesting safety of TKIs before and during pregnancy and others reporting toxicity and adverse outcomes. TKIs have become a well-established treatment option for CML, significantly improving prognosis, and yet have been reported to be fetotoxic...
2017: Case Reports in Oncological Medicine
Nicola Sgherza, Elisabetta Abruzzese, Gianni Perla, Maria Marta Minervini, Vincenzo Chiello, Natale Sciannamè, Nicola Cascavilla
Approximately 10%-12% of patients in chronic-phase chronic myeloid leukemia (CP-CML) have additional chromosomal aberrations at diagnosis; moreover, CML occurs in up to 10% of pregnancy-associated leukemias, with an annual incidence of 1 per 100,000 pregnancies. In this report we describe the case of a 36-year-old female with CP-CML diagnosed in the 18th week of pregnancy and with a new complex variant translocation t(4;9;22;21)(q24;q34;q11;q22) and an additional chromosomal aberration t(1;20)(p36;p11). In consideration of her pregnancy, the patient strictly monitored her blood cell count without any specific treatment...
2017: Therapeutics and Clinical Risk Management
Langeza Saleh, Raaho Samantar, Ingrid M Garrelds, Anton H van den Meiracker, Willy Visser, A H Jan Danser
Patients with preeclampsia display elevated placenta-derived sFlt-1 (soluble Fms-like tyrosine kinase-1) and endoglin levels and decreased placental growth factor levels. Proton pump inhibitors (PPIs) decrease trophoblast sFlt-1 and endoglin secretion in vitro. PPIs are used during pregnancy to combat reflux disease. Here, we investigated whether PPIs affect sFlt-1 in women with confirmed/suspected preeclampsia, making use of a prospective cohort study involving 430 women. Of these women, 40 took PPIs (6 esomeprazole, 32 omeprazole, and 2 pantoprazole) for 8 to 45 (median 29) days before sFlt-1 measurement...
September 2017: Hypertension
Ekaterina Chelysheva, Anna Turkina, Evgenia Polushkina, Roman Shmakov, Alexey Zeifman, Sergey Aleshin, Igor Shokhin, Dorel Guranda, Oksana Oksenjuk, Sergey Mordanov, Khamida Kazakbaeva, Ghermes Chilov
Both favorable pregnancy outcomes and fetal abnormalities have been associated with the use of tyrosine kinase inhibitors (TKIs) during pregnancy. The placental transfer of TKIs in humans is poorly understood. We observed women with chronic myeloid leukemia who used imatinib or nilotinib during the late pregnancy stages. The newborns had no birth abnormalities. We evaluated the drug concentrations in maternal blood, umbilical cord blood, and placental samples collected during labor. We found limited placental transfer of the TKIs...
July 13, 2017: Leukemia & Lymphoma
Juanjuan Chen, Raouf A Khalil
Normal pregnancy is associated with marked hemodynamic and uterine changes that allow adequate uteroplacental blood flow and uterine expansion for the growing fetus. These pregnancy-associated changes involve significant uteroplacental and vascular remodeling. Matrix metalloproteinases (MMPs) are important regulators of vascular and uterine remodeling. Increases in MMP-2 and MMP-9 have been implicated in vasodilation, placentation, and uterine expansion during normal pregnancy. The increases in MMPs could be induced by the increased production of estrogen and progesterone during pregnancy...
2017: Progress in Molecular Biology and Translational Science
James A Lambert, Matthew A Carlisle, Adam Lam, Saurabh Aggarwal, Stephen Doran, Changchun Ren, Wayne E Bradley, Louis Dell'Italia, Namasivayam Ambalavanan, David A Ford, Rakesh P Patel, Tamas Jilling, Sadis Matalon
Inhalation of oxidant gases has been implicated in adverse outcomes in pregnancy, but animal models to address mechanisms and studies to identify potential pregnancy-specific therapies are lacking. Herein, we show that inhalation of bromine at 600 parts per million for 30 minutes by pregnant mice on the 15th day of embryonic development results in significantly lower survival after 96 hours than an identical level of exposure in nonpregnant mice. On the 19th embryonic day, bromine-exposed pregnant mice have increased systemic blood pressure, abnormal placental development, severe fetal growth restriction, systemic inflammation, increased levels of circulating antiangiogenic short fms-like tyrosine kinase-1, and evidence of pulmonary and cardiac injury...
August 2017: Hypertension
Richard M Burwick, Kelly Kuo, Diana Brewer, Brian J Druker
BACKGROUND: Pregnant women with chronic myeloid leukemia (CML) can be treated effectively with the tyrosine-kinase inhibitor imatinib, but data regarding fetal and neonatal exposure and safety are limited. CASE: We present a patient with newly diagnosed CML in early pregnancy. Leukapheresis and interferon-α were initiated in the second trimester with limited benefit. Imatinib was subsequently started at 28 weeks of gestation with complete hematologic response within 4 weeks...
May 2017: Obstetrics and Gynecology
Gaby A M Eliesen, Petra van den Broek, Jeroen J van den Heuvel, Albert Bilos, Jeanne Pertijs, Joris van Drongelen, Frans G M Russel, Rick Greupink
Tyrosine kinase inhibitors (TKIs) play an important role in cancer pharmacotherapy, yet there is limited data on their use during pregnancy. We studied placental disposition and placental toxicity of crizotinib, a TKI used to treat nonsmall cell lung cancer. Term placentas were perfused for 3 h with crizotinib (1 µM) using the ex vivo dual-side cotyledon perfusion technique. Interference of TKIs with trophoblast viability was studied using BeWo cells. Expression of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) in placental tissue was assessed by immunohistochemistry and inhibition of these transporters was determined in vitro by transport studies with membrane vesicles overexpressing human P-gp or BCRP...
June 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
Tsung-Chun Huang, Yu-Kai Cheng, Tsung-Wei Chen, Yung-Chang Hsu, En-Wei Liu, Hsin-Han Chen
Thyroid cancer with cranial metastasis in a pregnant woman is very rare. In the literature, most cases are diagnosed early from neurogenic signs or symptomatic thyroid gland. Pregnancy also contributes to a hesitation toward early surgical and medical treatments. We reported a scalp tumor in a physically healthy 37-year-old pregnant female with a follicular thyroid carcinoma (FTC) with lung, bone and cranial metastasis in initial presentation. Silent neurogenic and physical examinations make an early diagnosis very challenging...
2017: Endocrinology, Diabetes & Metabolism Case Reports
Kenji Onda, Stephen Tong, Sally Beard, Natalie Binder, Masanaga Muto, Sevvandi N Senadheera, Laura Parry, Mark Dilworth, Lewis Renshall, Fiona Brownfoot, Roxanne Hastie, Laura Tuohey, Kirsten Palmer, Toshihiko Hirano, Masahito Ikawa, Tu'uhevaha Kaitu'u-Lino, Natalie J Hannan
Preeclampsia is a severe complication of pregnancy. Antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury. Oxidative stress and vascular inflammation exacerbate the endothelial injury. A drug that can block these pathophysiological steps would be an attractive treatment option. Proton pump inhibitors (PPIs) are safe in pregnancy where they are prescribed for gastric reflux...
March 2017: Hypertension
Weiwei Sheng, Naitong Sun
INTRODUCTION: Complications associated with chronic myeloid leukemia (CML) during pregnancy are rare, and management is challenging because very limited data are available on this patient group. CASE DESCRIPTION: We herein report a successful pregnancy and delivery in a patient diagnosed with CML. The patient was treated with imatinib (400 mg/day) as a first-line therapy. However, she became pregnant while she was in complete hematological remission and had a complete cytogenetic response...
2016: SpringerPlus
Neil A Nadkarni, Augustine Rajakumar, Nikita Mokhashi, Suzanne D Burke, Sarosh Rana, Saira Salahuddin, Quynh Dang, Ravi Thadhani, Ramaswamy Krishnan, Thomas P Stossel, S Ananth Karumanchi
BACKGROUND: Preeclampsia, a pregnancy-specific inflammatory disorder, is characterized by high levels of anti-angiogenic protein, soluble fms-like tyrosine kinase 1 (sFlt1), in the maternal circulation. sFlt1 producing molecular machinery is present in syncytiotrophoblast extracellular vesicles that are released by the placenta into maternal plasma during normal pregnancy, a process greatly accelerated in preeclampsia. We hypothesized that syncytiotrophoblast extracellular vesicles exposes cytoplasmic actin to plasma resulting in depletion of plasma gelsolin (pGSN), an abundant plasma protein that scavenges circulating actin and other pro-inflammatory mediators...
October 2016: Pregnancy Hypertension
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