Safety Evaluation of Tadalafil Treatment for Fetuses with Early-Onset Growth Restriction (TADAFER): Results from the Phase II Trial

Maki, Seijiro; Tanaka, Hiroaki; Tsuji, Makoto; Furuhashi, Fumi; Magawa, Shoichi; Kaneda, Masanori; Nii, Masafumi; Tanaka, Kayo; Kondo, Eiji; Tamaru, Satoshi; Ogura, Toru; Nishimura, Yuki; Endoh, Masayuki; Kimura, Tadashi; Kotani, Tomomi; Sekizawa, Akihiko; Ikeda, Tomoaki

doi:10.3390/jcm8060856

Cited by 28 publications

(55 citation statements)

References 29 publications

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“…There were no severe fetal and neonatal adverse events that seemed to be related to tadalafil. Adverse events were expressed by grade based on the Common Terminology Criteria for Adverse Events v4.0, as with the TADAFER II study [11].…”

Section: Resultsmentioning

confidence: 99%

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Maternal Blood Concentration of Tadalafil and Uterine Blood Flow in Pregnancy

et al. 2019

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Background and Objectives: Tadalafil for treatment of fetal growth restriction (FGR) or preeclampsia is given once a day orally. The drug kinetics of tadalafil were investigated to determine the ideal dosage to promote uterine blood flow. Materials and Methods: We recruited five pregnant women with FGR or preeclampsia before administration of tadalafil, all of which were administered tadalafil (20 mg/day, once-daily dosing). The blood concentration of tadalafil was measured 1, 2, 4, 6, 8, and 24 h after administration, and uterine blood flow was measured before tadalafil administration and 2–4 and 20–24 h after. We then analyzed the correlation between tadalafil blood concentration and uterine artery blood flow. Results: The blood concentration of tadalafil correlated with uterine artery blood flow in pregnant women. The blood concentration of tadalafil and uterine artery blood flow decreased 5 h after administration of tadalafil. Conclusions: The blood concentration of tadalafil and uterine artery blood flow fluctuate in parallel, the latter was decreased by reduced blood concentration. Thus, a study of tadalafil administered twice a day in pregnant women will be needed to stabilize uterine artery blood flow.

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Section: Resultsmentioning

confidence: 99%

“…In fact, the TADAFER II study revealed that tadalafil administration prolonged gestation, in contrast to the STRIDER study [10]. Sildenafil, as a PDE5 inhibitor, did not prolong gestation in FGR in the STRIDER study [11,12]. The differences between the STRIDER study and the TADAFER study are shown in Table 1.…”

Section: Introductionmentioning

confidence: 99%

Maternal Blood Concentration of Tadalafil and Uterine Blood Flow in Pregnancy

et al. 2019

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“…In the present study, we report, for the first time, a developmental evaluation of infants who had received tadalafil in utero as a novel therapeutic treatment for FGR. Although the TADAFER II trial was suspended without completing registration of the original planned number of cases, the study concluded (as a short-term prognosis) that fetal, neonatal, and infant deaths decreased, and that this observation was potentially due to the prolongation of the gestational period in the case of early-onset FGR [1].…”

Section: Discussionmentioning

confidence: 99%

“…Tadalafil, a phosphodiesterase 5 (PDE5) inhibitor, has been reported to be a potential drug for the treatment of FGR. The results of a phase II trial (TADAFER II) using tadalafil for the treatment of fetuses with early-onset growth restriction have already been published [1]. Although the Japan Agency for Medical Research and Development (AMED) recommended suspension of TADAFER II based on the results of the STRIDER-UK trial showing negative effects of sildenafil in the treatment of FGR [2] and the recruitment of new candidates for the trial was ceased, the study demonstrated a decrease in the mortality rate of FGR fetuses, neonates, and infants.…”

Section: Introductionmentioning

confidence: 99%

Developmental Evaluation of Infants Who Have Received Tadalafil in Utero for Fetal Growth Restriction

Maki

Kato

Enomoto

et al. 2020

JCM

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To assess the long-term effects of tadalafil, a therapeutic agent for fetal growth restriction (FGR), we evaluated the developmental progress of 1.5-year-old infants whose mothers had taken tadalafil during pregnancy. Twenty-four infants were assessed. We evaluated infant body weight, height, and head circumference, and performed the Kyoto Scale of Psychological Development (KSPD) test, a standardized developmental assessment covering Postural–Motor (P–M), Cognitive–Adaptive (C–A), and Language-Social (L–S) functions. The sum score was converted to a developmental quotient (DQ). The mean gestational week of the included cases was 36.1 (29–39) weeks, and the mean birth weight was 1841 (874–2646) g. Twenty-one and 20 out of the 24 cases, respectively, attained body weight and height similar to those of age-matched normal infants (within the 3rd percentile); all cases caught up in head circumference. KSPD was performed for 18 cases at 1.5 years of corrected age. The mean DQ scores were 87 (in total): 82 in P–M, 90 in C–A, and 88 in L–S. The total DQ score in one case (5.6%) was less than 70, and ranged from 70 to 85 in five cases (27.7%), and was more than 85 in 11 cases (61.1%). The growth and development of infants born of tadalafil-treated mothers seem to show good progress at a corrected age of 1.5 years.

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“…Written informed consent was obtained from a Japanese pregnant woman. The placental sample in FGR and FGR + tadalafil cases used case in clinical trial [ 19 ]. Control case selected randomly the normal case during clinical trial.…”

Section: Methodsmentioning

confidence: 99%

Tadalafil Treatment Ameliorates Hypoxia and Alters Placental Expression of Proteins Downstream of mTOR Signaling in Fetal Growth Restriction

Tsuchiya

Tanaka

et al. 2020

Medicina

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Background and Objectives: Fetal growth restriction (FGR) is associated with fetal mortality and is a risk factor for cerebral palsy and future lifestyle-related diseases. Despite extensive research, no effective treatment strategy is available for FGR. Mammalian target of rapamycin (mTOR) signaling is important for the growth of fetal organs and its dysregulation is associated with miscarriage. Here, we focused on mTOR signaling and investigated how the activities of phospho-ribosomal protein S6 (rps6) and phospho-eukaryotic translation initiation factor 4E (eIF-4E), which act downstream of mTOR signaling in the human placenta, change following treatment of FGR with tadalafil and aimed to elucidate the underlying mechanism of action. Placental hypoxia was investigated by immunostaining for hypoxia-inducible factor (HIF)-2α. Materials and Methods: Phosphor-rps6 and phosphor-eIF4E expression were examined by Western blotting and enzyme-linked immunosorbent assay, respectively. Results: HIF-2α expression significantly increased in FGR placenta compared with that in the control placenta but decreased to control levels after tadalafil treatment. Levels of phospho-rps6 and phospho-eIF-4E were significantly higher in FGR placenta than in control placenta but decreased to control levels after tadalafil treatment. Conclusions: Tadalafil restored the levels of HIF-2α, phospho-rps6, and eIF-4E in FGR placenta to those observed in control placenta, suggesting that it could be a promising treatment strategy for FGR.

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Safety Evaluation of Tadalafil Treatment for Fetuses with Early-Onset Growth Restriction (TADAFER): Results from the Phase II Trial

Cited by 28 publications

References 29 publications

Maternal Blood Concentration of Tadalafil and Uterine Blood Flow in Pregnancy

Maternal Blood Concentration of Tadalafil and Uterine Blood Flow in Pregnancy

Developmental Evaluation of Infants Who Have Received Tadalafil in Utero for Fetal Growth Restriction

Tadalafil Treatment Ameliorates Hypoxia and Alters Placental Expression of Proteins Downstream of mTOR Signaling in Fetal Growth Restriction

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