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Effects of PDE4 gene polymorphisms on efficacy and adverse drug events of ritodrine therapy in preterm labor patients: a prospective observational study

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Phosphodiesterase (PDE) terminates the signaling pathway of myometrial relaxation by degradating cAMP to the inactive 5′-AMP. The PDE4 family is one of the most predominant PDE families that display high affinity to cAMP. The objective of this study was to evaluate the effects of PDE4 gene polymorphisms on tocolytic effects and adverse drug events (ADEs) of ritodrine therapy in patients with preterm labor.

Methods

A total of 170 preterm labor patients were included in this study. To elucidate the effects of genetic polymorphisms on the inter-individual variability of ritodrine efficacy and ADEs, 8 single nucleotide polymorphisms (SNPs) were genotyped: PDE4D (rs1544791, rs983280, rs1504982, rs10940648, rs829259) and PDE4B2 (rs598961, rs2180335, and rs17128809). Additionally, rs1042719 of the ADRB2 gene was included for multivariate analysis. The primary endpoint of this prospective study was the time to delivery (hr). The secondary endpoint was ritodrine-induced ADEs.

Results

The mutant-type homozygote carriers of PDE4B2 rs598961 polymorphism showed shorter median time to delivery than those with other genotypes (adjusted hazard ratio 1.6, 95% confidence interval 1.0 to 2.4, P = 0.035). On the other hand, patients with wild-type homozygotes of PDE4B2 rs17128809 showed 2.6~2.9 times higher ADEs compared to those with other genotypes. Among demographic characteristics, gestational age at start of drug therapy and modified Bishop score were significant factors for time to delivery, whereas height, weight, and BSA were significant factors for ritodrine-induced ADEs after adjusting other factors.

Conclusions

This pharmacogenomic study suggested that PDE4 genetic polymorphisms impact individual susceptibility to β2-adrenergic receptor targeted therapy in patients with preterm labor.

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Sources of funding

This work was supported by the National Research Foundation of Korea (NRF) grant (No. NRF-2010-0022544) funded by the Korea Government (MEST), the Korea Health Industry Development Institute (KHIDI) (No. HI14C0306) funded by the Ministry of Health and Welfare, and the Ewha Womans University scholarship of 2018.

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Authors and Affiliations

  1. College of Pharmacy and Division of Life & Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea

    Jeong Yee, Jin Young Park & Hye Sun Gwak

  2. Department of Obstetrics and Gynecology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, 05030, South Korea

    Han Sung Hwang

  3. College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, 15588, South Korea

    Jee Eun Chung

  4. College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk, 28644, South Korea

    Kyung Eun Lee

  5. Department of Obstetrics and Gynecology, Ewha Womans University School of Medicine, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul, 07985, Republic of Korea

    Young Ju Kim

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  1. Jeong Yee
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  2. Han Sung Hwang
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  3. Jee Eun Chung
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  4. Jin Young Park
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  6. Young Ju Kim
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  7. Hye Sun Gwak
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Contributions

All authors have contributed significantly to the work and have read and approved the manuscript for publication. H. H, Y. K., and H. G. were responsible for the study concept and design. J. Y. and J. P participated in data collection. J.Y., J. C., and K. L. analyzed the data. J. Y., Y. K., and H. S. contributed to the manuscript writing and discussion.

Corresponding authors

Correspondence to Young Ju Kim or Hye Sun Gwak.

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This study was approved by Ethics Committee of the Ewha Womans University Mokdong Hospital Institutional Review Board (IRB No.: 217-1-26)

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The authors declare that they have no conflict of interest.

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Yee, J., Hwang, H.S., Chung, J.E. et al. Effects of PDE4 gene polymorphisms on efficacy and adverse drug events of ritodrine therapy in preterm labor patients: a prospective observational study. Eur J Clin Pharmacol 75, 1379–1386 (2019). https://doi.org/10.1007/s00228-019-02719-9

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  • DOI: https://doi.org/10.1007/s00228-019-02719-9

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