TY - JOUR
T1 - Effects of PDE4 gene polymorphisms on efficacy and adverse drug events of ritodrine therapy in preterm labor patients
T2 - a prospective observational study
AU - Yee, Jeong
AU - Hwang, Han Sung
AU - Chung, Jee Eun
AU - Park, Jin Young
AU - Lee, Kyung Eun
AU - Kim, Young Ju
AU - Gwak, Hye Sun
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
AB - 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.
KW - Adverse drug events
KW - Phosphodiesterase 4B2 gene
KW - Phosphodiesterase 4D gene
KW - Preterm labor
KW - Ritodrine
KW - Single nucleotide polymorphism
KW - Time to delivery
UR - http://www.scopus.com/inward/record.url?scp=85069456493&partnerID=8YFLogxK
U2 - 10.1007/s00228-019-02719-9
DO - 10.1007/s00228-019-02719-9
M3 - Article
C2 - 31324945
AN - SCOPUS:85069456493
VL - 75
SP - 1379
EP - 1386
JO - European Journal of Clinical Pharmacology
JF - European Journal of Clinical Pharmacology
SN - 0031-6970
IS - 10
ER -