Caffeine for the Pharmacological Treatment of Apnea of Prematurity in the NICU: Dose Selection Conundrum, Therapeutic Drug Monitoring and Genetic Factors

Long, Jia-Yi; Guo, Hongli; He, Xin; Hu, Yahui; Xia, Ying; Cheng, Rui; Ding, Xiaowen; Chen, Feng; Xu, Jing

doi:10.3389/fphar.2021.681842

Cited by 17 publications

(19 citation statements)

References 114 publications

(185 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The AOP phenotype has been attributed solely to immature respiratory system control consequent to preterm birth, but there may also be important genetic influences ( Erickson et al, 2021 ). Therefore, the influence of genetics on the efficacy of caffeine in preterm infants should be better explored ( Long et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Caffeine Therapy for Apnea of Prematurity: Role of the Circadian CLOCK Gene Polymorphism

Guo

Long

et al. 2022

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

Standard-dose caffeine citrate has been routinely prescribed for apnea of prematurity (AOP) management; however, some preterm infants respond well to the therapy while others do not. The AOP phenotype has been attributed solely to the immature control of the respiratory system consequent to preterm birth, but there are also important genetic influences. Based on our previous report, we tested the hypothesis that the human circadian locomotor output cycles kaput (CLOCK) gene polymorphisms play a role in the response to caffeine citrate therapy in preterm infants. We also studied the interactions of the circadian clock with aryl hydrocarbon receptor (AHR) signaling pathways in preterm babies who received caffeine citrate. This single-center study collected data from 112 preterm infants (<35 weeks gestational age) between July 2017 and July 2018, including apnea-free (n = 48) and apneic (n = 64) groups. Eighty-eight candidate single nucleotide polymorphisms (SNPs) were tested using the MassARRAY system. Association analysis was performed using the PLINK Whole Genome Data Analysis Toolset and SNPStats software. Linkage disequilibrium (LD) and haplotype analyses were performed using Hapview software. No significant intergroup differences in allele distributions or genotype frequencies of CYP1A2, CYP3A4, CYP3A5, and CYP3A7 were detected in our study on preterm babies. Two more SNPs in AHR were found to be associated with determining the response to caffeine citrate therapy in our pediatric patients. Of the 46 candidate SNPs in the CLOCK gene, 26 were found to be associated with determining the response to caffeine treatment in these babies. Interestingly, a significant association was retained for 18 SNPs in the CLOCK gene after false discovery rate correction. Moreover, strong LD formed in those variants in AHR, ADORA2A, and CLOCK genes was confirmed to be significantly associated with a better response to standard-dose caffeine therapy. In summary, CLOCK gene polymorphisms play a role in determining the response to caffeine therapy in premature neonates with AOP. However, whether the AHR and CLOCK signaling pathways crosstalk with each other during caffeine treatment remains largely unclear. Future clinical studies including more immature babies and basic research are needed to explore the mechanism by which circadian rhythms affect the response to caffeine therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Caffeine Therapy for Apnea of Prematurity: Role of the Circadian CLOCK Gene Polymorphism

Guo

Long

et al. 2022

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Caffeine acts as a potent analgesic adjuvant and is often added to a variety of over-the-counter and prescription analgesics due to its anti-inflammatory and vasoconstrictive effects ( Cappelletti et al, 2015 ; van Dam et al, 2020 ; Rodak et al, 2021 ). More strikingly, caffeine is the drug of choice for the treatment of apnea of prematurity (AOP) ( Eichenwald et al, 2016 ; Kumar and Lipshultz, 2019 ; Moschino et al, 2020 ; Long et al, 2021 ) and becomes one of the most commonly prescribed medications in the neonatal intensive care unit (NICU) ( Hsieh et al, 2014 ; Krzyżaniak et al, 2016 ), evidenced by its short-term and long-term efficacy and safety in reducing apnea, facilitating extubation, preventing bronchopulmonary dysplasia, ameliorating retinopathy of prematurity, reducing patent ductus arteriosus, and improving neurodevelopmental outcome that have been demonstrated in the Caffeine for Apnea of Prematurity (CAP) trial ( Schmidt et al, 2006 ; Schmidt et al, 2007 ). Assuredly, compared with other methylxanthines, caffeine has higher therapeutic index, longer half-life, and better tolerability ( Henderson-Smart and De Paoli, 2010 ; Henderson-Smart and Steer, 2010 ; Abdel-Hady et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Precision caffeine therapy for apnea of prematurity and circadian rhythms: New possibilities open up

Dai

Guo

et al. 2022

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

Caffeine is the globally consumed psychoactive substance and the drug of choice for the treatment of apnea of prematurity (AOP), but its therapeutic effects are highly variable among preterm infants. Many of the molecular underpinnings of the marked individual response have remained elusive yet. Interestingly, the significant association between Clock gene polymorphisms and the response to caffeine therapy offers an opportunity to advance our understanding of potential mechanistic pathways. In this review, we delineate the functions and mechanisms of human circadian rhythms. An up-to-date advance of the formation and ontogeny of human circadian rhythms during the perinatal period are concisely discussed. Specially, we summarize and discuss the characteristics of circadian rhythms in preterm infants. Second, we discuss the role of caffeine consumption on the circadian rhythms in animal models and human, especially in neonates and preterm infants. Finally, we postulate how circadian-based therapeutic initiatives could open new possibilities to promote precision caffeine therapy for the AOP management in preterm infants.

show abstract

“…Different options, such as prophylactic vitamin K, coagulating factors, angiogenic inhibitors, COX-2 inhibitor celecoxib, or endothelial growth factor R2 inhibitors, might have beneficial effects in the GM-IVH management by stabilizing the GM at different levels, but more studies are required before use in clinical care (for review (Deger et al, 2021)). Other approaches have focused on caffeine (Caf), regularly used to treat the apnea of prematurity (Long et al, 2021). Caf has antioxidant, neuroprotective, and anti-inflammatory properties, and studies in newborn and young animals have shown its capacity to reduce brain hypoxic damage (Yang et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Caffeine Restores Neuronal Damage and Inflammatory Response in a Model of Intraventricular Hemorrhage of the Preterm Newborn

Alves-Martínez

Atienza-Navarro

Vargas-Soria

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Germinal matrix-intraventricular hemorrhage (GM-IVH) is the most frequent intracranial hemorrhage in the preterm infant (PT). Long-term GM-IVH-associated sequelae include cerebral palsy, sensory and motor impairment, learning disabilities, or neuropsychiatric disorders. The societal and health burden associated with GM-IVH is worsened by the fact that there is no successful treatment to limit or reduce brain damage and neurodevelopment disabilities. Caffeine (Caf) is a methylxanthine that binds to adenosine receptors, regularly used to treat the apnea of prematurity. While previous studies support the beneficial effects at the brain level of Caf in PT, there are no studies that specifically focus on the role of Caf in GM-IVH. Therefore, to further understand the role of Caf in GM-IVH, we have analyzed two doses of Caf (10 and 20 mg/kg) in a murine model of the disease. We have analyzed the short (P14) and long (P70) effects of the treatment on brain atrophy and neuron wellbeing, including density, curvature, and phospho-tau/total tau ratio. We have analyzed proliferation and neurogenesis, as well as microglia and hemorrhage burdens. We have also assessed the long-term effects of Caf treatment at cognitive level. To induce GM-IVH, we have administered intraventricular collagenase to P7 CD1 mice and have analyzed these animals in the short (P14) and long (P70) term. Caf showed a general neuroprotective effect in our model of GM-IVH of the PT. In our study, Caf administration diminishes brain atrophy and ventricle enlargement. Likewise, Caf limits neuronal damage, including neurite curvature and tau phosphorylation. It also contributes to maintaining neurogenesis in the subventricular zone, a neurogenic niche that is severely affected after GM-IVH. Furthermore, Caf ameliorates small vessel bleeding and inflammation in both the cortex and the subventricular zone. Observed mitigation of brain pathological features commonly associated with GM-IVH also results in a significant improvement of learning and memory abilities in the long term. Altogether, our data support the promising effects of Caf to reduce central nervous system complications associated with GM-IVH.

show abstract

Caffeine for the Pharmacological Treatment of Apnea of Prematurity in the NICU: Dose Selection Conundrum, Therapeutic Drug Monitoring and Genetic Factors

Cited by 17 publications

References 114 publications

Caffeine Therapy for Apnea of Prematurity: Role of the Circadian CLOCK Gene Polymorphism

Caffeine Therapy for Apnea of Prematurity: Role of the Circadian CLOCK Gene Polymorphism

Precision caffeine therapy for apnea of prematurity and circadian rhythms: New possibilities open up

Caffeine Restores Neuronal Damage and Inflammatory Response in a Model of Intraventricular Hemorrhage of the Preterm Newborn

Contact Info

Product

Resources

About