Clinical Pharmacology of Theophylline in Preterm Infants: Effects, Metabolism and Pharmacokinetics

Pacifici, Gian Maria

doi:10.2174/1573396311666150113213352

Cited by 18 publications

(17 citation statements)

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“…The present review endeavored to summarize the state of the art concerning this facet of neonatology. Stimulation of the central nervous system has been the focus of other recent reviews 36,37.…”

Section: Discussionmentioning

confidence: 99%

Metabolism and pharmacokinetics of morphine in neonates: A review

Pacifici¹

2016

Clinics

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Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief, sedation, euphoria and respiratory depression. Morphine is glucuronidated and sulfated at positions 3 and 6; the plasma concentration ratios correlate positively with birth weight, which probably reflects increased liver weight with increasing birth weight. Moreover, morphine clearance correlates positively with gestational age and birth weight. Steady-state morphine plasma concentrations are achieved after 24-48 hours of infusion, but the glucuronide metabolite plasma concentrations do not reach steady state before 60 hours. The morphine-3-glucuronide metabolite has lower clearance, a shorter half-life and a smaller distribution volume compared with the morphine-6 metabolite, which is the most active morphine-like agonist. Ordinary doses cause constipation, urinary retention and respiratory depression. Neonatal pain relief may require a blood level of approximately 120 ng/ml, whereas lower levels (20-40 ng/ml) seem adequate for children. A bibliographic search was performed using the PubMed database and the keywords “morphine metabolism neonate” and “morphine pharmacokinetics neonate”. The initial and final cutoff points were January 1990 and September 2015, respectively. The results indicate that morphine is extensively glucuronidated and sulfated at positions 3 and 6, and that the glucuronidation rate is lower in younger neonates compared with older infants. Although much is known about morphine in neonates, further research will be required to ensure that recommended therapeutic doses for analgesia in neonates are evidence based.

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Section: Discussionmentioning

confidence: 99%

Metabolism and pharmacokinetics of morphine in neonates: A review

Pacifici¹

2016

Clinics

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“…Clinically, caffeine is recognized as the first-line therapeutic agent for apnea of prematurity [ 5 ], because of its safer clinical profile compared to the older drug theophylline and its oral form aminophylline [ 6 ]. For this indication, there is an internationally proposed dosage regimen for caffeine base (10 mg/kg load dose and 2.5 mg/kg maintenance dose) [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

HPLC Method for Quantification of Caffeine and Its Three Major Metabolites in Human Plasma Using Fetal Bovine Serum Matrix to Evaluate Prenatal Drug Exposure

López-Sánchez

Díaz

Aranda-Gutierrez

et al. 2018

Journal of Analytical Methods in Chemistry

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Caffeine is recognized as the first-line therapeutic agent for apnea of prematurity. The dosage regimen is 10 mg/kg loading dose and 2.5 mg/kg maintenance dose. However, the plasma concentration achieved, not always, is therapeutically useful. It makes necessary to increase the doses to reach plasma concentration up to 30 or 35 μg/mL or even higher to attain therapeutic effect. To study why neonates have these differences, and whether these effects are linked to prenatal caffeine exposure, we had to develop an analytical method for an accurate measurement of caffeine and metabolites concentration. The analysis was carried out using fetal bovine serum (FBS) as biological matrix in a high-performance liquid chromatography with an ultraviolet detector method. This method allows acceptable chromatographic resolution between analytes in 15 minutes. It was validated and proved to be linear in the 0.1–40 µg/mL range for caffeine, paraxanthine, theobromine, and theophylline in the same chromatographic analysis. Accuracy for quality control samples for intra- and interday assays was ranged from 96.5 to 105.2% and 97.1 to 106.2%. Precision had CV no more than 10% in all concentration levels for all analytes. No differences were observed between quantification in human and FBS. This method was applied to quantify plasma drug concentration in mothers and their newborns in a Mexican northeast population. In our study, we confirmed self-reported caffeine maternal intake in 85.2% (n=23); meanwhile, in their newborn's plasma, it was detected only in 78% (n=21). Caffeine plasma concentrations in mother and newborn had a linear relationship, and no differences were observed between groups (mothers versus children). These results suggest that our analytical method and substitution of biological matrix was linear, precise, and accurate for caffeine quantification and could be used for measuring prenatal exposure and let us to study, in the future, concentration differences observed during apnea clinical treatment.

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“…Such mechanism has particular implication in preterm infants because pyridoxine which is usually supplemented in parenteral nutrition cannot be utilized. [15,16] Conversely, the methylation of caffeine is thought to be neuroprotective. [15,16] Aminophylline continues to be used in preterm infants in developing countries due to either lack of availability or cost of caffeine.…”

Section: Discussionmentioning

confidence: 99%

“…[15,16] Conversely, the methylation of caffeine is thought to be neuroprotective. [15,16] Aminophylline continues to be used in preterm infants in developing countries due to either lack of availability or cost of caffeine. [17][18][19] …”

Section: Discussionmentioning

confidence: 99%

Aminophylline-associated hyponatremia in a premature infant

et al. 2017

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Hyponatremia is common in preterm infants. The causes are usually related to the inability of the premature kidneys to excrete a given water load, excessive sodium losses, or inadequate sodium intake. Here, we present a case of severe hyponatremia in an extreme preterm infant, associated with the use of aminophylline. Aminophylline was administered intravenously on day 1 for the treatment of apnea of prematurity. On day 3, the patient developed hyponatremia which was not responsive to sodium replacement and fluid restriction. Due to concerns of aminophylline-induced hyponatremia, aminophylline was discontinued on day 6, and within 48 h of discontinuation, serum sodium normalized without the need for sodium supplementation. The purpose of the case report is to present a rare complication associated with aminophylline use and to shed light on potential deleterious effects associated with drug shortages.

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Clinical Pharmacology of Theophylline in Preterm Infants: Effects, Metabolism and Pharmacokinetics

Cited by 18 publications

References 0 publications

Metabolism and pharmacokinetics of morphine in neonates: A review

Metabolism and pharmacokinetics of morphine in neonates: A review

HPLC Method for Quantification of Caffeine and Its Three Major Metabolites in Human Plasma Using Fetal Bovine Serum Matrix to Evaluate Prenatal Drug Exposure

Aminophylline-associated hyponatremia in a premature infant

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