Theophylline pharmacokinetics in premature infants with apnea

Giacoia, George P.; Jusko, William J.; Menke, James A.; Koup, Jeffrey R.

doi:10.1016/s0022-3476(76)80818-9

Cited by 99 publications

(32 citation statements)

References 3 publications

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“…This is supported by the good agreement between our data and those published by other authors concerning cord blood C concentrations, clearance values, and metabolic pathway (4,8,12,16,17,19,22,26).…”

Section: Discussionsupporting

confidence: 92%

“…This agrees with the conclusions by Aldridge et al (I), "the adult-like metabolite pattern (of C) of partially demethylated xanthines and urates was attained by 7 to 9 months of age." Clearance values found for T are in agreement with figures already reported in the literature for adults (16,22,26) and neonates (4,12,17). Although recently Aranda et al (2) reported that " .…”

Section: Discussionsupporting

confidence: 91%

“…Newborns eliminate the drug very slowly (4,12,17,23,28) partially methylating it to caffeine (C) (7-9). a unique example of drug methylation in humans.…”

Section: Speculationmentioning

confidence: 99%

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Theophylline Metabolism during the First Month of Life and Development

et al. 1981

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Summary dose of 5.5 mg/kg of T IV followed by maintenance IV doses ofThe metabolic pathway of theophylline (T) was studied in 12 newborns, one young infant, six children, and three adult volunteers. T was injected IV, and blood and urine samples were assayed for T, caffeine (C), and their metabolites by a high-pressure liquid chromatography technique. We confirmed the methylation of T to C in newborn infants but not in older subjects. Demethylation of T to Imethylxanthine was found in the young infant, in children, and in adults, but not in newborns. The major products excreted by neonates were T, 1-methyluric acid, and 1.3-dimethyluric acid. Children excreted a larger fraction of methyluric acids than adults.Renal and body clearance of T and C are reported and discussed in relation to the age. SpeculationOn the grounds of blood and urine samples from subjects treated with theovvlline. our results could indicate that caffeine oxidation over N-demethylation, involving lower activity of the cytochrome P-450 monooxygenase system during the first month of life than in older infants or adults compared to data reported in literature for other drugs. Our results suggest different forms of enzymes are involved in these reactions.Since its introduction in the treatment of apnea the disposition of theophylline (T) has been well described, not only in children (18)(19)(20)32) and adults (10, 11,13,15,16,22,26,29,30,31), but also in the premature neonate. Newborns eliminate the drug very slowly (4,12,17,23,28) partially methylating it to caffeine (C) (7-9). a unique example of drug methylation in humans.T is metabolized in the liver by the P-450-dependent microsomal system, which has been shown to be deficient in the newborn, in relation to several substrates (25).Methylxanthine metabolism has been studied in the adult (5. l I, 15, 29-3 1 ) but except for the paper by Aldridge et al. (I ) on caffeine no data have been published so far on children and neonates. This study was undertaken to: (1) further study the unusual metabolism of T to C; (2) define the metabolic pattern of T in neonates; (3) describe progressive changes of T metabolism during development.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 91%

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Theophylline Metabolism during the First Month of Life and Development

et al. 1981

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“…1,2 Although the pharmacokinetics of theophylline in preterm infants have been well studied, 3,4 the dose-response relationship has not been clearly established. Serum theophylline concentrations between 6 and 15 μg/mL have been suggested as optimal maintenance levels 1,5,6 for the treatment and prevention of apnea and bradycardia in preterm infants under 34 weeks of gestation.…”

Section: Kn Haque M Al-kharashi C Waters Theophylline Therapy For mentioning

confidence: 99%

Theophylline Therapy for Apnea of Prematurity in Saudi Preterm Infants: Therapeutic Serum Level and Dosage

1989

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In a controlled study, 150 Saudi preterm infants were treated with 1.5 mg/kg/day of theophylline for apnea of prematurity. In 96.8% of infants the apnea was either reduced by more than 50% or abolished completely. The effective therapeutic plasma level for these infants was 4.5 ±2.1 μg/mL. A loading dose was found to be unnecessary. Theophylline at these doses appears to be effective and safe treatment for apnea of prematurity in Saudi infants. KN Haque, M Al-Kharashi, C Waters, Theophylline Therapy for Apnea of Prematurity in Saudi Preterm Infants: Therapeutic Serum Level and Dosage. 1989; 9(2): 178-181 Theophylline, a methylxanthine derivative, is widely used in the treatment of apnea of prematurity.1,2 Although the pharmacokinetics of theophylline in preterm infants have been well studied, 3,4 the dose-response relationship has not been clearly established. Serum theophylline concentrations between 6 and 15 μg/mL have been suggested as optimal maintenance levels 1,5,6 for the treatment and prevention of apnea and bradycardia in preterm infants under 34 weeks of gestation. However, there is no general agreement, 7 and levels as far apart as 1.3 and 17.7 μg/ mL have been found to abolish apnea in preterm infants. 7This study on the use of theophylline in controlling apnea of prematurity set out to establish if a loading dose was necessary, and whether theophylline in a maintenance dose of 1.5 mg/kg/ day would be effective. Patients and MethodsOne hundred fifty infants with a gestational age of less than 34 weeks (assessed by maternal dates and Ballard scoring system 8 ) were enrolled in the study. Apnea of prematurity was defined for this study as an absence of thoracic movement for more than 20 seconds or by a shorter arrest of respiration accompanied by bradycardia (heart rate less than 100 beats per minute) 9 or by cyanosis. Standard criteria were used to exclude other causes of apnea. Also excluded from the study were infants with obstructive apnea. Heart rate and chest wall movements were monitored by continuous recordings of an impedance pneumograph. Infants who had apnea due to sepsis, metabolic causes, necrotizing entercolitis, intracranial hemorrhage, or sedative ingestion, and those gestationally past 34 weeks were excluded from the study.Infants matched for gestational age, sex, and weight were randomly allocated into two groups. Group A received 5 mg/kg of aminophylline (1.25 mg aminophylline equals 1 mg of theophylline) intravenously as a loading dose. Group B did not receive such a loading dose. Both groups were given regular maintenance therapy of 1.5 mg/kg/day every 8 hours. The maintenance dose was administered intravenously if the infant was not being fed orally; otherwise an equivalent amount of theophylline was given orally. Therapy was started when spells of apnea were prolonged and repeated (i.e., more than 2 to 3 spells per hour) or when the infants required frequent bag and mask ventilation to recover from apnea. The infants acted as their own controls, as it would be unethical to wit...

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“…Furthermore, patients with toxic theophylline levels may develop seizures without preceding adverse effects (10). Monitoring of serum theophylline levels has therefore been increasingly recommended in recent years (7,(11)(12)(13)(14)(15). Usually, serum levels of theophylline between 10 and 20 mg/1 provide substantial improvements in pulmonary function with minimal toxicity (8).…”

Section: Introductionmentioning

confidence: 99%

Monitoring of Serum Theophylline Concentrations by a Fully Mechanized Enzyme Immunoassay (EMIT)

Oellerich¹,

Gw²,

Haeckel³

1979

Clinical Chemistry and Laboratory Medicine

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Summary: An evaluation of an enzyme immunoassay for the determination of theophylline in serum (EMIT, Syva Corp.) is presented. The EMIT assay was fully mechanized by the use of an Eppendorf analyzer 5010. The precision of this enzyme immunoassay was satisfactory (coefficients of variation from day to day ranged from 5-6%). The EMIT assay proved to be specific, rapid and easy to perform. A comparison of the results obtained by EMIT and ultraviolet spectrophotometry in a series of 100 patients showed a good correlation between both methods. Überwachung der Theophyllinkonzentration im Serum mit einem vollmechanisierten Enzymimmunotest (EMIT)Zusammenfassung: Es wird über die Erprobung eines Enzymimmunotests zur Bestimmung von Theophyllin im Serum (EMIT, Syva Corp.) berichtet. Der EMIT-Test wurde mit Hilfe eines Eppendorf Enzymautomaten 5010 vollmechanisiert. Die Präzision dieses Enzymimmunotests war zufriedenstellend (die Variationskoeffizienten von Tag zu Tag lagen bei 5-6%). Der EMIT-Test erwies sich als spezifisch sowie rasch und einfach durchführbar. Ein Vergleich der Ergebnisse, welche mit EMIT und einer UV-Methode bei einer Serie von 100 Patienten erhalten wurden, ergab eine gute Übereinstimmung beider Verfahren.

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Theophylline pharmacokinetics in premature infants with apnea

Cited by 99 publications

References 3 publications

Theophylline Metabolism during the First Month of Life and Development

Theophylline Metabolism during the First Month of Life and Development

Theophylline Therapy for Apnea of Prematurity in Saudi Preterm Infants: Therapeutic Serum Level and Dosage

Monitoring of Serum Theophylline Concentrations by a Fully Mechanized Enzyme Immunoassay (EMIT)

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