Richard Mo

Maturation of caffeine metabolic pathways in infancy.

The maturation of the different pathways of caffeine metabolism was studied during infancy. The group of children (n = 14) consisted of four premature newborn infants and 10 older infants who received caffeine citrate solution. Caffeine and 11 of its metabolites were measured by HPLC. Total demethylation and N3‐ and N7‐demethylation increase exponentially with postnatal age; the plateau is reached by 120 days and accounts for 58.6%, 90.5%, and 79.3%, respectively. N1‐demethylation shows no variation with postnatal age. It is suggested that N3‐demethylation is more important in young infants than in adults and that maturation of N1‐demethylation occurs later than 19 months of age. 8‐Hydroxylation is mature as early as 1 month of age and may be higher in infants than in adults. Acetylation is not mature before at least 1 year of age. Differences in maturation rate of acetylation may be related in part to genetic acetylator status.

Caffeine acetylator phenotyping during maturation in infants

ABSTRACT: Caffeine acetylator phenotype was studied during maturation in 54 8− to 447-d-old children hospitalized for minor disease (group A) and in five 3− to 630-d-old children with Pierre Robin syndrome (group B). In group A, the children received 2.5 mg/kg caffeine orally once between birth and 15 mo. Group B patients were chronically treated with caffeine (2.3 to 15.8 mg/kg/d) for prevention of apneas, and the acetylator phenotype was serially determined. Phenotyping was performed on a spot urine sample collected 2–6 h after drug administration. Caffeine metabolites [5-acetylamino-6-formylamino-3-methyl uracil (AFMU), 1-methylxanthine, 1-methyluric acid, 1,7-methyluric acid, and 1,7-methylxanthine) were measured using HPLC. Acetylator phenotype was determined on the basis of AFMU/1-methylxanthine (ratio 1) and AFMU/AFMU + 1-methyluric acid + 1-methylxanthine + 1,7-methylxanthine + 1,7-methyluric acid (ratio 2) molar ratios. In group A, all children were slow acetylators before 83 d of age (ratio 1 < 0.4; ratio 2 < 0.08), whereas older children included slow and fast acetylators. The acetylation molar ratios differed significantly between age groups and increased with age. The cumulative percentage of fast acetylators increased with age but the plateau was not yet reached at 15 mo. In three children, the phenotyping was repeated after 15 mo: the second determination was consistent with the first one. In group B, all children appeared as slow acetylators on the first phenotyping. Four of them appeared subsequently as fast acetylators; one remained a slow acetylator until 11 mo. These results suggest that maturation of caffeine acetylation occurs during at least the first 15 mo of life for fast acetylators but is not detectable in slow acetylators. Acetylator status cannot reliably be determined before at least 15 mo.

Maturation of caffeine N-demethylation in infancy: a study using the 13CO2 breath test.

ABSTRACT: Four premature neonates and eight infants 1–19 months old received caffeine for apnea. The usual morning oral dose was substituted by 1,3,7 13C-trimethylxanthine (13C-tri CAF) as the citrate salt. Five breath samples were collected the day before (day 1) and the day of 13C-tri CAF administration (day 2). Plasma (after each breath collection) and urine were collected on day 2.13C-CO2 exhalation was determined by isotope ratio mass spectrometry. Caffeine and its metabolites were measured using high-pressure liquid chromatography. Assessment of the labeled CO2 in the breath revealed no detectable 13C-tri CAF N-demethylation activity in infants before 45 wk postconceptional age. However, demethylation (as urinary metabolites) has been detected before that age. Two-, 4-, and 6-h cumulative excretion of 13C-tri CAF as 13C-CO2 increased with postnatal age and correlated with caffeine plasma clearance (r = 0.840, p < 0.01). These results were consistent with those obtained for urinary metabolites. In one infant (19 months old) the cumulative excretion of 13C-CO2 while crying was 65% of the value observed during quiet breathing. The measurement of caffeine demethylation using the caffeine CO2 breath test is feasible in infants and is a safe and noninvasive method to determine age related changes in P4501-dependent N-demethylase activity.

Developmental changes of caffeine elimination in infancy

Five neonates (4 premature) and 16 infants (6 prematurely born), 15-588 days old, received caffeine as citrate salt for apnea. Plasma samples were collected 0, 2, 4, 6 h after a dose and before the next scheduled one. Patients 8 and 9 were serially studied. Caffeine plasma concentrations were determined using HPLC. The caffeine elimination half-life and clearance varied linearly with gestational age and exponentially with postnatal age, the plateau being reached during the second trimester of life. Dose regimen guidelines as a function of postnatal age were derived from individually calculated doses and dosing intervals in order to achieve, at steady state, a caffeine mean plasma concentration of 11 mg/l with a minimum of 7.5 mg/l and a maximum of 14.5 mg/l. We suggest dosing intervals for infants before 1 month, 1-2 months, 2-4 months and after 4 months to be equal to 24, 12, 8 and 6 h, respectively. The individual recommended dose varies from 2 to 10 mg/kg (as caffeine base) making caffeine monitoring mandatory in infants.

Transfer of Salbutamol in the Human Placenta in vitro

The maternal-fetal transfer of Salbutamol was studied in vitro, in dual perfusion of isolated human placental lobules. The fraction of drug transferred to the fetal side was compared to reference substances:((14)C)-antipyrine and ((3H)-inulin. Salbutamol transfer (12%) represents about 39% of antipyrine and five times of inulin transfer. Studies with varying Salbutamol concentrations in the maternal arterial perfusate revealed that the drug transfer to the fetal side was effected by a flow-dependent diffusion process. We conclude that the reported effects on the fetus following a maternal drug infusion are mediated by the drug transferred across the placenta.

Influence of aspirin on the hemodynamic effects of sublingual nitroglycerin.

We studied the possible interaction between aspirin and nitroglycerin (NTG) in seven healthy volunteers. Effects of NTG (0.8 mg sublingual spray) were assessed by the decrease in diastolic arterial pressure, increase in heart rate, and decrease in M-mode echocardiographic end-diastolic and end-systolic diameters of the left ventricle. Measurements were performed before and during 30 min after NTG. Plasma levels of NTG were monitored during the experimental procedure. Each of the following trials was repeated three times, in random order, in each volunteer: NTG without aspirin pretreatment, NTG 1 h after 1 g of oral aspirin, and NTG after 8 days of aspirin. 500 mg every 48 h. Aspirin at the 1-g dose level significantly increased the effects of NTG on diastolic blood pressure (p < 0.05) and left ventricular end-diastolic (p < 0.001) and end-systolic (p < 0.001) diameters. Aspirin (1 g) significantly increased (p < 0.01) mean NTG plasma levels from 0.24 ± 0.13 ng . ml−1 (control) to 0.37 ± 0.26 ng . ml−1. We conclude that pretreatment with 1 g of aspirin increases NTG plasma levels and therefore significantly enhances the pharmacodynamic effects of NTG.

I. Catecholamines in developing rat lung

Abstract The development of the catecholaminergic system of lung was investigated in Sprague-Dawley rats during the perinatal period and in young adults. A radio-enzymatic procedure allowed to measure as little as 1 pg of noradrenaline or dopamine in each sample. The dopamine levels were low and independent of age. The noradrenaline levels increased significantly with the age until the 20th post-partum day. No significant differences were found between noradrenaline levels for males vs females at any age. Small differences between males and females for dopamine levels existed only near birth.

Pharmacokinetic Interactions between Theophylline and Rioprostil

The study is of double-blind crossover design. The effects of rioprostil, an analogue of prostaglandin E1, at a dose of 300 micrograms b.d., and placebo on the kinetic of slow-release theophylline are investigated. Eight healthy male volunteers participate in the study, each study period lasting for one week. During the first period, the doses of theophylline are altered in response to measured theophylline levels, 200 mg or 400 mg b.d. Regardless of placebo or rioprostil treatment, side effects appear before day 6 and are related specifically to theophylline administration. Blood samples are taken on days 4 and 5 to check steady-state plasma levels of theophylline and on days 6 and 7 to determine the main pharmacokinetic parameters. The same schedule is used for the second period of treatment. The achievement of steady-state concentration is verified. The mean pharmacokinetic parameters do not show a significant difference when slow-release theophylline is given alone or with rioprostil. These results are likely to be clinically relevant and, therefore, the theophylline dose should not be changed if rioprostil is prescribed at the same time as the theophylline.

[3H]-Salbutamol placental transfer in pregnant rats on the 19th day of gestation.

[3H]-salbutamol added in tracer doses (approximately equal to 250 nmol per animal) to the carrier solution (20 mg/kg) was injected intraperitoneally to pregnant rats on the 19th day of gestation. Some experiments were performed with intravenous administration (approximately equal to 2.5 microCi in 300 microliters 9 g/l NaCl). Drug distribution was studied in the maternal and fetal plasma, lung and liver, and in the placenta and amniotic fluid. 10% of the maternal salbutamol plasma radioactivity was recovered in the fetal plasma, in accordance with earlier findings reported from our laboratory using human placental lobules in vitro.

Maternofetal transfer of two benzodiazepines. Effect of plasma protein binding and placental uptake.

The influence of plasma protein binding on the maternofetal transfer of diazepam was studied in the perfused human placental lobule. Substitution of buffered salt perfusate in both maternal and fetal circuits for a perfusate with plasma proteins did not alter diazepam transfer significantly. Diazepam placental uptake was shown to be important in perfusion, with both types of perfusates. Comparison with the less liposoluble and less protein-bound benzodiazepine, fosazepam, revealed a marked difference in placental uptake but not in maternofetal transfer. In incubation studies, the kinetics of placental uptake confirmed this difference.