Theophylline in children

Ellis EF, Koysooko R, Levy G (1976) Pharmacokinetics of theophylline in children with asthma. Pediatrics 58 542-547. 

Hendeles, L. Weinberger, M. Szefler, S. Safety and efficacy of theophylline in children with asthma. J. Pediatr. 1992, 120, 177-183. 

Dosage Guideline for Theophylline (based on anhydrous theophylline) in Children Older Than 6 Months and Adults Who Have No Risk Factors for Decreased Theophylline Clearance ... 

Garty M, Scobiik D, Danziger Y, Volovitz B, Ilfeld DN, Vaisano I. Non-interaction of ketotifen and theophylline in children with astiima an acute stuffy. EurJClinPhannacol( 9S7)... 

The quinolones have been found to cause erosion of cartilage in the joints of immature animals [56]. This observation, which has been seen in several studies, has resulted in the contraindication of quinolones for the treatment of children. A study analyzing the risk-benefit situation for the use of pefloxacin in children (clinically, several adverse athralgic effects have been attributed to this agent) has appeared [57]. The underlying mechanism responsible for these effects has yet to be established, and the development of an agent which is safe for paediatric use would be a major advance in quinolone therapy. Some of the quinolones, such as enoxacin, have been shown to interfere with theophylline metabolism [58], and side-effects associated with this agent may be related to this property. 

In summary, the adverse effects associated with the quinolones appear presently to be mild to moderate in severity and reversible upon discontinuation of therapy. Severe systemic adverse reactions are rare [62], It is suggested that the use of these agents should be avoided, as far as possible, in children and pregnant women and that caution be used in their administration to patients with a seizure disorder or those taking theophylline or warfarin [62]. Articles suggesting the appropriate clinical usage for these important antibacterials have appeared [64],... 

As with adults, the primary organ responsible for drug metabolism in children is the liver. Although the cytochrome P450 system is fully developed at birth, it functions more slowly than in adults. Phase I oxidation reactions and demethylation enzyme systems are significantly reduced at birth. However, the reductive enzyme systems approach adult levels and the methylation pathways are enhanced at birth. This often contributes to the production of different metabolites in newborns from those in adults. For example, newborns metabolize approximately 30% of theophylline to caffeine rather than to uric acid derivatives, as occurs in adults. While most phase I enzymes have reached adult levels by 6 months of age, alcohol dehydrogenase activity appears around 2 months of age and approaches adult levels only by age 5 years. 

Most drugs are administered to infants and children for the same therapeutic indications as for adults. However, a few drugs have found unique uses in children. Among these are theophylline and caffeine, which are used to treat apnea of prematurity indomethacin, which closes a patent ductus arteriosus and prostaglandin Ej, which maintains the patency of the ductus arteriosus. Paradoxically, drugs such as phenobarbital, which have a sedating action on adults, may produce hyperactivity in children, and some adult stimulant drugs, such as methyl-phenidate, are used to treat children with hyperactivity. 

Warnings Safety and efficacy of ciprofloxacin has not been established in children, adolescents, pregnant women, and lactating women Convulsions have been reported in patients receiving ciprofloxacin Serious and fatal reactions have been reported after the co-administration of ciprofloxacin and theophylline Serious hypersensitivity reactions have occurred Pseudomembranous colitis has been reported... 

In the rat, development to adult levels of activity takes about 30 days after which levels decline toward old age. In humans, however, hydroxylase activity increases up to the age of 6 years, reaching levels greater than those in the adult, which only decrease after sexual maturation. Thus the elimination of antipyrine and theophylline was found to be greater in children than in adults. It should be noted, however, that proportions of isoenzymes may be very different in neonates from the adult animal, and the development of the isoenzymes may be different. Thus, in the rat there seem to be four types of development for phase 1 metabolizing enzymes linear increase from birth to adulthood, type A (aniline 4-hydroxylation) low levels until weaning, then an increase to adult levels, type B (N-demethylation) rapid development after birth followed by rapid decline to low levels in adulthood, type C (hydroxylation of 4-methylcoumarin) and rapid increase after birth to a maximum and then decline to adult levels, type D. Patterns of development may be different between sexes as well as between species. For example, in the rat, steroid 16-a-hydroxylase activity toward androst-4-ene-3,17-dione develops in type B fashion in both males and females, but in females, activity starts to disappear at 30 days of age and is undetectable by 40 days. It seems that the monooxygenase system develops largely as a unit, with the rate dependent on species and sex of the animal and the particular substrate. 

Ginsberg G, Hattis D, Russ A, Sonawane B (2004c) Physiologically based pharmacokinetic (PBPK) modeling of caffeine and theophylline in neonates and adults Implications for assessing children s risks from environmental agents. J Toxicol Environ Health A, 67(4) 297-329. 

The concern that cognitive function may be impaired in children taking theophylline is still not resolved (SEDA-14, 1) (SEDA-15, 1) a review has suggested that detrimental effects of theophylline on various measures of cognitive function may be measure-specific (615). 

The quinolones are contraindicated in patients with a history of hypersensitivity to any drug in this family. Absorption of the fluoroquinolones is reduced by antacids, iron, and zinc salts, and thus they should not be taken concurrently. Oral ciprofloxacin and enoxacin inhibit the metabolism of theophylline, and toxicity can occur when these two drugs are administered concurrently. Oral administration of the fluoroquinolones can cause convulsions and should therefore be done with caution in patients with central nervous system disorders. These drugs are not recommended for systemic administration in children, adolescents younger than age 18 years, or pregnant women. Topical administration is contraindicated for use in patients younger than 1 year of age. 

Ueno K, Kasuhiko T, Shokawa M, HoriuchiY. Age-dependent changes of renal clearance of theophylline in asthmatic children [letter]. Ann Pharmacother 1994 28 281-2. 

Most medications have shorter half-lives in children than in adults, and therefore children may need sustained-release products to maintain serum concentrations in the therapeutic range. For example, a sustained-release theophylline product may be needed for a child with asthma. It may need to be administered every 8h to the child as compared to every 12 h for a healthy, non-smoking adult to maintain therapeutic serum concentrations. When choosing a sustained-release theophylline preparation for a child, it must be remembered that because of differences in release properties, theophylline sustained-release products are not interchangeable. A product selected for the pediatric asthma patient should be reliably absorbed with a minimal serum concentration variation and not a preparation that has exhibited a difference in bioavailability when administered with or without food.[ > - ]... 

Miura T, Kimura K. Theophylline-induced convulsions in children with epilepsy. Pediatrics 2000 105(4 Part 1) 920. 

The emergency department use of aminophylline, a moderate bron-chodUator, for acute asthma has not been recommended for a number of years. Clinical trials of aminophylline in adults and children hospitalized with acute asthma have not reported sufficient evidence of efficacy (improvement in lung function and reduced hospital stay) but have reported an increased risk of adverse effects. However, two smdies of aminophylline in children with severe disease suggested a possible small benefit in reducing intensive care unit admissions. Adverse effects of theophylline include nausea and vomiting and potentiation of the cardiac effects of the inhaled /32-agonists. 

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