Allen H. Neims

Pharmacokinetic Aspects of Theophylline in Premature Newborns

To characterize further the pharmacokinetics of theophylline in premature infants, its concentraion in blood was measured by high-pressure liquid chromatography after intravenous infusion given to six apneic premature newborns three to 15 days of age. Theophyllines apparent volume of distribution was 0.690 +/- 0.095 liters per kilogram (mean +/- S.E.), a value similar to that of children, but the half-life (30.2 +/- 6.5 hours) was nine times longer. Blood clearance rate (17.6 +/- 2.3 ml per kilogram per hour) was lower than plasma clearance rate (100 ml per kilogram per hour) of young children. At a total plasma concentration of 17 mg per liter, 56.4 +/- 3.8 and 36.4 +/- 3.8 per cent of the theophylline was bound to adult or full-term cord plasma proteins, respectively. Bilirubin and theophylline did not compete for plasma protein. Calculations suggest that a loading doses of 5.5 mg per kilogram and a maintenance dose rate of 1.1 mg per kilogram per eight hours would achieve and maintain a mean blood concentration of 8 mg per liter (about 10 mg per liter in plasma).

Pharmacokinetic analysis of the disposition of intravenous theophylline in young children

The disposition of a single intravenous dose of theophylline, 3.2 mg/kg, was studied using a high-pressure liquid chromatographic assay in ten asthmatic children one to four years of age. The man plasma theophylline clearance was 0.100 +/- 0.036 l/kg/hr, kel 0.49 +/- 0.30 hr-1, betat1/2 3.38 +/- 1.11 hr, alphat1/2 0.13 +/- 0.09 hr, and V1 0.25 +/- 0.13 1/kg. Plasma theophylline clearance was approximately 40% greater in these children than that reported in adults, mainly due to an increased rate of drug elimination. Large interindividual differences were observed. Analysis of data using either a two- or one-compartment model yielded almost identical dosage regimens designed to rapidly achieve and maintain a chosen plasma theophylline concentration. Calculations based upon mean values of pharmacokinetic constants predict that a maintenance dose rate for aminophylline of 30 mg/kg/day, after a loading dose of 5.6 mg/kg, would rapidly achieve and maintain a mean steady-state plasma concentration of theophylline of 10 mg/1. Potential toxicity of such a regimen has not been excluded, since therapeutic trials (with achievement of steady state) have not yet been conducted.

Pharmacokinetic profile of caffeine in the premature newborn infant with apnea.

The pharmacokinetic profile of caffeine was studied in 32 premature newborn infants with apnea: 12 following a single intravenous dose; 3 after a single oral dose; 7 during treatment with an initial empirical (high) maintenance dose schedule; and 10 during treatment with a revised (lower) dose schedule. Mean (+/- SE) AV d, t 1/2, ke1, and clearance following a single intravenous dose were 0.916 +/- 0.070 1/kg, 102.9 +/- 17.9 hours, 0.009 +/- 0.001/hours and 8.9 +/- 1.5 ml/kg/hour, respectively. Rapid absorption was noted with plasma concentrations of 6 to 10 mg/l achieved within 30 minutes to two hours following an oral dose of 10 mg/kg. Cpss of caffeine in infants given a high empirical dose (11.2 +/- 1.5 mg/kg/day) ranged from 22.5 to 84.2 mg/l (mean = 45.3) whereas a dose schedule based on kinetic data (2.5 mg/kg/day) yielded plasma concentrations ranging from 7.4 to 19.4 mg/l (mean = 13.7). We suggest a loading dose of 10 mg/kg intravenously or orally followed by a daily maintenance dose of 2.5 mg/kg/day administered as a single dose for the treatment and prevention of neonatal apnea.

Mitochondrial dna damage by bleomycin

We have modified a specific and sensitive method of detecting different forms of mitochondrial DNA (mtDNA) and utilized it to study bleomycin (BLM)-induced mtDNA damage. Intact, nicked circular, and linear forms of mtDNA were separated by gel electrophoresis, detected by Southern blot hybridization, and characterized by size markers and alkali treatment. DNA from BLM-treated mitochondria from liver, lung, and L1210 tumors were all equally sensitive to damage by BLM. The extent of BLM-induced mtDNA damage was dependent on experimental conditions. In vitro incubation of isolated mitochondria with BLM showed that 100 microM BLM caused complete conversion of intact to nicked and linear forms. Scission of mtDNA was more extensive if mitochondria were lysed in the presence of BLM than after several washings to remove the drug from the incubation media. Isolated mtDNA was extremely sensitive to BLM such that 10 nM BLM caused loss of intact form. The extent of mtDNA damage by BLM was decreased by the addition of EDTA.

Relative efficacy of phenytoin and phenobarbital for the prevention of theophylline-induced seizures in mice

We evaluated the efficacy of pretreatment with phenytoin and phenobarbital to prevent seizures in mice given convulsive doses of theophylline. The control LD50 for theophylline was determined in 48 mice by intraperitoneal injections of increasing doses without anticonvulsant treatment. Anticonvulsant effects were determined in 105 additional mice pretreated with either phenytoin 30 mg/kg (n = 35), phenobarbital 35 mg/kg (n = 30), or phenobarbital 60 mg/kg (n = 40) one hour before theophylline administration. The theophylline LD50 (95% confidence interval) was 239 mg/kg (range, 229 to 248 mg/kg) for controls, 204 mg/kg (range, 194 to 214 mg/kg) for phenytoin, 305 mg/kg (range, 288 to 323 mg/kg) for low-dose phenobarbital, and 319 mg/kg (range, 307 to 331 mg/kg) for high-dose phenobarbital. Each LD50 differed significantly from control (P less than .05). The phenobarbital groups were significantly different from phenytoin (P less than .05) but not from each other. Theophylline serum concentrations were not significantly different among groups after adjustment for different doses. The mean +/- SEM time to seizure in minutes after adjustment for theophylline dose was 23.5 +/- 4.0 minutes for controls, 5.7 +/- 7.5 minutes for phenytoin, 44.1 +/- 7.1 minutes for low-dose phenobarbital, and 63.7 +/- 6.5 minutes for high-dose phenobarbital.(ABSTRACT TRUNCATED AT 250 WORDS)

The two-compartment open-system kinetic model: A review of its clinical implications and applications

The purpose of this communication is to present an outline of the principles and methods of two-compartment kinetic analysis. Particular emphasis is given to the therapeutic significance of these concepts and to the magnitude of errors which can result from inappropriate use of simpler kinetic models. This outline should assist in the interpretation of the data reported in the follosing paper describing the pharmacokinetics of theophylline in young children.

Identification of children for whom routine monitoring of aminoglycoside serum concentrations is not cost effective

On the basis of our clinical impression that aminoglycoside serum concentration measurements did not result in dosage changes in many children with normal renal function, data collected during pharmacokinetic consultations were evaluated to identify pediatric patients for whom routine serum concentration monitoring would not be cost effective. The frequency of peak or trough concentrations outside the desired ranges was related to age and duration of therapy in 88 children with normal renal function who were given recommended doses of gentamicin or tobramycin. Trough concentrations were outside the target range (greater than 2 micrograms/ml) in five of 26 patients who had received more than 10 days of therapy or were older than 18 years of age. In contrast, troughs were less than 2 micrograms/ml and did not significantly increase over the course of therapy in all patients who were younger than 18 years of age and had received less than 10 days of therapy. This latter group represented 36% of all aminoglycoside pharmacokinetic consultation requests to our service. In addition, when infusion technique and sample time were meticulously controlled, peak concentrations were greater than or equal to 4 micrograms/ml in all patients who had received a dose of approximately 2.5 mg/kg. We conclude that routine peak and trough measurements are unnecessary in patients between 3 months and 18 years of age unless duration of therapy extends beyond 10 days, renal function is impaired, there is a clinical need for higher doses or shorter dosing intervals, or a potential nephrotoxin has been administered in the previous 3 months.

High intravenous phenytoin dosage requirement in a newborn infant

A term neonate was being treated with intravenous phenytoin. To maintain a serum level above 10 μg per milliliter and abolish seizure activity, it was necessary to carry out repeated serum concentration measurements, administer several loading doses, and administer an unusually large maintenance dose (25 mg per kilogram per day), divided into a short dosing interval (6 hours). Declining serum levels from postnatal days 8 to 13 on a constant dose of 9 mg per kilogram per day suggested that the rate of phenytoin metabolism was gradually increasing; rapid elimination was documented on day 18 by a half-life measurement of 8.8 hours from three samples. The changing pharmacokinetics were attributed to maturation of oxidative metabolism of phenytoin, concurrent phenobarbital administration, or both. The need for additional loading doses and maintenance dose increases must be guided by serum concentration measurements to obtain maximum benefit with minimal risk of toxicity.

Nitrofurantoin inhibition of mouse liver mitochondrial respiration involving NAD-linked substrates☆☆☆

In our study, nitrofurantoin (NF) and nitrofurazone (NZ) inhibited respiration of isolated mouse (C57B/6J, adult, male) liver mitochondria. Other aromatic nitro compounds, nitroimidazole, metronidazole, and p-nitrobenzoic acid, did not have any significant effect. The primary site of activity for NF was complex I NADH-ubiquinone oxidoreductase mediated respiration, since only complex I substrates, glutamate, beta-hydroxybutyrate, and alpha-ketoglutarate-mediated respiration were decreased. Respiration supported by succinate, a complex II substrate, was not affected by any of the compounds. NF at a concentration of 50 microM decreased state 3 and dinitrophenol-uncoupled respiration to 28 +/- 1 and 25 +/- 5% of control, respectively, of mitochondria oxidizing glutamate. Studies with mitoplasts oxidizing glutamate showed that NF inhibited both state 3 and 4 respiration. The inhibition of state 3 was prevented by the simultaneous addition of superoxide dismutase (240 micrograms/ml) and catalase (200 micrograms/ml). These results suggest that the mitochondrion, in particular complex I of the electron transport system, is a target for NF toxicity. The effect on respiration may be mediated by NF redox cycling and the generation of reactive oxygen intermediates resulting in the interference of electron flow.

Metabolism of caffeine by mouse liver microsomes: GSH or cytosol causes a shift in products from 1, 3, 7-trimethylurate to a substituted diaminouracil

Incubation of [14C]caffeine with hepatic microsomes from male AKR/J mice resulted in the formation of several metabolites including 1,3,7-trimethylurate and 6-amino-5-(N-formylmethyl-amino)-1,3-dimethyluracil. These two compounds comprised about 60% of products and are major urinary metabolites in several animals. When cytosol was included during incubation, there was a 14-fold increase in yield of the uracil at the expense of the urate; the combination of the two metabolites remained about 60% of total products. Cytosol alone was catalytically inert. Glutathione and other sulfhydryl compounds reproduced the effect of cytosol, and the action of cytosol was accounted for quantitatively by its sulfhydryl content. We propose that an oxidized intermediate of caffeine en route to trimethylurate is reduced by glutathione to the ring-opened uracil derivative.