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A descriptive profile for antipyretic drug action has been documented for children. However, a linked pharmacokinetic–pharmacodynamic (PK/PD) model is central to the understanding of antipyretic drug action in febrile children. This was examined for previously reported data from 178 febrile children who received a single oral dose of acetaminophen (APAP) (12.5 mg/kg), ibuprofen (IBU) (5 or 10 mg/kg), or placebo. Rectal temperatures and plasma levels (μg/ml) of APAP and IBU were measured for up to 12 hr after drug administration. Nonlinear regression analyses were applied to these measurements and yielded simultaneous solutions of an integrated one-compartment PK, link, and SigmoidEmaxeffect model in 102/153 febrile children given APAP or IBU. The PK parameters (tlag,ka, β,T1/2β,AUC0–∞,Vd/F,andClp/F) were not different than those reported previously, except the APAPkawas significantly lower. The link component yieldedkeos of 0.58±0.06 (X±SE), 0.70±0.11 and 0.57 ± 0.11 hr-1for APAP, IBU05, and IBU10, respectively: the SigmoidEmaxcomponent yieldedEC50s (μg/ml) and sigmoidicity (γ) of 4.63±0.39 and 3.98±0.42 for APAP, 11.33±1.35 and 3.97±0.58 for IBU05 and 12.83±1.89 and 4.27±0.63 for IBU10. On visual inspection of the efficacy–time profiles of the febrile children, a number of them had an apparent linear function (slope; Δ°C/hr) and/or a sinusoidal cyclic function “confounding” standard approaches to PD analysis. Thus, the temperature profiles of 91/102 children given APAP or IBU required the addition of a slope (Δ°C/hr) and/or a sinusoidal cyclic function to the SigmoidEmaxcomponent to fit the data satisfactorily. All 22 children given a placebo also required a slope and/or a cyclic function in their PD model. The residual Δ°Cs (observed-predicted) of the placebo group were not significantly different from 0. Thus, no placebo antipyretic effect was observed. Dose dependency of IBUAUC0–∞was confirmed; doubling the dose from 5 to 10 mg/kg increased theAUC0→∞by only 1.5-fold. The confounding effect of initial temperature (Tempi) on antipyretic efficacy in all treatment groups except placebo was also confirmed to expose nonlinear pharmacodynamics. A significant (p=0.03) contribution ofTempi(but not age) on the value of the slope function was found. There was no consistent effect of age orTempi, on the cyclic component of the integrated model of antipyresis. In addition, a multiple linear relationship of age andTempiwas observed with a large number of the PK, link, and PD variables in those who received IBU. Dose, age, andTempiinteracted with β in a significant multiple linear relationship withAUC0–∞. The effects of IBU dose, age, andTempiare pervasive and cascade down the chain of events leading to the PD response. The etiology of pyresis may create the slope function, the magnitude of which may be partially due to the underlying disease. In some cases, the cyclic function may be explained by temperature regulation. Regardless of their cause, both confound analysis of drug action and make the simple, unmodified SigmoidEMaxeffect model less than satisfactory for interpretation of antipyretic drug effects. The influence of Tempion the magnitude of antipyretic drug response is also a finding with major impact on PD investigations of antipyretic medications. In children receiving IBU, dose and age are also confounders, in addition toTempi. A multiplicity of covariables must be taken into account when developing appropriate dosing regimens for these antipyretics in febrile children.

Ibuprofen was evaluated as an antipyretic agent in 178 children (aged 3 months to 12 years) to compare dosage (5 vs 10 mg/kg), establish absolute efficacy (with a placebo control group), determine relative efficacy (ibuprofen vs acetaminophen), evaluate maximum efficacy, and identify potential confounding variables. Ibuprofen 5 mg/kg was minimally effective in children less than 6 years of age who had an initial temperature of at least 38.8 degrees C (101.9 degrees F). Ibuprofen 10 mg/kg was more effective for febrile children. The area under the curve for temperature (or change in temperature) captured the net effect of each drug and provided the best estimate for efficacy comparison during a defined period. A linear correlation between initial temperature and measures of efficacy was observed. A twofold increase in efficacy was observed for children with an initial temperature less than 38.8 degrees C. A similar effect was noted for each treatment group. Age was also found to have confounding effects on antipyretic response. A complex interaction between antipyretic response, initial temperature, and age raises questions about the pharmacodynamics of the antipyretic response. We conclude that the most important variable in antipyretic study design is initial temperature. The influence of initial temperature on the magnitude of the response to an antipyretic drug is a previously unappreciated finding with potential impact on pharmacodynamic investigations of antipyretic medications. We describe this finding as nonlinear pharmacodynamics.

Current acetaminophen (APAP) formulations approved for antipyretic use in children require up to five doses/day, which compromise compliance and risk breakthrough fever over 4 hours after dosing. A total of 112 evaluable febrile children received oral APAP-equivalent doses of either one dose of APAP controlled release (CR) as sprinkles on applesauce or one dose q 4 hours x 2 of APAP immediate-release (IR) elixir in an 8-hour, double-blind, double-dummy, randomized, multicenter study. Prior or concurrent antibiotic use did not significantly affect either the magnitude or the pattern of temperature reduction during the 8-hour observation period. Significantly greater aural temperature reductions were found with APAP-CR than with APAP-IR at 4 and 5 hours. However, the 8-hour AUCs of temperature reduction were not significantly different between treatments. Pharmacokinetic/pharmacodynamic modeling of APAP was performed in 8 patients with values in both treatments similar to previous results, except for expected differences in AUC0-infinity. Similar 8-hour temperature reduction for APAP-CR (one dose) and APAP-IR (two doses) demonstrates the efficacy of APAP-CR as an antipyretic in children 2 to 11 years of age. A decrease in the number of APAP daily doses and the prolonged antipyretic effect of APAP-CR may assist those who care for febrile children at home.

The developing rat is hypersensitive to aminoglycoside ototoxicity during the period of anatomical and functional development of the cochlea. Toxicity is expressed only after a few days of treatment when kanamycin is given during the most sensitive period for production of ototoxicity (postnatal days 11-20). In contrast, when the drug is administered after the 20th postnatal day, the same dose and duration of treatment do not produce an ototoxic effect. Only after prolonged treatment (e.g., > or = 20 days) is there an observed effect. We characterized the pharmacokinetics of kanamycin in the serum of 12- and 25-day-old rats and observed a greater than 2.5-fold increase in elimination half-life in the 12- versus 25-day-old rat. The longer duration half-life of kanamycin in younger rats may explain the hypersensitivity of immature mammals to aminoglycoside ototoxicity.

Conflicting reports raise a question about decreased plasma clearance (Cl p ) of theophylline in man during viral infections. Thus a dilemma exists concerning requisite dose adjustments. We examined this issue by retrospectively evaluating theophylline Cl p in children infected with respiratory syncytial virus (RSV). Two pharmacokinetic approaches were applied to a one-compartment open model to fit theophylline concentrations during 83 hospitalizations of 76 children, 6 to 48 months of age, who received intravenous theophylline therapy and were tested for RSV infection. Iterative linear regression analyses of all theophylline data were used to estimate apparent volume of distribution, elimination rate constant, plasma half-life, and Cl p in 39 of the hospitalizations. When insufficient data were available to distinguish apparent volume of distribution and elimination rate constant (n=44), steady-state estimates of Cl p were calculated. An age-matched and percentile body weight-matched cohort design presented RSV as the primary covariate. Theophylline Cl p was similar in 29 matched RSV-infected and -uninfected pairs (1.32±0.14 and 1.25±0.05 ml/kg perminute, respectively), as were other pharmacokinetic values. Unexpectedly, a significant, inverse linear relationship was found for Cl p and percentile body weight. Additionally, children born prematurely and hospitalized in the neonatal intensive care unit had significantly higher theophylline Cl p ; this did not affect findings regarding RSV infection. Theophylline Cl p was not decreased in RSV-infected children. Current theophylline dosing recommendations for young children infected with RSV should not be altered, but careful monitoring of plasma theophylline levels should be continued.

Twenty-seven cats were recorded from the scala media of the cochlea in order to evaluate the reduction in the positive endocochlear dc potential (EP) produced by iv bumetanide and to compare these changes to the bumetanide-induced N1 depression observed previously. A linear relationship does exist between the dose of bumetanide administered and the resultant mV reduction of the EP. The equation for the regression line of this dose-response to bumetanide is y (maximal reduction of EP) = 259.5 + 92.8 × (log mmol/kg iv bumetanide). The maximal reduction of EP occurring within 1 min after the larger doses of bumetanide correlates well with changes in N1 previously observed after similar doses. When multiple linear regression analysis is performed, the amount of N1 depression produced by a particular dose of bumetanide is found to be linearly related to the amount of EP reduction produced by that dose of bumetanide. These data indicate that the acute ototoxicity produced by this “loop” diuretic is due to its effect on EP.

Ototoxicity limited the use of the antitubercular drug, streptomycin, and there are many other drugs with similar damaging side-effects. Cochlear toxicity represents one form of ototoxicity, and studies may include analyses of behavioral, anatomical, electrophysiological and biochemical changes. However, each parameter has drawbacks and limitations, and in this review Charles Henley and Don Brown discuss why a combined electrophysiological and anatomical approach represents the most effective method of assessing risk of ototoxicity.

The plasma and milk disposition of flurbiprofen (FB) was assessed in healthy women during the early post-partum period after multiple doses of FB. The results confirmed that a pragmatic study design is an attainable requirement for definitive statements about the excretion of FB in transitional milk. Nine doses of FB (50 mg per dose) were administered during three days. Paired milk and plasma samples were obtained during this period of dosing as well as after the last dose. The plasma data were used to derive an equation, which was then used to simulate cumulative plasma profiles for multiple doses given at unequal time intervals. The observed data corresponded to the simulated cumulative profiles of FB in plasma. The plasma elimination half-life of FB during early lactation was slightly prolonged (mean 4.8 hrs) as compared to reported values for normal adult men. The peak plasma concentrations of FB were comparable to those reported for healthy volunteers. In 10 of 12 women (3-5 days post-partum) the FB concentration in breast milk was less than 0.050 micrograms/ml. In two women the milk concentrations of FB were 0.06, 0.07 and 0.07 micrograms/ml as found in only three samples. We conclude that, on the basis of dose found in milk, FB is safe for women breast feeding their infants in the early post-partum period.

Many antimicrobial medications may be administered to paediatric patients with a degree of impunity because they are relatively non-toxic and have a wide therapeutic margin. However, because of different pharmacokinetics from those in adults, the potential for toxicity exists with the use of some of these agents. Drug absorption in paediatric patients, either orally or parenterally, is generally similar to that in adults, except among neonates and, particularly, premature neonates. Similarly, in neonates, drug distribution is altered, plasma protein binding is decreased and hepatic metabolism and renal excretory capacity are limited by physiological immaturity. Thus, in neonates, only drugs that have pharmacokinetically derived dosage schedules should be used, and therapeutic monitoring of plasma drug concentrations is recommended during therapy with aminoglycosides, vancomycin and chloramphenicol. In older infants and children, the pharmacokinetics of antimicrobial drugs generally approximate those in adults, and recommended dosages have been determined relative to bodyweight. Therapeutic monitoring of plasma drug concentrations may be important in certain patients, such as those with major organ failure, and may be useful in cases of suspected noncompliance. Additional pharmacokinetic considerations concerning antimicrobial medication and paediatric patients are the extent to which drug therapy penetrates the cerebrospinal fluid in meningitis, and the potential for and implications of exposure of infants to antimicrobial medications excreted in breast milk.

In response to "Aspirin and Reye Syndrome" by the Committee on Infectious Diseases of the American Academy of Pediatrics (p 810), we offer comments which are restricted to our analysis of existing epidemiologic study data, portions of which were provided to us by the Ohio, Michigan, and Arizona investigators. This commentary should not be construed as our approval or disapproval of aspirin use in children. Rather, it summarizes our specific disagreements with the interpretation of the state epidemiologic data that were the basis of the report by the Committee on Infectious Diseases. We have found that an unassessed confounding variable of large magnitude is common to the state studies.

Comparisons were made of the effects of various doses of intravenous bumetanide and furosemide on the primary auditory afferent activity (N1) and cochlear microphonics (CM) of beagles. The dose-response relationships of the N1 depressions to bumetanide and furosemide are parallel; those of the CM depressions are also parallel but have a much shallower slope than those of the N1 depressions. With both drugs, N1 depression occurs at lower doses than does CM depression. The N1 depression produced by a particular dose of bumetanide or furosemide bore a linear relationship to the CM depression produced. This finding supports the postulate that the cochlear site and mechanism of ototoxic action of the loop diuretics are directed at an earlier step of the cochlear transduction process than N1. Using N1 depression as the gross electrophysiologic index of ototoxicity, the acute ototoxic potency of bumetanide in beagles is approximately 6.5 times that of furosemide, whereas its diuretic potency is 40 to 60 times that of furosemide. Therefore, when clinical dosages of the two drugs are considered, the relative acute ototoxic potency of bumetanide in the beagle is 0.11 to 0.16 that of furosemide. This range is identical to the relative ototoxic potency of 0.11 to 0.16 previously obtained in the cat. Serum concentrations of bumetanide and furosemide increased linearly with the doses of the two drugs, except for the highest dose given (100 mg/kg for both drugs). The serum concentrations at that dose of both drugs are less than the mathematically predicted values. Histologic (light-microscopic) examination of the cochleas did not reveal any significant pathology.

We have emphasized the variance of the M/P ratio with time after dosing (1). This variance is kinetically determined. Accordingly, variance in the M/P ratio may be confounded by factors altering the kinetic profile of drug concentration in the fluid of reference i.e., blood or milk. These factors include dose, route and duration of administration. We have evaluated each of these for their contribution to the temporal variance of the M/P ratio (2). These pharmacological manipulations were performed by using the goat as an animal model and with acetaminophen (APAP) as the test drug. Acetaminophen was chosen because it has a short elimination half-life and can be administered by either the oral or intravenous route in the goat.

A single-point estimate of the milk to plasma (M/P) drug ratio presupposes an invariant ratio. This may lead to erroneous conclusions about the amount of drug excreted in breast milk. A variance of the M/P ratio with regard to time has been shown for acetaminophen under standardized biologic conditions in the lactating goat. This ratio is potentially confounded by such factors as route of administration, dose amount and duration of exposure to the drug. Each factor was evaluated by computer simulations of the M/P ratio and by derivation of a ratio from empirical data in the goat. Route of administration was found to influence both the pattern and magnitude of the M/P ratio after acetaminophen dosing in the goat. Similar, but less, effects were found for duration of dosing. Dose itself did not influence the ratio. A temporal basis exists for each confounding factor. We thus propose that the M/P ratio is fundamentally variant with time under a standard set of biologic conditions. The contributing variance of confounding factors must be assessed if drug in milk dosing of the infant is to be accurately evaluated by use of the M/P ratio.

Cats were prepared to record from the cochlear round window. The cochlear potential (N 1 ) is depressed by 15–30 μg of acetylcholine administered intra-arterially before and after section of the eighth cranial nerve. The acute administration of 1.0 mg of quinine, streptomycin, kanamycin, and neomycin blocked the peripheral effectiveness of acetylcholine for durations of 20, 20, 60, and more than 120 min, respectively. The effects of dihydrostreptomycin were similar but not statistically significant. Animals treated for 7–9 days with daily subcutaneous injections of streptomycin (300 mg/kg) or neomycin (100 mg/kg) displayed a different type of dose-response than that of the controls. Eighth nerve section eliminated these responses, indicating that the antibiotics blocked the peripheral effects of acetylcholine and activated central efferent sites. While it is likely that the ototoxicity produced by these agents is correlated with their known ability to concentrate in the cochlear fluids, an additional central action upon neurons of the auditory pathways can be postulated. The disruption of the normal activity in this modulatory system could play an important role in the initiation of events resulting in ototoxicity.

Previously described experiments [Arch. Int. Pharmacodyn. 162, 20 (1966)] have shown that acetylcholine bromide (20 μg/dose) injected into the arterial supply (i.a.) of the cochlea will produce suppression of the N1 recorded from the round window of the cat. This depression is similar to that produced by stimulation of the olivocochlear bundle (Nature 192, 1263 (1961)]. With such evidence and other indications from the literature, it is possible to consider that some role may be played by acetylcholine in the cochlea. In an acutely sectioned cat in i. a., injection of acetylcholine is as effective as before the section (25% N1 depression, 17 observations). We concluded that the system responsive to acetylcholine is in the cochlea proper. Subsequently, cats that had previously had their left eighth cranial nerves sectioned from two to five days were tested as to their responsiveness to i.a. acetylcholine. In six animals, four or five days after section, 2 μg of acetylcholine produced a 22% depression of N1...