To determine the effect of iron status on the seizure threshold, measures of iron sufficiency were prospectively evaluated in 51 children presenting to a pediatric emergency department with a febrile illness with (26) or without (25) an associated febrile seizure. A higher proportion of children from the febrile seizure group had a family history of mental retardation (5/26 versus 0/25, P = .02) or of previous febrile seizures (10/26 versus 2/23, P = .01). The two groups were otherwise comparable for age, sex, race, family history of afebrile seizures, temperature at presentation, white blood cell count, differential, and vitamin and antibiotic use. Patients with febrile seizures were less frequently iron deficient as defined by a free erythrocyte protoporphyrin level above 0.80 ng/L (2/23 versus 10/25, P < .01), hemoglobin concentration less than 110 g/L (1/26 versus 6/25, P < .03), hematocrit less than 0.30 L/L (0/22 versus 4/25, P < .02), mean corpuscular hemoglobin less than 20 pg (0/25 versus 3/24, P < .04), mean corpuscular volume less than 65 fL (0/26 versus 4/24, P < .02), and platelet count higher than 550 x 10(9)/L (0/26 versus 3/25, P < .04). This association was even stronger when adjusted for differences in family history. None of the patients in the febrile seizure group was being treated for iron deficiency at presentation, whereas three of 25 controls used an iron supplement (P < .04). Iron deficiency may protect against the development of febrile seizures.
All eight components tested were contaminated with trace elements not intended to be present in the product, and similarly, the multi-trace element component contained trace elements either above or below that which the label claimed.
The combination of pharmacokinetic and pharmacodynamic monitoring of immunosuppressive drugs provides a novel method for the optimization of drug dosing. We chose to investigate this with the use of mycophenolic acid (MPA), an immunosuppressive drug that mediates its effect by the inhibition of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo biosynthesis of purines. The relationship between MPA concentration in plasma, IMPDH activity in whole blood, and nucleotide concentration in lymphocytes was investigated in renal-transplant recipients, who were randomized to receive either mycophenolate mofetil (MMF) (n = 5) or azathioprine (AZA) (n = 7), in combination with cyclosporine and prednisone. Blood samples were collected throughout the dosing interval. Pharmacokinetic analysis revealed substantial variability among the patients in the absorption and clearance of MPA. An inverse relationship was found between the MPA concentration of IMPDH activity in whole blood. The peak concentration of MPA achieved at 1 hr after dosing resulted in approximately 40% inhibition of IMPDH activity. As the MPA concentration decreased throughout the dosing interval, there was a gradual restoration of IMPDH activity. The inhibition of IMPDH activity (P < 0.05) in MMF-treated patients as compared with the AZA-treated controls was maintained for approximately 8 hr after dosing. No statistically significant (P > 0.05) difference between the predose and the 12 hr postdose activity was observed. The concentrations of guanine nucleotides, GDP and GMP, were significantly lower than in the AZA-treated group at most of the time points after dosing; however, considerable variability was observed. The measurement of the pharmacodynamic response to immunosuppressive drugs may provide not only a mechanism to predict the most appropriate dosing regimen, but also a viable alternative to traditional therapeutic drug monitoring, by assessing the overall state of immunosuppression.
The combination of pharmacokinetic and pharmacodynamic (measurement of the biological effect) monitoring of immunosuppressive drugs provides a method for the optimization of drug dosing. We chose to investigate this using mycophenolic acid (MPA), an immunosuppressive drug that mediates its effect by the inhibition of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo biosynthesis of purines. Using an assay developed for measurement of IMPDH activity in whole blood, the concentration required for 50% inhibition of IMPDH activity was approximately 200 mg/L (58 +/- 8.3% for whole blood [n = 6] and 55 +/- 10.0% for isolated lymphocytes). To ascertain the relationship between MPA concentration and IMPDH inhibition in vivo, dogs were administered a single dose of mycophenolate mofetil, the pro-drug of MPA, at 20 or 40 mg/kg orally. Pharmacokinetic analysis revealed that the Cmax of the 40-mg/kg group was statistically greater than that of the 20-mg/kg group (P < 0.05). There were no statistical differences in the other parameters investigated (area under the curve, beta half-life, mean residence time, volume of distribution at steady state, and clearance) between the two treatment groups. The half-life was calculated at approximately 8 hr for both dose groups. There was also substantial variability among the dogs in the absorption and clearance of MPA. An inverse relationship was found between the MPA concentration and IMPDH. Maximal inhibition of IMPDH activity of 30-40% occurs approximately 2-4 hr after dosing, followed by a gradual restoration in enzyme activity. After 24 hr, there is an increase in IMPDH activity that exceeds the pre-dosing levels in some cases by 3-fold. Evaluation of the pharmacokinetic and the pharmacodynamic responses to MPA in the canine model suggests that the drug should be administered ever 8 hr to optimize its immunosuppressive efficacy. This combined approach can be used for optimization of doses of this and other immunosuppressive drugs.
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