No abstract

Pharmacodynamic models for "directly suppressive" effects of methylprednisolone are based on the premise that receptor interactions of steroids are followed by immediate suppression of either the circadian secretion of cortisol or the constant rate recirculation of histamine-containing basophils that persists until inhibitory concentrations of methylprednisolone disappear. Methylprednisolone doses of 0, 10, 20, and 40 mg were given as the 21-succinate sodium salt in a balanced crossover study to six normal men. Plasma steroid concentrations and blood histamine were measured simultaneously. Both forms of methylnisolone exhibited linear kinetic parameters. One dynamic model quantitates the baseline circadian pattern and the decline and return of cortisol with similar parameter estimates for all three dose levels. A similar model describes the monoexponential decline and the log-linear return to steady-state baseline of blood histamine. Similar inhibitory concentration values for both effects approximated the equilibrium dissociation constant of in vitro steroid receptor binding. The new models are more physiologically appropriate for these steroid effects than three other models that are commonly employed in pharmacodynamics. Steroid effects generally appear to be receptor mediated with either nongene immediate responses or gene-mediated delayed effects. These models allow quantitation of the rapid effects of steroids with simple equations and common fitted parameters for all steroid dose levels.The diverse immunosuppressive and the antiinflammatory effects of glucocorticoids in human beings complicate the development of realistic and comprehensive kinetic and dynamic models for this class of agents. This is partly because of the complex mode of action of corticosteroids, which involves receptor binding and the formation of second messengers and proteins (which is mediated by deoxyribonucleic acid [DNA]). Such responses are typically characterized by a slow and delayed induction period. This receptorReprint requests: William J. Jusko, PhD, 565 Hochstetter Hall, School of Pharmacy, State University of New York at Buffalo, Buffalo, NY 14260. Presented in part at the Third Annual Meeting of American Association of Pharmaceutical Scientists (AAPS), Orlando, Florida, Oct. 30 to Nov. 3, 1988. NIH Public Access Author ManuscriptClin Pharmacol Ther. Author manuscript; available in PMC 2014 October 23. Published in final edited form as:Clin Pharmacol Ther. 1989 December ; 46(6): 616-628. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript gene mode of action has been successfully modeled for prednisolone effects in rats. 1,2 In human beings, pharmacodynamic modeling of glucocorticoid responses has focused on Sheiner's model 3 of linkage of a hypothetical "effect compartment" to the plasma concentration. This approach has been used to characterize the fall and return of OKT3-and OKT4-positive lymphocytes in peripheral blood after single oral doses of prednisolone. 4 A threshold concentratio...

Intravenous pentamidine was safe and effective for the prevention of PCP in pediatric HSCT patients. Given the potential neutropenic effects of trimethoprim-sulfamethoxazole, compliance with drug administration and inferior efficacy of other PCP prophylactic medications, intravenous pentamidine should be considered as first-line therapy for the prevention of PCP in children undergoing HSCT.

achievement of steady state. The half life (t 1/2) of voriconazole was 5.0965.15 hours. The dose normalized (per mg) AUC (mg*hr/ml) was 0.11160.081. Voriconazole dose did not correlate with AUCo-N (r 2 5 0.028). There was a good correlation between AUCo-N and C trough (r 2 5 0.94). Population estimates of bioavailability, clearance, apparent volume of the central compartment (Vc) and apparent volume of peripheral compartment (Vp) were 46.5%, 5.76L/hr, 19.4L and 58.8L. Conclusions: The bioavailability of voriconazole was significantly lower in pediatric BMT patients than in non-transplant adult subjects. The t 1/2 at steady state tended to be lower than adult patients. Our study suggests that pediatric patients may require dosing higher than 7 mg/kg twice daily. The wide individual variability and the lack of correlation between dose and AUC support therapeutic monitoring of voriconazole and dose adjustments based on steady state blood levels.

Fifty patients were randomly selected who had markedly elevated titers of serum venom-specific IgE (range 100–340 IU, mean 144 IU), and compared with 50 patients with low titers (range 0–50 IU, mean 25 IU). At the time serum was obtained, none of the patients had received venom immunotherapy (VIT). Analysis of the demographic data showed more children in the high-RAST group, and comparable matching of the groups for sex, presence of atopy, and culprit insect identification. The nature of the reaction preceding evaluation was similar in both groups. In the high-RAST group, there were 12 local, 15 mild systemic, and 23 severe systemic reactions. In the low-RAST group, there were 8 local, 15 mild systemic, and 27 severe systemic reactions. Other prior local reactions had occurred in 4 high-RAST and 4 low-RAST patients, and other prior systemic reactions had occurred in 3 high-RAST and 8 low-RAST patients. The incidence of systemic and local reactions following VTT was low in both groups. All but 1 patient in each group reached maintenance venom doses. Following initiation of VIT, 10 of 28 patients in the high-RAST group and 5 of 29 patients in the low-RAST group had a further rise in antibody titers. Patients in both groups showed a decrease in titers over a period of time, with or without VTT. Serum venom-specific IgG was greater in the high-RAST group (mean 9.4 U) than in the low-RAST group (mean 3.8 U). The absolute titers of serum venom-specific IgE appear unrelated to any specific feature of stinging insect sensitivity.