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66 Phenylpropanolamine (PPA) pharmacokinetics and pharmacodynamics in children with allergic rhinitis
J ALLERGY CLIN IMMUNOL VOLUME 97, NUMBER 1, PART 3
65
Pseudoephedrine (PDE) Pharmacokinetics and Pharmacodynnm|es i n C h i l d r e n w i t h A l l e r g i c R h i n i t i s .
Abstracts
67
Phenylpropanolamlne (PPA) Pharmacoidnetics and Pharmacodynamies i n C h i l d r e n w i t h Allergic R h i n i t i s . JCM St. Vincent BN, KJ Simons PhD, X (~u PhD. WTA Watson MD. JD Ree,,in MD, PER Simons MD, Winnipeg, Canada. The pharmacokinetics of PPA have not been reported in children. We hypothesized that the terminal elimination half-life 01/2) would be even shorter in children than it is in adults. In a double-blind, parallel-group, slngle-dose study, 20 children (age 9.2_.+0.3 yr, weight 31.8_.+1.3 kg) received either PPA 20 rag, PPA 37.5 rag, or placebo. Before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 7 hours after dosing, serum PPA concentrations and nasal resistance were measured, and pulse rate and blood pressure were recorded. Before, and 2.5 h post-dose, CNS stimulation was assessed using the latency of the P300 event-related potential on the electrocncephalogram. Data were analyzed using PC-NONLIN and ANOVA, ANCOVA, and Tukey and Bonferroni multlple-range tests on PC-SAS. RESULTS: *p < 0.05 PPA 20 me PPA 37.5 me C = (ng/mL) 185 +__~* 285__+45* t=~ (h) 2.1_.+0.3 2.7_.+0.4 t l / 2 (h) 2.4_.+0.6 2.8_.+0.5 AUC (ng/mL/h) 680+133" 1214+.._240" CI (mL/min/kg) 13.6+1.7 13.3+2.4 Vd (L/kg) 2.5+0.3 2.8__+0.4 The t l / 2 of PPA was shorter in children (2-3 h) than reported in adults (4-5 h). In the dose range studied, PPA kinetics were not dose-dependent. No significant decrease in nasal resistance was observed. Pulse rate increased significantly at times, especially after the 37,5 mg dose, but no clinically important adverse effects on blood pressure or on the CNS were apparent.
Recombinant Human Monoclonal Anti-lgE Therapy In Allergic R h i n i t i s . TB Casale MD. IL Berust¢in MD. WW Buss¢ MD. CF LaForce MD. DG Tinkelman IV[D, RR Stoltz MD, RJ .O..qckhorn MD, DC Adchnan MD, Iowa City, IA. Cincinnati, OH, Madison, Wl, Raleigh, NC, Atlanta, GA, Evansville, IN, Lenexa, KS, and San Francisco, CA, USA Since an increased serum level of IgE is often associated with allergic respiratory disorders, we h)laothesized that decreasing total serum IgE would reduce sTmptoms. Rhu MAb-E25, a humanized monoclonai antibody, has been shown to decrease free serum IgE. We therefore enrolled 240 subjects into 5 groups to determine the safety and tolerance of multiple administration of rhu MAb-E25 in adultswitl~ ragweed-induccdallcrgic rbinitis. 181 active treatment subjocts rcccivcd aa initial IV loading dose (day 0, one month prior to ragweed season) followed by either 0.15 SQ, 0.15 IV or 0.5 IV of rim MAb-E25 (in mg/kg body weight) on days 7, 14, 28, 42, 56, 70 and 84. A SQ and IV placebo group were included. The total evaluation time included the 84 day treatment period followed by a 42 day observation period. Adverse events were mild and no differences were observed in the rates between the 3 active and 2 placebo treatment groups. Rhu MAb-E25 decreased serum free IgE levels in a dose and baseline IgE..dependent fashion. However, only 11 subjects had suppressed IgE levels to undetectable Icvcls, a sample too small to demonstrate significant differences. As a result, clinical efficacy was also not demonstrated. Nonetheless, the study confirms that it is safe to repeatedly administer rhu MAb-E25 ever montl~s. Furtherulote, the results suggest that if given in sufficient quantities to lower serum free IgE, rhu MAb-E25 may be an effective therapy for allergic diseases.
X Gu PhD. KJ Simons PhD. JCM St. Vincent BN, WTA Watso q MD. JD R e ~ i n MD, PER Simons MD, Winnipeg, Canada. PDE pharmacokinetics have not been well studied in children, in whom we hypothesized that the PDE terminal elimination halflife (tl/2) would be shorter than it is in adults. In a double-bllnd, parallel-group, single-dose study in 21 children (age 8.8+._0.3 yr, weight 32.2.+1 kg), we administered either PDE 30 rag, PDE 60 rag, or placebo. Before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 7 hours after dosing, serum PDE concentrations and nasal resistance were measured, and pulse rate and blood pressure were recorded. Before and 2.5 h after dosing, CNS stimulation was assessed using the latency of the P300 event-related potential on the electroencephalogram. Data were analyzed using PC-NONLIN and ANOVA, ANCOVA, and Tukey and Bonferroni multiple-range tests on PC-SAS. .RESULTS: *p < 0.05 PDE 30 m~, PDE 60 me C,ffi, (ng/mL) 244__+21" 492_.+72* t== (h) 2.1 +__0.3 2.4+._0.2 t l / 2 (h) 3.1__+0.5 3.1+0.4 AUC (ng/mL/h) 1260..%+126* 2414_.*.336" Cl (mL/min/kg) 10.3_.+1.2 9.2_.+0.7 Vd (L/kg) 2.6__+0.3 2.4+_.0.4 The t l / 2 of PDE in children (2-3 h) was shorter than reported by other investigators in adults (5-7 h). Kinetics were not dosedependent in the dose range studied. No significant decrease in nasal resistance was observed. Pulse rate increased significantly, especially after the 60 mg dose, but no clinically important adverse effects on blood pressure or on the CNS were found.
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199
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N-Acetyl-Aspartyl-Glutamic Add Inbiblts Late A n t i g e n - I n d u c e d R e a c t i o n in t h e Nose. A Miedonna MD. M Cotfini MD. M Lorini MTedt, C Candiani MD, A Tedeschi MD, N Milazzo MD, Milano, Saronno and Betgamo, Italy N-aeetyl-aspartyl-glutamie acid (NAAGA) is a uaturally occurnng dipeptide which has antinflammatory properties. The aim of this study was to evaluate the effects of NAAGA on late antigen-indueed reaction in the nose. Tea symptom-free patients with seasonal allergic rhinitis due to grass pollen were included in a randomized double-blind cross-over trial of a 6% solution of NAAGA (daily dosage: 48 rag) vs placebo. The drug and the placebo were admin~"tered intranasally for one week each with a two-week interval between the two treatments. A nasal antigen challenge (2000 BU, Lofarma) followed by symptom registration and sequential nasal lavages Coaselme, 6h and 24h after slimulation) was performed before and after treatment. Cytological analysis of nasal lavages was performed by Wrighfs staining of cytocentrifuge smears. Eosinophil cationic protein (ECP) and myeloperoxidase (MPO) levels in nasal washings were measured by RIA (Pharmacia). Treatment with NAAGA caused a significant reduction of nasal obstruction (p<0.001, NAAGA vs placebo) and of nasal neutrophilia (6h after sILmulation, p<0.0 !) and eosinophilia (6h and 24h after challenge, p<0.001). Furthermore, ECP and MPO levels in the nasal lavages collected at 6h (ECP: p<0.01, MPO: p<0.05) and 24h (ECP: p<0.05) after anligen challenge were significantly decreased by NAAGA. These results indicate that a'eatment with NAAGA can attenuate late antigen-induced nasal obstruction, inflammatory cell recruitment and mediator release in human nasal airways.
65
Pseudoephedrine (PDE) Pharmacokinetics and Pharmacodynnm|es i n C h i l d r e n w i t h A l l e r g i c R h i n i t i s .
Abstracts
67
Phenylpropanolamlne (PPA) Pharmacoidnetics and Pharmacodynamies i n C h i l d r e n w i t h Allergic R h i n i t i s . JCM St. Vincent BN, KJ Simons PhD, X (~u PhD. WTA Watson MD. JD Ree,,in MD, PER Simons MD, Winnipeg, Canada. The pharmacokinetics of PPA have not been reported in children. We hypothesized that the terminal elimination half-life 01/2) would be even shorter in children than it is in adults. In a double-blind, parallel-group, slngle-dose study, 20 children (age 9.2_.+0.3 yr, weight 31.8_.+1.3 kg) received either PPA 20 rag, PPA 37.5 rag, or placebo. Before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 7 hours after dosing, serum PPA concentrations and nasal resistance were measured, and pulse rate and blood pressure were recorded. Before, and 2.5 h post-dose, CNS stimulation was assessed using the latency of the P300 event-related potential on the electrocncephalogram. Data were analyzed using PC-NONLIN and ANOVA, ANCOVA, and Tukey and Bonferroni multlple-range tests on PC-SAS. RESULTS: *p < 0.05 PPA 20 me PPA 37.5 me C = (ng/mL) 185 +__~* 285__+45* t=~ (h) 2.1_.+0.3 2.7_.+0.4 t l / 2 (h) 2.4_.+0.6 2.8_.+0.5 AUC (ng/mL/h) 680+133" 1214+.._240" CI (mL/min/kg) 13.6+1.7 13.3+2.4 Vd (L/kg) 2.5+0.3 2.8__+0.4 The t l / 2 of PPA was shorter in children (2-3 h) than reported in adults (4-5 h). In the dose range studied, PPA kinetics were not dose-dependent. No significant decrease in nasal resistance was observed. Pulse rate increased significantly at times, especially after the 37,5 mg dose, but no clinically important adverse effects on blood pressure or on the CNS were apparent.
Recombinant Human Monoclonal Anti-lgE Therapy In Allergic R h i n i t i s . TB Casale MD. IL Berust¢in MD. WW Buss¢ MD. CF LaForce MD. DG Tinkelman IV[D, RR Stoltz MD, RJ .O..qckhorn MD, DC Adchnan MD, Iowa City, IA. Cincinnati, OH, Madison, Wl, Raleigh, NC, Atlanta, GA, Evansville, IN, Lenexa, KS, and San Francisco, CA, USA Since an increased serum level of IgE is often associated with allergic respiratory disorders, we h)laothesized that decreasing total serum IgE would reduce sTmptoms. Rhu MAb-E25, a humanized monoclonai antibody, has been shown to decrease free serum IgE. We therefore enrolled 240 subjects into 5 groups to determine the safety and tolerance of multiple administration of rhu MAb-E25 in adultswitl~ ragweed-induccdallcrgic rbinitis. 181 active treatment subjocts rcccivcd aa initial IV loading dose (day 0, one month prior to ragweed season) followed by either 0.15 SQ, 0.15 IV or 0.5 IV of rim MAb-E25 (in mg/kg body weight) on days 7, 14, 28, 42, 56, 70 and 84. A SQ and IV placebo group were included. The total evaluation time included the 84 day treatment period followed by a 42 day observation period. Adverse events were mild and no differences were observed in the rates between the 3 active and 2 placebo treatment groups. Rhu MAb-E25 decreased serum free IgE levels in a dose and baseline IgE..dependent fashion. However, only 11 subjects had suppressed IgE levels to undetectable Icvcls, a sample too small to demonstrate significant differences. As a result, clinical efficacy was also not demonstrated. Nonetheless, the study confirms that it is safe to repeatedly administer rhu MAb-E25 ever montl~s. Furtherulote, the results suggest that if given in sufficient quantities to lower serum free IgE, rhu MAb-E25 may be an effective therapy for allergic diseases.
X Gu PhD. KJ Simons PhD. JCM St. Vincent BN, WTA Watso q MD. JD R e ~ i n MD, PER Simons MD, Winnipeg, Canada. PDE pharmacokinetics have not been well studied in children, in whom we hypothesized that the PDE terminal elimination halflife (tl/2) would be shorter than it is in adults. In a double-bllnd, parallel-group, single-dose study in 21 children (age 8.8+._0.3 yr, weight 32.2.+1 kg), we administered either PDE 30 rag, PDE 60 rag, or placebo. Before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 7 hours after dosing, serum PDE concentrations and nasal resistance were measured, and pulse rate and blood pressure were recorded. Before and 2.5 h after dosing, CNS stimulation was assessed using the latency of the P300 event-related potential on the electroencephalogram. Data were analyzed using PC-NONLIN and ANOVA, ANCOVA, and Tukey and Bonferroni multiple-range tests on PC-SAS. .RESULTS: *p < 0.05 PDE 30 m~, PDE 60 me C,ffi, (ng/mL) 244__+21" 492_.+72* t== (h) 2.1 +__0.3 2.4+._0.2 t l / 2 (h) 3.1__+0.5 3.1+0.4 AUC (ng/mL/h) 1260..%+126* 2414_.*.336" Cl (mL/min/kg) 10.3_.+1.2 9.2_.+0.7 Vd (L/kg) 2.6__+0.3 2.4+_.0.4 The t l / 2 of PDE in children (2-3 h) was shorter than reported by other investigators in adults (5-7 h). Kinetics were not dosedependent in the dose range studied. No significant decrease in nasal resistance was observed. Pulse rate increased significantly, especially after the 60 mg dose, but no clinically important adverse effects on blood pressure or on the CNS were found.
66
199
68
N-Acetyl-Aspartyl-Glutamic Add Inbiblts Late A n t i g e n - I n d u c e d R e a c t i o n in t h e Nose. A Miedonna MD. M Cotfini MD. M Lorini MTedt, C Candiani MD, A Tedeschi MD, N Milazzo MD, Milano, Saronno and Betgamo, Italy N-aeetyl-aspartyl-glutamie acid (NAAGA) is a uaturally occurnng dipeptide which has antinflammatory properties. The aim of this study was to evaluate the effects of NAAGA on late antigen-indueed reaction in the nose. Tea symptom-free patients with seasonal allergic rhinitis due to grass pollen were included in a randomized double-blind cross-over trial of a 6% solution of NAAGA (daily dosage: 48 rag) vs placebo. The drug and the placebo were admin~"tered intranasally for one week each with a two-week interval between the two treatments. A nasal antigen challenge (2000 BU, Lofarma) followed by symptom registration and sequential nasal lavages Coaselme, 6h and 24h after slimulation) was performed before and after treatment. Cytological analysis of nasal lavages was performed by Wrighfs staining of cytocentrifuge smears. Eosinophil cationic protein (ECP) and myeloperoxidase (MPO) levels in nasal washings were measured by RIA (Pharmacia). Treatment with NAAGA caused a significant reduction of nasal obstruction (p<0.001, NAAGA vs placebo) and of nasal neutrophilia (6h after sILmulation, p<0.0 !) and eosinophilia (6h and 24h after challenge, p<0.001). Furthermore, ECP and MPO levels in the nasal lavages collected at 6h (ECP: p<0.01, MPO: p<0.05) and 24h (ECP: p<0.05) after anligen challenge were significantly decreased by NAAGA. These results indicate that a'eatment with NAAGA can attenuate late antigen-induced nasal obstruction, inflammatory cell recruitment and mediator release in human nasal airways.