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Biphasic generalized allergic reaction (Anaphylaxis)
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ABSORPTION PHARMACOKINETIC DATA OF SUSTAINEDRELEASE THEOPHYLLINE (SRT) PREPARATIONS OVER 48 HOURS. C.L.Saccar,Pharm.D.,L.D.Green,M.D.,J.A. DiConcetto,M.D.,C.L.Helsel,B.S.N.,H.C.Mansmann, Jr.,M.D.&S.J.McGeady,M.D., Phila., Pa. SRT bioavailability (F) studies have primarily been over a 24-36 hr period. A capsule (C) and a tablet (Ta) formulation were studied over a 48 hr period allowing for a more accurate assessment, in comparison to a theophylline (T) syrup. Subjects were 18 healthy non-smokers in a singledose phase and 15 in a multi-dose phase (age range 23-43 yrs). Serial blood samples were drawn for 48 hrs after single dose (300 mg) administration and on 5th day in the multi-dose phase for serum T levels by HPLC. Pharmacokinetic analysis was performed by model-independent linear regression methodology and trapezoidal rule programs for area under the curve (AUC) determinations. F's were calculated from ratios of SRT AUC's to T syrup AUC, zero to infinity for single-dose phase and over a dosing interval for multi-dose phase. The mean absorption pharmacokinetic parameters are as follows: Sin le-Dose Phase Multi-Dose Phase
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meg/ml I hrs I % mcg/ml mcg/ml 3.68 I 8"701 95.5 9.68 7.06 4.75 I 103.0 (6~.8-132.9~ (62-129.0) SRT Ta 4.6018.471 87.7 9.96 6.45 5.351 101.4 (50.9-116..6) (57-141.8) *Range F's in parentheses Although the mean F values are near the 100% value, the ranges are quite disparate and point to a great subject variability in absorption of SRT products having profound implications for clinical dosing. SRT C
178
EFFECTS OF HEMODIALYSIS ON THEOPHYLLINE KINETICS. J.R. Anderson~ M.D.~ R.C. McQueen~ M.D., A. Poklis~ Ph.D., J.N. Purtell, M.D., and R.G. Slavin, M.D. St. Louis, Missouri Difficulties encountered in controlling theophylline blood levels in an asthmatic patient on hemodialysis prompted us to study the effect of hemodialysis on theophylline kinetics. Plasma theophylline extraction ratios, clearance and half lives were determined during dialysis for eleven adults given an intravenous infusion of 4 mg/kg aminophylline. For comparison, 8 of these patients were evaluated for theophylline half lives when not dialyzed. Extraction ratios of theophylline during dialysis ranged from 0.220 to 0.510 (mean S.D.: 0.359 + 0.084) for these patients indicating that a mean of 36% of plasma theophylline was removed during each pass through the dialyzer. This compares with a mean extraction of urea of 0.631 + 0.079. Plasma clearance of theophylline during dialysis ranged from 52.10 - 124.0 ml/minute (mean ! S.D.: 82.77 19.45). Plasma theophylline half lives during dialysis ranged from 1.6 - 3.4 hrs. (mean + S.D. :2.33 + 0.54). Theophylline half lives when not on dialysis, ranged from 3.5 - 8.2 hrs.(4.96 + 1.70). Theophylline clearance was significantly faster in every patient during dialysis. Asthmatics requiring hemodialysis should receive additional theophylline during dialysis if therapeutic blood levels are to be maintained. Routine hemodialysis will significantly speed clearance in a toxic patient in whom life threatening toxicity is occurring and charcoal hemoperfusion is unavailable.
THEOPHYLLINE COMPLIANCE IN ASTHMATIC CHILDREN ~. G. Weinstein, M.D., :.~. Cuskey, Ph.D.Wilm, De A Thirty-seven asthmatic children (ages 2-19 yrs) were evaluated for theophylline compliance (Slophyllin Gyrocap-Dooner-Rorer) during a 6 month study period in an allergist's office. The study design included: i. Children requiring daily bronchodilators; 2. At least 4 theophylline levels (TL), (Emit-Metpath) during the study period; 3. Trough TL's ~.5~g/ml as a measure of full compliance; 4. Monthly visits to evaluate frequency of illness, chest exam, Wright Peak Flow measurements; 5. Behavioral intervention (BI) to promote drug compliance: (a) encouragement, (b) increasing supervision of medications, (c) exercise challenge, (d) stopping all medication. Compliance ratings were derived from the average of TL's during the 6 month study period. Results were as follows: 1. Full Compliance TL ~.5~r 70%; 2. Partial Compliance TL ~.2 ~ g / m l r 19%; 3. Non-Compliance T L < 2~g/ml: 11%. Fully compliant patients were more likely to require 2 or less Bl's when compared to less compliant groups. See Table below: COMPLIANCE NUMBER OF INTERVENTIONS 0-2 ~2 p Non and Partial 1 i0 r Full 17 9 Of those requiring multiple interventions, 47% achieved full compliance. Despite the difference in compliance ratings, both compliant and less compliant groupings had significant reduction in frequency of wheezing symptom scores (p~.05). Asthmatic children can achieve good compliance records and reduce morbidity with the aid of drug monitoring and application of appropriate BI's.
180 BIPHASIC GENERALIZED ALLERGIC REACTION (ANAPHYLAXIS). V. Popa, M.D. and S. Lerner, M.D., The biphasic airway responses to inhaled allergen are well known. However, biphasic systemic allergic reactions (BSR) have not been reported. Three male patients (20-47 years of age) presented with such a reaction. The 2 phases of BSR occured 15-30 minutes and 4-5 hours after exposure to allergen: ryegrass extract, injected subcutaneously (Patient A), antirabies vaccine prepared in duck embryo (Patient B), and yellow jacket sting (Patient C). The reaction consisted in generalized urticaria, edema of lips and eyelids, and shortness of breath with wheezing. Blood pressure, which was normal before the reaction, decreased by 20-40 mmHg but did not reach values lower than 90 mmHg systolic. After administration of epinephrine, and antihistaminic drugs, the symptoms and signs subsided, only to recur. Each patient was hospitalized at this time and successfully treated with the same regimen. As determined by RAST, each patient had IgE antibodies against the offending allergen, duck egg white, ryegrass pollen, or yellow jacket venom. Patient B had low IgE antibodies and used to eat duck eggs without any incident. He could be vaccinated against yellow fever (vaccine prepared in chicken embryo). After immunotherapy, patient C did not react to yellow jacket sting. In conclusion, we describe BSR associated with circulating specific IgE. The late phase of BSR was probably not related to insufficient treatment or rebound after a severe, hypotensive episode. Immuno-therapy can be successful in patients with BSR. The exact immunologic mechanism of BSR remains to be defined.
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ABSORPTION PHARMACOKINETIC DATA OF SUSTAINEDRELEASE THEOPHYLLINE (SRT) PREPARATIONS OVER 48 HOURS. C.L.Saccar,Pharm.D.,L.D.Green,M.D.,J.A. DiConcetto,M.D.,C.L.Helsel,B.S.N.,H.C.Mansmann, Jr.,M.D.&S.J.McGeady,M.D., Phila., Pa. SRT bioavailability (F) studies have primarily been over a 24-36 hr period. A capsule (C) and a tablet (Ta) formulation were studied over a 48 hr period allowing for a more accurate assessment, in comparison to a theophylline (T) syrup. Subjects were 18 healthy non-smokers in a singledose phase and 15 in a multi-dose phase (age range 23-43 yrs). Serial blood samples were drawn for 48 hrs after single dose (300 mg) administration and on 5th day in the multi-dose phase for serum T levels by HPLC. Pharmacokinetic analysis was performed by model-independent linear regression methodology and trapezoidal rule programs for area under the curve (AUC) determinations. F's were calculated from ratios of SRT AUC's to T syrup AUC, zero to infinity for single-dose phase and over a dosing interval for multi-dose phase. The mean absorption pharmacokinetic parameters are as follows: Sin le-Dose Phase Multi-Dose Phase
179
meg/ml I hrs I % mcg/ml mcg/ml 3.68 I 8"701 95.5 9.68 7.06 4.75 I 103.0 (6~.8-132.9~ (62-129.0) SRT Ta 4.6018.471 87.7 9.96 6.45 5.351 101.4 (50.9-116..6) (57-141.8) *Range F's in parentheses Although the mean F values are near the 100% value, the ranges are quite disparate and point to a great subject variability in absorption of SRT products having profound implications for clinical dosing. SRT C
178
EFFECTS OF HEMODIALYSIS ON THEOPHYLLINE KINETICS. J.R. Anderson~ M.D.~ R.C. McQueen~ M.D., A. Poklis~ Ph.D., J.N. Purtell, M.D., and R.G. Slavin, M.D. St. Louis, Missouri Difficulties encountered in controlling theophylline blood levels in an asthmatic patient on hemodialysis prompted us to study the effect of hemodialysis on theophylline kinetics. Plasma theophylline extraction ratios, clearance and half lives were determined during dialysis for eleven adults given an intravenous infusion of 4 mg/kg aminophylline. For comparison, 8 of these patients were evaluated for theophylline half lives when not dialyzed. Extraction ratios of theophylline during dialysis ranged from 0.220 to 0.510 (mean S.D.: 0.359 + 0.084) for these patients indicating that a mean of 36% of plasma theophylline was removed during each pass through the dialyzer. This compares with a mean extraction of urea of 0.631 + 0.079. Plasma clearance of theophylline during dialysis ranged from 52.10 - 124.0 ml/minute (mean ! S.D.: 82.77 19.45). Plasma theophylline half lives during dialysis ranged from 1.6 - 3.4 hrs. (mean + S.D. :2.33 + 0.54). Theophylline half lives when not on dialysis, ranged from 3.5 - 8.2 hrs.(4.96 + 1.70). Theophylline clearance was significantly faster in every patient during dialysis. Asthmatics requiring hemodialysis should receive additional theophylline during dialysis if therapeutic blood levels are to be maintained. Routine hemodialysis will significantly speed clearance in a toxic patient in whom life threatening toxicity is occurring and charcoal hemoperfusion is unavailable.
THEOPHYLLINE COMPLIANCE IN ASTHMATIC CHILDREN ~. G. Weinstein, M.D., :.~. Cuskey, Ph.D.Wilm, De A Thirty-seven asthmatic children (ages 2-19 yrs) were evaluated for theophylline compliance (Slophyllin Gyrocap-Dooner-Rorer) during a 6 month study period in an allergist's office. The study design included: i. Children requiring daily bronchodilators; 2. At least 4 theophylline levels (TL), (Emit-Metpath) during the study period; 3. Trough TL's ~.5~g/ml as a measure of full compliance; 4. Monthly visits to evaluate frequency of illness, chest exam, Wright Peak Flow measurements; 5. Behavioral intervention (BI) to promote drug compliance: (a) encouragement, (b) increasing supervision of medications, (c) exercise challenge, (d) stopping all medication. Compliance ratings were derived from the average of TL's during the 6 month study period. Results were as follows: 1. Full Compliance TL ~.5~r 70%; 2. Partial Compliance TL ~.2 ~ g / m l r 19%; 3. Non-Compliance T L < 2~g/ml: 11%. Fully compliant patients were more likely to require 2 or less Bl's when compared to less compliant groups. See Table below: COMPLIANCE NUMBER OF INTERVENTIONS 0-2 ~2 p Non and Partial 1 i0 r Full 17 9 Of those requiring multiple interventions, 47% achieved full compliance. Despite the difference in compliance ratings, both compliant and less compliant groupings had significant reduction in frequency of wheezing symptom scores (p~.05). Asthmatic children can achieve good compliance records and reduce morbidity with the aid of drug monitoring and application of appropriate BI's.
180 BIPHASIC GENERALIZED ALLERGIC REACTION (ANAPHYLAXIS). V. Popa, M.D. and S. Lerner, M.D., The biphasic airway responses to inhaled allergen are well known. However, biphasic systemic allergic reactions (BSR) have not been reported. Three male patients (20-47 years of age) presented with such a reaction. The 2 phases of BSR occured 15-30 minutes and 4-5 hours after exposure to allergen: ryegrass extract, injected subcutaneously (Patient A), antirabies vaccine prepared in duck embryo (Patient B), and yellow jacket sting (Patient C). The reaction consisted in generalized urticaria, edema of lips and eyelids, and shortness of breath with wheezing. Blood pressure, which was normal before the reaction, decreased by 20-40 mmHg but did not reach values lower than 90 mmHg systolic. After administration of epinephrine, and antihistaminic drugs, the symptoms and signs subsided, only to recur. Each patient was hospitalized at this time and successfully treated with the same regimen. As determined by RAST, each patient had IgE antibodies against the offending allergen, duck egg white, ryegrass pollen, or yellow jacket venom. Patient B had low IgE antibodies and used to eat duck eggs without any incident. He could be vaccinated against yellow fever (vaccine prepared in chicken embryo). After immunotherapy, patient C did not react to yellow jacket sting. In conclusion, we describe BSR associated with circulating specific IgE. The late phase of BSR was probably not related to insufficient treatment or rebound after a severe, hypotensive episode. Immuno-therapy can be successful in patients with BSR. The exact immunologic mechanism of BSR remains to be defined.
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