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580 Inhalational therapy exacerbates gastroesophageal reflux in asthmatics
579
THE EFFECT OF TERFENADINE ON PULNONABY FUNCTION AND BRONCHIAL CNALLENGES UITN NNBULIZED rylTsLe JJNDW) AND COLD AIR (CANC). A. Bewtra. R. HODD, N. Nair. R. Tonnlev, Omaha, NE
581
AHR-5333, A NEW ANTIALLERGY COMPOUND IV: RECEPTOR BINDING STUDIES AND PHARMACOLOGICAL CORRELATES. B. F. Kilpatrick, Ph.D., R. D. Tabor, J. C. Nolan, Ph.D., J. M. Yanni, Ph.D., Richmond, VA. USA. The receptor-radioligand bindin propertiesof AHR-5333 were investiaated to 8 etermine the mechanism(s) of action that are related to its antiallergy properties. AHR-5333 showed no affinity (ICso>lO,OOO nM) for 5-HT,, ,, pz, and M, receptors, whereas the I& values Por H,, 5-Hi*, and Dz receptor binding were 14, 3.7, and 1,700 nM respectively. Scatchard analysis of the effect of AHR-5333 on [jH]mepyramine and [sH]ketanserin binding revealed that the compound was a potent and competitive inhibitor at both H, (Ki = 2.2 nM) and 5-HTz (Ki = 0.93 nM) receptors. When H1 binding was compared with blockade of histamine-induced guinea pig lethalit for AHR5333 and several antiallergy/antl 4. lstamine compounds, a significant correlation (r = 0.86987, P = 0.002) was found between these effects. When 5-HTz binding wascompared with blockade of 5-HT-induced rat paw edema for AHR-5333 and other antiallergy/an&serotonin compounds, a significant correlation (r = 0.46008. P = 0.0941 was not found. Howe&r, AHR-5333 was a potent inhibitor of both 5-HT-mediated effects. These results indicate that H, and 5-HTz receptor antagonism contributes to the antiallergy activity of AHR-5333; however, other mechanisms may be involved in its antiallergy profile.
582
THE IN VIVO ANTI-ALLERGIC ACTIVITY OF CI-949, 5-METHOXY-3-(l-METHYLETHOXY)-l-PHENYL-N-lHTETRAZOL-5-Yi-lH-INDOLE-2-CARBOXAMIDE - LARGININE SALT. martin P. Finkel, M.AI; Stanley P. Mallard. B.A.: David 0. Thueson, Ph.D.; and Mary Carol Conroy, Ph. D.; Ann Arbor, Michigan. The novel anti-allergy compound, CI-949, inhibits allergic bronchopulmonary anaphylaxis in guinea pigs and dogs. CI-949 is effective both orally and parenterally. When administered intraperitoneally 20 min. before antigen challenge, CI-949 increased the 50 w/kg, collapse time from a control of 1.9 min. to 3.4 min. in actively sensitized guinea pigs exposed to antigen aerosol. Oral administration of CI-949, 100 mg/kg 2 hours before antigen exposure, was just as effective. A 200 mg/kg dose gave maximum protection in this model for several hours. In allergic dogs, intravenous CI-949. 0.1. 1.0 and 3.0 ma/ka inhibited the ascari&ind&ed changes in-. total pulmonary resistance by lo%, - 40%, 62% and. dynami; compliance bv 5%. 29%. and 58%. resoectivelv. When given orally 4.5’hours before ihallenge, CI-949 20 mg/kg, inhibited the resistance change 71% and the dynamic compliance decrease 33% respectively compared to the animals’ own control responses. Thus, CI-949 is an orally effective antiallergy compound which exhibits its protective effects for several hours.
Terfenadine, a nonsedatiqg Ii1 antihistamine, has been shown to block histamine and attenuate exercise challenges. We determined if it affects UNDW and CAAC, both of which may induce mast cell degranulation. Twelve asthmatics underwent UNDW and CAHC challenges in separate double-blind, placebo-controlled, crossover trials. Challenges were performed 4 hrs following drug, during which time pulmonary functions.were followed. The UNDW was given in a dose-response fashion and the CAHC by a single timed ventilatory effort. The response to these test were compared for placebo, 120 and 240 mg. Terfenadine. The baseline FEVl on the 3 study days for the two trials were comparable. Terfenadine had a significant bronchodilatory effect, at both doses, at the 2nd, 3rd. and 4th hours before UNDW (max. increase +5.2% FEV ), and at the 2nd and 3rd hr. Before CAHC (+6. I % FEV ). the fall Terfenadine significantly a $tenuated in FEVl during the UNDW challenge, p = -01 for 240 mg., but less so at 120 ag, p =.058. Terfenadine did protect against CANC in 7/12 at 120 mg. and 6112 at 240 mg., but it was not significant as a group.. Since Terfenadine had a significant and equal effect on pulmonary function before UNDWand CAHC the challenge results may suggest different mechanisms of action or it may suggest a difference in the antagonism of Terfenadine against the challenges.
INHALATIONAL THERAPY EXACERBATES CASTROESOPHAGEAL REFLUX IN ASTHMATICS. David Elkayam, M.D., Denver, CO. Twelve pediatric patients underwent continuous pH monitoring b;y use of a distal esophageal probe for periods ranging from 19 to 23 hours. The patients were five years to 18 years of age. All had moderate to severe asthma requiring chronic utilization of bronchodilator medications. All were receiving theophylline and beta agonist medications; 9/12 (75%) were on daily or alternate da steroid therapy. Castroesophageal reflux (CER r was diagnosed radiographically in 9/12 (75%) of these patients; all patients had a history suggestive of CER and/or significant nocturnal exacerbations of their asthma. A retrospective review of the DH monitorine records of these patients re;ealed a big: incidence of GER, II/12 (92%) oatients. as assessed by the Johnson’ h Dime&e; or Eul;?r & Byrne criteria. CER was temporally associated with respiratory treatments (RT’s), either by MD1 or nebulization,in IO/12 (83%) patients. A total of 51 RT’s were monitored; CER was temoorallv associated with inhalational therapy in’ 27/.5i (52%) of these and probably associated in 9/51 (18%) others, for a total of 26/51 (71%). GER associated with RT’s occurred in IO/12 (83%) of this select group of patients. Operative factors for this apparent association may be drug effect(s) and/or mechanical factors associated with the breathing pattern noted with RT’s. We conclude that there may be a temporal association between inhalational therapy and GER in certain asthmatic patients.
313
THE EFFECT OF TERFENADINE ON PULNONABY FUNCTION AND BRONCHIAL CNALLENGES UITN NNBULIZED rylTsLe JJNDW) AND COLD AIR (CANC). A. Bewtra. R. HODD, N. Nair. R. Tonnlev, Omaha, NE
581
AHR-5333, A NEW ANTIALLERGY COMPOUND IV: RECEPTOR BINDING STUDIES AND PHARMACOLOGICAL CORRELATES. B. F. Kilpatrick, Ph.D., R. D. Tabor, J. C. Nolan, Ph.D., J. M. Yanni, Ph.D., Richmond, VA. USA. The receptor-radioligand bindin propertiesof AHR-5333 were investiaated to 8 etermine the mechanism(s) of action that are related to its antiallergy properties. AHR-5333 showed no affinity (ICso>lO,OOO nM) for 5-HT,, ,, pz, and M, receptors, whereas the I& values Por H,, 5-Hi*, and Dz receptor binding were 14, 3.7, and 1,700 nM respectively. Scatchard analysis of the effect of AHR-5333 on [jH]mepyramine and [sH]ketanserin binding revealed that the compound was a potent and competitive inhibitor at both H, (Ki = 2.2 nM) and 5-HTz (Ki = 0.93 nM) receptors. When H1 binding was compared with blockade of histamine-induced guinea pig lethalit for AHR5333 and several antiallergy/antl 4. lstamine compounds, a significant correlation (r = 0.86987, P = 0.002) was found between these effects. When 5-HTz binding wascompared with blockade of 5-HT-induced rat paw edema for AHR-5333 and other antiallergy/an&serotonin compounds, a significant correlation (r = 0.46008. P = 0.0941 was not found. Howe&r, AHR-5333 was a potent inhibitor of both 5-HT-mediated effects. These results indicate that H, and 5-HTz receptor antagonism contributes to the antiallergy activity of AHR-5333; however, other mechanisms may be involved in its antiallergy profile.
582
THE IN VIVO ANTI-ALLERGIC ACTIVITY OF CI-949, 5-METHOXY-3-(l-METHYLETHOXY)-l-PHENYL-N-lHTETRAZOL-5-Yi-lH-INDOLE-2-CARBOXAMIDE - LARGININE SALT. martin P. Finkel, M.AI; Stanley P. Mallard. B.A.: David 0. Thueson, Ph.D.; and Mary Carol Conroy, Ph. D.; Ann Arbor, Michigan. The novel anti-allergy compound, CI-949, inhibits allergic bronchopulmonary anaphylaxis in guinea pigs and dogs. CI-949 is effective both orally and parenterally. When administered intraperitoneally 20 min. before antigen challenge, CI-949 increased the 50 w/kg, collapse time from a control of 1.9 min. to 3.4 min. in actively sensitized guinea pigs exposed to antigen aerosol. Oral administration of CI-949, 100 mg/kg 2 hours before antigen exposure, was just as effective. A 200 mg/kg dose gave maximum protection in this model for several hours. In allergic dogs, intravenous CI-949. 0.1. 1.0 and 3.0 ma/ka inhibited the ascari&ind&ed changes in-. total pulmonary resistance by lo%, - 40%, 62% and. dynami; compliance bv 5%. 29%. and 58%. resoectivelv. When given orally 4.5’hours before ihallenge, CI-949 20 mg/kg, inhibited the resistance change 71% and the dynamic compliance decrease 33% respectively compared to the animals’ own control responses. Thus, CI-949 is an orally effective antiallergy compound which exhibits its protective effects for several hours.
Terfenadine, a nonsedatiqg Ii1 antihistamine, has been shown to block histamine and attenuate exercise challenges. We determined if it affects UNDW and CAAC, both of which may induce mast cell degranulation. Twelve asthmatics underwent UNDW and CAHC challenges in separate double-blind, placebo-controlled, crossover trials. Challenges were performed 4 hrs following drug, during which time pulmonary functions.were followed. The UNDW was given in a dose-response fashion and the CAHC by a single timed ventilatory effort. The response to these test were compared for placebo, 120 and 240 mg. Terfenadine. The baseline FEVl on the 3 study days for the two trials were comparable. Terfenadine had a significant bronchodilatory effect, at both doses, at the 2nd, 3rd. and 4th hours before UNDW (max. increase +5.2% FEV ), and at the 2nd and 3rd hr. Before CAHC (+6. I % FEV ). the fall Terfenadine significantly a $tenuated in FEVl during the UNDW challenge, p = -01 for 240 mg., but less so at 120 ag, p =.058. Terfenadine did protect against CANC in 7/12 at 120 mg. and 6112 at 240 mg., but it was not significant as a group.. Since Terfenadine had a significant and equal effect on pulmonary function before UNDWand CAHC the challenge results may suggest different mechanisms of action or it may suggest a difference in the antagonism of Terfenadine against the challenges.
INHALATIONAL THERAPY EXACERBATES CASTROESOPHAGEAL REFLUX IN ASTHMATICS. David Elkayam, M.D., Denver, CO. Twelve pediatric patients underwent continuous pH monitoring b;y use of a distal esophageal probe for periods ranging from 19 to 23 hours. The patients were five years to 18 years of age. All had moderate to severe asthma requiring chronic utilization of bronchodilator medications. All were receiving theophylline and beta agonist medications; 9/12 (75%) were on daily or alternate da steroid therapy. Castroesophageal reflux (CER r was diagnosed radiographically in 9/12 (75%) of these patients; all patients had a history suggestive of CER and/or significant nocturnal exacerbations of their asthma. A retrospective review of the DH monitorine records of these patients re;ealed a big: incidence of GER, II/12 (92%) oatients. as assessed by the Johnson’ h Dime&e; or Eul;?r & Byrne criteria. CER was temporally associated with respiratory treatments (RT’s), either by MD1 or nebulization,in IO/12 (83%) patients. A total of 51 RT’s were monitored; CER was temoorallv associated with inhalational therapy in’ 27/.5i (52%) of these and probably associated in 9/51 (18%) others, for a total of 26/51 (71%). GER associated with RT’s occurred in IO/12 (83%) of this select group of patients. Operative factors for this apparent association may be drug effect(s) and/or mechanical factors associated with the breathing pattern noted with RT’s. We conclude that there may be a temporal association between inhalational therapy and GER in certain asthmatic patients.
313