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201. Effect of single doses of lodoxamide tromethamine on allergen inhalation provocation tests
Abstracts of papers
WLUME 61 NUMBER 3
included either generalized dermatitis, facial dermatitis, lmyositis, or gastroenteritis, all of which were reversible. Specific anticromolyn antibodies of the IgE class were assayed by the galactosidase immunosorbent test (GIST), results of which were statistically indistinguishable in cromolyn-intolerant , cromolyn-tolerant , and untreated controls. The occurrence of possibly toxic chemical degradation products of cromolyn was determined from absorbance and fluorescence spectra. The absorbance maxima at 326 nm (0.26), 260 nm (sh 0.52), and 240 nm (0.86) and the fluorescence maximum at 4YO nm were unchanged for at least 5 days in neutral and basic solutions of cromolyn in the light or dark. Thus the chromone rings of cromolyn appear stable for prolonged periods of time. Fluorescence emission of free cromolyn was unpolarized but the quantum yield was too Iow to permit estimation of binding to serum proteins from fluorescence polarization. However, binding of either H3- or C14-labeled cromolyn to serum proteins was not detected. These results indicate that the adverse responses to cromolyn are not true allergies mediated by IgE and are not due to spontaneous breakdown products of cromolyn. Adverse reactions to cromolyn may be due either to immunologic mechanisms not mediated by circulating IgE antibodies or to idiosyncratic responses to the drug.
ffect of single doses of lodoxamide tromethamine on allergen inhalation provocation tests. T. Bui, M.D., K. Burke, B.S., G. Watt, B.A., A. Bewtra, D., Omaha, Nebr.
M.D.r and R. Townley,
Lodoxamide tromethamine (LT), a cromolyn-like drug, is intended for prophylaxis of asthma and allergic rhinitis. We compared the effect of LT in different doses with placebo on allergen inhalation provocation tests. Eight mild to moderate extrinsic asthmatic patients, pretreated with aerosol LT or placebo, were challenged with increasing concentrations of allergen (2 Alternaria, 6 ragweed) until: l-set forced expiratory volume (FEV1) fell to <80% of baseline (32/40 tests) or maximum dose of allergen was administered (8/40). All subjects were off antihistamines 72 hr and bronchodilators 12 hr prior to test. Each subject had 5 challeges separated by at least 48 hr. A single-blind placebo challenge with sterile water established baseline allergen provocative dose (PD), and this was excluded from subsequent statistical analysis. Subsequent challenges after pretreatment with 1 ml of placebo or LT (0.01, 0.1, 1 mg/ml) were conducted in randomized double-blind fashion. Best-fit parabolic curves for dose (adjusted cummulative log dose of allergen) vs response (% of baseline FEVJ were calculated and PDls derived. Among subjects variation was substantial. All doses of LT significantly increase the calculated PDls over placebo (x: = 8.2 for 4 treatments for 8 subjects, p > 0.05). Excluding one unprotected subject with a cold during LT challenges, the amount of allergen to produce a >2Q% fall in FEV, was 2 to 65 times more than
1
placebo. Lodoxamide tromethamine appears to protect extrinsic asthmatic patients from allergen-induced bronchoconstriction.
202. Effects of pretreatment lodoxamide tromethamine responses to allergen and
wit
N. Nair, M.D., K. Burke, B.S., G. A. Bewtra, M.D., and R. Town Omaha, N&r. Lodoxamide tromethamine (LT) appears to inhibit release of mast cell allergic mediators. It appears to be orally active and is over 1,000 times as potent as cromolyn which does not inhibit allergen skin test reactions in man. We evaluated the ability of LT to inhibit release of mediators from skin mast cells challenged with allergen and cutaneous response elicited by intrademal (KD) histamine injection. Five male subjects with positive skin reactions to ID allergen were tested. All subjects were off drugs: sympathomimetics, xanthines, and caffeine for 12 hr, antihistamines for 72 hr. Twenty sites on outer arm surfaces were injected with 0.1 ml of LT at 10ms, 10p4, IOm3, 10mz mg/ml; 5 sites were injected with saline-diluent placebo (P). Twenty of these sites were injected with Q.02 mI of allergen at 10e6, 10e5, 10-4, lO-3 w/v; 5 sites were injected with P. Similar procedure was used for histamine; 0.02 ml IG at 10m4 and 10e3 mg/ml. Crossed diameters of wheals were measured 15 min after challenge; square root of wheal area (mm) was used as the response variable. Mean response to histamine was not significantly affected by pretreatment with LT. In 4 of 5 of the subjects, response to allergen was reduced by pretreatment (F = 7.06 df = 4, p s 0.01). Ranking, for efficacy, the mean response summed over all allergen levels: p G 0.05 for 4 subjects for 20 treatment combinations. Lodoxamide tromethamine reduced the size of allergen-induced wheal apparently by inhibiting release of mast cell mediators without direct antihistaminic effect.
203. Clinical control of her angioedema with oxymeth A, L. Sheffer, K, F, Austen,
M.D.? D. T. Fearon, M.D., and M.D., f3oston, Mass.
Prophylactic administration of anabolic agents with impeded androgenic effects has been shown by others to prevent hereditary angioedema (HAE) attacks and reverse the biochemical and clinical abnormalities associated with HAE. In a dose-finding study, 16 patients with biochemically proved HAE, including 12 with absent and 4 with nonfunctional CiIIdH, received oxymethoione. Whereas incapacitating attacks occurred about evev 4 wk during prior periods without therapy, 15 patients failed to experience attacks on 5 mg daiIy and 1 on IO mg daily. Two of IO patients subsequently receiving 5 mg every other day and ail 5 receiving 5 mg every third day began to experience attacks
WLUME 61 NUMBER 3
included either generalized dermatitis, facial dermatitis, lmyositis, or gastroenteritis, all of which were reversible. Specific anticromolyn antibodies of the IgE class were assayed by the galactosidase immunosorbent test (GIST), results of which were statistically indistinguishable in cromolyn-intolerant , cromolyn-tolerant , and untreated controls. The occurrence of possibly toxic chemical degradation products of cromolyn was determined from absorbance and fluorescence spectra. The absorbance maxima at 326 nm (0.26), 260 nm (sh 0.52), and 240 nm (0.86) and the fluorescence maximum at 4YO nm were unchanged for at least 5 days in neutral and basic solutions of cromolyn in the light or dark. Thus the chromone rings of cromolyn appear stable for prolonged periods of time. Fluorescence emission of free cromolyn was unpolarized but the quantum yield was too Iow to permit estimation of binding to serum proteins from fluorescence polarization. However, binding of either H3- or C14-labeled cromolyn to serum proteins was not detected. These results indicate that the adverse responses to cromolyn are not true allergies mediated by IgE and are not due to spontaneous breakdown products of cromolyn. Adverse reactions to cromolyn may be due either to immunologic mechanisms not mediated by circulating IgE antibodies or to idiosyncratic responses to the drug.
ffect of single doses of lodoxamide tromethamine on allergen inhalation provocation tests. T. Bui, M.D., K. Burke, B.S., G. Watt, B.A., A. Bewtra, D., Omaha, Nebr.
M.D.r and R. Townley,
Lodoxamide tromethamine (LT), a cromolyn-like drug, is intended for prophylaxis of asthma and allergic rhinitis. We compared the effect of LT in different doses with placebo on allergen inhalation provocation tests. Eight mild to moderate extrinsic asthmatic patients, pretreated with aerosol LT or placebo, were challenged with increasing concentrations of allergen (2 Alternaria, 6 ragweed) until: l-set forced expiratory volume (FEV1) fell to <80% of baseline (32/40 tests) or maximum dose of allergen was administered (8/40). All subjects were off antihistamines 72 hr and bronchodilators 12 hr prior to test. Each subject had 5 challeges separated by at least 48 hr. A single-blind placebo challenge with sterile water established baseline allergen provocative dose (PD), and this was excluded from subsequent statistical analysis. Subsequent challenges after pretreatment with 1 ml of placebo or LT (0.01, 0.1, 1 mg/ml) were conducted in randomized double-blind fashion. Best-fit parabolic curves for dose (adjusted cummulative log dose of allergen) vs response (% of baseline FEVJ were calculated and PDls derived. Among subjects variation was substantial. All doses of LT significantly increase the calculated PDls over placebo (x: = 8.2 for 4 treatments for 8 subjects, p > 0.05). Excluding one unprotected subject with a cold during LT challenges, the amount of allergen to produce a >2Q% fall in FEV, was 2 to 65 times more than
1
placebo. Lodoxamide tromethamine appears to protect extrinsic asthmatic patients from allergen-induced bronchoconstriction.
202. Effects of pretreatment lodoxamide tromethamine responses to allergen and
wit
N. Nair, M.D., K. Burke, B.S., G. A. Bewtra, M.D., and R. Town Omaha, N&r. Lodoxamide tromethamine (LT) appears to inhibit release of mast cell allergic mediators. It appears to be orally active and is over 1,000 times as potent as cromolyn which does not inhibit allergen skin test reactions in man. We evaluated the ability of LT to inhibit release of mediators from skin mast cells challenged with allergen and cutaneous response elicited by intrademal (KD) histamine injection. Five male subjects with positive skin reactions to ID allergen were tested. All subjects were off drugs: sympathomimetics, xanthines, and caffeine for 12 hr, antihistamines for 72 hr. Twenty sites on outer arm surfaces were injected with 0.1 ml of LT at 10ms, 10p4, IOm3, 10mz mg/ml; 5 sites were injected with saline-diluent placebo (P). Twenty of these sites were injected with Q.02 mI of allergen at 10e6, 10e5, 10-4, lO-3 w/v; 5 sites were injected with P. Similar procedure was used for histamine; 0.02 ml IG at 10m4 and 10e3 mg/ml. Crossed diameters of wheals were measured 15 min after challenge; square root of wheal area (mm) was used as the response variable. Mean response to histamine was not significantly affected by pretreatment with LT. In 4 of 5 of the subjects, response to allergen was reduced by pretreatment (F = 7.06 df = 4, p s 0.01). Ranking, for efficacy, the mean response summed over all allergen levels: p G 0.05 for 4 subjects for 20 treatment combinations. Lodoxamide tromethamine reduced the size of allergen-induced wheal apparently by inhibiting release of mast cell mediators without direct antihistaminic effect.
203. Clinical control of her angioedema with oxymeth A, L. Sheffer, K, F, Austen,
M.D.? D. T. Fearon, M.D., and M.D., f3oston, Mass.
Prophylactic administration of anabolic agents with impeded androgenic effects has been shown by others to prevent hereditary angioedema (HAE) attacks and reverse the biochemical and clinical abnormalities associated with HAE. In a dose-finding study, 16 patients with biochemically proved HAE, including 12 with absent and 4 with nonfunctional CiIIdH, received oxymethoione. Whereas incapacitating attacks occurred about evev 4 wk during prior periods without therapy, 15 patients failed to experience attacks on 5 mg daiIy and 1 on IO mg daily. Two of IO patients subsequently receiving 5 mg every other day and ail 5 receiving 5 mg every third day began to experience attacks