Protective effect of furosemide combined with non-steroidal anti-inflammatory drugs administered by inhalation route on guinea-pigs anaphylaxis model.
The exposure of ovalbumin sensitized guinea-pig to an areosol of the specific antigen causes a respiratory crisis in approximately 100 s (dispnoea time) associated with a substantial increase in blood concentration of both histamine (from 27.5 +/- 1.8 ng/ml to 1570 +/- 26 ng/ml; n = 8) and thromboxane B2 (TXB2, from 0.52 +/- 0.03 ng/ml to 18.1 +/- 0.6 ng/ml; n = 8). The aerosol treatment of the animals (20 min) with furosemide (CAS 54-31-9, frusemide, FRU), nimesulide (CAS 51803-78-2, NIM), acetylsalicylic acid (CAS 50-78-2, ASA) and indometacin (CAS 53-86-1, INDO) at the concentrations of 1-3-10 and 30 mg/ml, before ovalbumin challenge, brought about an attenuation of anaphylactic response. The rank order of potency for the prolongation of dyspnoea time was FRU > NIM > ASA > INDO. In these experiments blood evaluation performed at the peak of the dyspnoea time for histamine concentration in the treated animals indicated that whereas FRU (ED25 = 2.14 mg/ml (1.97-2.38) and NIM (ED25 = 2.74 mg/ml (2.37-3.19)) were equiactive in reducing the release of histamine, ASA and INDO were devoid of this activity. On the contrary, the results obtained with ASA and INDO indicated a greater intrinsic activity in antagonizing TXB2 formation than that shown by the log-dose response curves of NIM and FRU. In another series of experiments the interaction of FRU with the other anti-inflammatory drugs in protecting guinea-pig from immune bronchoconstriction has been evaluated using the combination of two equiactive doses. The mixture considered were FRU+NIM, FRU+INDO and FRU+ASA. The results obtained indicated that FRU interacts positively with the three non-steroidal anti-inflammatory drugs in delaying the onset of the dyspnoeic crisis in guinea-pig. However, when FRU was combined with NIM the gain obtained (209%) appeared superior to that reached when FRU was combined with ASA (180%) or INDO (126%). Taken together these results suggest that non-steroidal anti-inflammatory compounds given by aerosol may represent a valid pharmacological intervention in protecting guinea-pig from anaphylactic bronchoconstriction.
Berti
F
F
Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Italy.
Rossoni
G
G
Robuschi
M
M
Mandelli
V
V
D000280:Administration, Inhalation; D000707:Anaphylaxis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004232:Diuretics / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005665:Furosemide / Q000008:administration & dosage / Q000627:therapeutic use*; D006168:Guinea Pigs; D006636:Histamine Release / Q000187:drug effects; D008297:Male; D010047:Ovalbumin / Q000276:immunology; D013929:Thromboxane B2 / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004232:Diuretics; D013929:Thromboxane B2; D005665:Furosemide; D010047:Ovalbumin