Strategy for NSAID administration to aspirin-intolerant asthmatics in combination with PGE2 analogue: a theoretical approach

Abstract

Aspirin-induced asthma (AIA) is a severe inflammatory disease, which affects aspirin-intolerant patients after ingestion of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs). In this article, a mathematical model describing arachidonic acid metabolism and its interaction with NSAIDs, is used to study the strategy for safe managing of NSAIDs to AIA patients. Three different AIA patient populations are taken into consideration. First, the values of aspirin and ibuprofen limiting doses that might induce symptoms of AIA are calculated and compared to experimentally observed threshold doses to enlighten which AIA patient population is susceptible to aspirin and ibuprofen. Second, the methodology of NSAID administration is studied on AIA populations susceptible to aspirin and ibuprofen by using 1,000 mg dose of aspirin and 200 or 400 mg dose of ibuprofen followed by PGE(2) analogue dosing. Our model results show that successive doses of PGE(2) analogue applied at appropriate time after aspirin or ibuprofen ingestion would enable administration of both NSAIDs to AIA patients. PGE(2) analogue doses and the corresponding times of their applications are calculated. The model is also used to estimate the duration of symptoms of AIA for different aspirin and ibuprofen doses.

Dynamic model of eicosanoid production with special reference to non‐steroidal anti‐inflammatory drug‐triggered hypersensitivity

“…Therefore we considered in our present model the differences in v max of COX‐2 for the characterisation of the model states of NI and of inflammation. By assuming diminished v max of LTC 4 S our previous model [41, 43, 49] described AIA patients most consistently. Based thereon, we considered the same assumptions for the definition of model populations based on LTC 4 S, applying v max of LTC 4 S and fold‐ratios as used in [41, 43, 49].…”

“…By assuming diminished v max of LTC 4 S our previous model [41, 43, 49] described AIA patients most consistently. Based thereon, we considered the same assumptions for the definition of model populations based on LTC 4 S, applying v max of LTC 4 S and fold‐ratios as used in [41, 43, 49]. Accordingly, the measured five‐fold higher expression of LTC 4 S in patient group AIA compared to ATA [10, 39] is reflected in our recent model by a five‐fold higher value of v max of LTC 4 S in the model populations AIA (2) and AIA (3) compared to ATA.…”

“…Our previous model [41, 43, 49] could not consider differences in v max of PGES. On the other hand, our present model considers differences in v max of PGES twice; first, in the definitions of the model states inflammation and NI, and, second, in the definition of the model populations.…”

“…We considered also the inhibitory effect of PGE 2 on 5-LOX [12,[16][17][18][19] in the model. Since the entire mechanism of this inhibition is not completely elucidated [9,11,18,40], a reversible competitive enzyme inhibition was considered here as in our previous [41][42][43] and the other models [44]o f eicosanoid production. Equation (4) was used in the case of reaction step 17, in which enzyme LTC 4 S catalyses conversion of substrate LTA 4 into the product LTC 4 .…”

Hypersensitivity to antipyretics: pathogenesis, diagnosis, and management

“…Nonetheless desensitisation should only be Detailed history taking, physical examination, record review, Naranjo probability score, 41 underlying diseases, co-factor carried out in medical facilities with resuscitation equipment and expertise in drug allergy. Alternative theoretical choices (approach 4) include subthreshold or low-dose paracetamol, 47,53 COX-2 inhibitors, 54 pre-medication with antihistamines with or without leukotriene receptor antagonist, 55 co-administration of a PGE 2 analogue, 56 and traditional Chinese medicine. 57 Future studies are needed to define the safety and efficacy of these unconventional treatments.…”