Prophylactic effect of pemirolast, an antiallergic agent, against hypersensitivity reactions to paclitaxel in patients with ovarian cancer

Abstract

We have previously shown that sensory nerve peptides contribute to the pathogenesis of pulmonary hypersensitivity reactions (HSRs) to paclitaxel in rats. Moreover, pemirolast, an antiallergic agent, reverses the HSRs to paclitaxel, although the mechanism is considered to result from the blockade of paclitaxel-induced release of sensory peptides, rather than the inhibition of histamine release. In the present study, we investigated the preventive effect of pemirolast against acute HSRs in a total of 84 patients who undertook postoperative paclitaxel plus carboplatin chemotherapy every 4 weeks for ovarian cancer. Patients were assigned to receive oral lactose (placebo) or pemirolast (10 mg), 2 hr before paclitaxel infusion. All patients received conventional premedication, including oral diphenhydramine, intravenous ranitidine and intravenous dexamethasone, 30 min before paclitaxel infusion. The HSRs that led to the discontinuance of paclitaxel infusion (grade 2) occurred in 5 of 42 patients in placebo group, whereas none of pemirolast-treated 42 patients showed any signs of HSRs. Plasma histamine concentrations were not changed after paclitaxel infusion in either group. Our present findings suggest that pemirolast is potentially useful for prophylaxis of paclitaxelinduced HSRs. In this respect, the use of pemirolast as premedication is expected to be beneficial to the safety management in patients who undergo chemotherapy containing paclitaxel. ' 2005 Wiley-Liss, Inc.Key words: paclitaxel; hypersensitivity reactions; pemirolast; histamine; ovarian cancer Paclitaxel (Taxol) is a widely used chemotherapeutic agent for several malignancies, including ovarian cancer, breast cancer, endometrial cancer, nonsmall-cell lung cancer and stomach cancer. However, the use of paclitaxel is sometimes limited due to the incidence of severe hypersensitivity reactions (HSRs). The HSRs to paclitaxel are characterized by flushing, chest discomfort, respiratory distress and pulmonary edema, 1-4 and the incidence is particularly high in patients with ovarian cancer who undertook postoperative chemotherapy containing paclitaxel. 5 To avoid the HSRs, premedication containing histamine H 1 and H 2 antagonists in combination with glucocorticoids is always prescribed, [6][7][8][9][10] although the preventive effect is by no means complete. However, there has been no direct evidence suggesting that the HSRs to paclitaxel are mediated by the release of histamine from mast cells or basophils. We have recently shown that paclitaxel causes pulmonary vascular hyperpermeability and edema and the decrease in arterial partial oxygen pressure in rats.11 The toxic effects of paclitaxel in rat lungs are attenuated by neurokinin NK 1 and NK 2 receptor antagonists, or chemical sensory denervation with repeated capsaicin treatment, but not by histamine H 1 or H 2 antagonists, thereby suggesting that the pulmonary adverse reactions induced by paclitaxel are mediated by sensory nerve peptides such as substance P and neurokinin A, but not by mast cell hista...

G Protein-Coupled Receptors (GPCRs)-Mediated Calcium Signaling in Ovarian Cancer: Focus on GPCRs activated by Neurotransmitters and Inflammation-Associated Molecules

“…The hypersensitivity reactions to chemotherapeutic agents, involving mast cell and basophils activation, can be monitored in ovarian cancer patients by quantifying the serum levels of tryptase, which is released together with histamine after mast cell activation [110]. The reduction of hypersensitivity reactions to chemotherapeutic drugs (i.e., paclitaxel) in patients with ovarian cancer was also obtained by premedication with pemirolast, an antiallergic agent, that is rather diminishing the release of sensory peptides than inhibiting the histamine release [111]. In a retrospective study, women with ovarian cancer that received premedication with antagonists of H1 and H2, in addition to dexamethasone, had approximately half the risk of carboplatin hypersensitivity reactions compared with patients without premedication and the overall incidence of carboplatin hypersensitivity reactions decreased after addition of premedication [112], Figure 7.…”

Involvement of Substance P in Peripheral Neuropathy Induced by Paclitaxel but Not Oxaliplatin

“…We reported previously that paclitaxel markedly increases substance P in plasma and bronchoalveolar lavage fluid in rats and in plasma in patients with ovarian cancer (Itoh et al, 2004a;Sendo et al, 2004). Moreover, we have reported that pemirolast, an antiallergic agent, attenuates paclitaxel-induced pulmonary hypersensitivity reactions through inhibition of the release of sensory nerve peptides including substance P, neurokinin (NK) A, and calcitonin gene-related peptide (CGRP) in rat bronchoalveolar lavage fluid (Itoh et al, 2004b) and also prevents paclitaxel-induced hypersensitivity reactions in patients with ovarian cancer (Yahata et al, 2006). Thus, sensory nerve peptides such as substance P play an important role in paclitaxel-induced hypersensitivity reactions.…”

Factors Influencing the Appearance of Oxaliplatin-Induced Allergy

“…With respect to aprepitants, which are reported to inhibit the selective binding of Substance P to neurokinin-1 receptors and suppress paclitaxel-induced hypersensitivity reactions, [15][16][17][18] there was no difference related to the presence or absence of medication. This may have been associated with differences in the pathogenesis of allergy.…”