Suspected anaphylactic reaction to Cremophor EL.

Dye, Danielle E.; Watkins, J.

doi:10.1136/bmj.280.6228.1353

Cited by 163 publications

(71 citation statements)

References 4 publications

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“…The aetiology of paclitaxel-associated HSR is multifactorial and several mechanisms have been postulated: (A) an IgE-mediated mast-cell degranulation induced by paclitaxel (Weiss et al, 1990) or Cremophor EL (Dye and Watkins, 1980;Weiss and Baker, 1987); (B) a non-IgE-mediated idiosyncratic mast-cell degranulation by paclitaxel or by Cremophor EL (Gelderblom et al, 2001) and (C) complement activation (Szebeni et al, 2001). The rapid and overwhelming onset of the HSR as observed in our patient is not compatible with the natural course of an IgE hypersensitivity reaction and points towards one of the two other mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Fatal outcome of a hypersensitivity reaction to paclitaxel: a critical review of premedication regimens

et al. 2004

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Hypersensitivity reactions (HSRs) to paclitaxel are frequently encountered in patients receiving this antitumour drug. Administration of histamine H1-and H2-receptor antagonists and corticosteroids has been shown to reduce significantly the risk of developing an HSR in patients receiving taxanes. In this case report, we describe the fatal outcome of an HSR in a patient receiving paclitaxel despite short-course premedication. The level of evidence supporting the short-course i.v. premedication schedule is challenged, as it is not compatible with the pharmacokinetic properties of dexamethasone.

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Section: Discussionmentioning

confidence: 99%

Fatal outcome of a hypersensitivity reaction to paclitaxel: a critical review of premedication regimens

et al. 2004

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“…Our previous studies of oral paclitaxel have shown that following oral administration of the drug the co-solvent Cremophor EL is not absorbed (Meerum Terwogt et al, 1998Malingré et al, 2000). This is important, first of all, because systemic exposure to Cremophor EL can induce severe hypersensitivity reactions requiring extensive premedication (Dye and Watkins, 1980;Weiss et al, 1990). Consequently, paclitaxel can be administered orally without premedication, which has been done in the current study and without complications.…”

Section: Gf120918mentioning

confidence: 99%

“…Severe hypersensitivity reactions have been observed after i.v. infusion of paclitaxel and it is now well established that the pharmaceutical vehicle Cremophor EL contributes largely to this effect (Dye and Watkins, 1980;Weiss et al, 1990). Oral administration of paclitaxel is very attractive, because it is convenient and practical for patients and it may circumvent systemic exposure to the toxic vehicle Cremophor EL.…”

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confidence: 99%

Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients

et al. 2001

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SummaryOral bioavailability of paclitaxel is very low, which is due to efficient transport of the drug by the intestinal drug efflux pump P-glycoprotein (P-gp). We have recently demonstrated that the oral bioavailability of paclitaxel can be increased at least 7-fold by co-administration of the P-gp blocker cyclosporin A (CsA). Now we tested the potent alternative orally applicable non-immunosuppressive P-gp blocker GF120918. Six patients received one course of oral paclitaxel of 120 mg/m 2 in combination with 1000 mg oral GF120918 (GG918, GW0918). Patients received intravenous (i.v.) paclitaxel 175 mg/m 2 as a 3-hour infusion during subsequent courses. The mean area under the plasma concentration-time curve (AUC) of paclitaxel after oral drug administration in combination with GF120918 was 3.27 ± 1.67 µM.h. In our previously performed study of 120 mg/m 2 oral paclitaxel in combination with CsA the mean AUC of paclitaxel was 2.55 ± 2.29 µM.h. After i.v. administration of paclitaxel the mean AUC was 15.92 ± 2.46 µM.h. The oral combination of paclitaxel with GF120918 was well tolerated. The increase in systemic exposure to paclitaxel in combination with GF120918 is of the same magnitude as in combination with CsA. GF120918 is a good and safe alternative for CsA and may enable chronic oral therapy with paclitaxel.

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“…DMSO is known to cause adverse events when administered to patients (nausea, vomiting, mal-odor) and to be potentially hepatotoxic and cardiotoxic (14,15). Cremophor is known to induce hypersensitivity reactions and anaphylaxis and requires pretreatment with antihistamines and steroids (16). Clinical trials with 17-AAG in these excipients may confound the true maximum tolerated dose of 17-AAG and identification of the optimal dosing regimen in patients.…”

mentioning

confidence: 99%

Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90

Sydor

Normant

Pien

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

220

160

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Heat shock protein 90 (Hsp90) is an emerging therapeutic target of interest for the treatment of cancer. Its role in protein homeostasis and the selective chaperoning of key signaling proteins in cancer survival and proliferation pathways has made it an attractive target of small molecule therapeutic intervention. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), the most studied agent directed against Hsp90, suffers from poor physical-chemical properties that limit its clinical potential. Therefore, there exists a need for novel, patient-friendly Hsp90-directed agents for clinical investigation. IPI-504, the highly soluble hydroquinone hydrochloride derivative of 17-AAG, was synthesized as an Hsp90 inhibitor with favorable pharmaceutical properties. Its biochemical and biological activity was profiled in an Hsp90-binding assay, as well as in cancer-cell assays. Furthermore, the metabolic profile of IPI-504 was compared with that of 17-AAG, a geldanamycin analog currently in clinical trials. The anti-tumor activity of IPI-504 was tested as both a single agent as well as in combination with bortezomib in myeloma cell lines and in vivo xenograft models, and the retention of IPI-504 in tumor tissue was determined. In conclusion, IPI-504, a potent inhibitor of Hsp90, is efficacious in cellular and animal models of myeloma. It is synergistically efficacious with the proteasome inhibitor bortezomib and is preferentially retained in tumor tissues relative to plasma. Importantly, it was observed that IPI-504 interconverts with the known agent 17-AAG in vitro and in vivo via an oxidation-reduction equilibrium, and we demonstrate that IPI-504 is the slightly more potent inhibitor of Hsp90.T he heat shock response, first identified in 1962 by Ritossa (1), was initially characterized as the induction of select polypeptides in response to an acute cellular heat shock. These polypeptides were proteins that bound to partially unfolded proteins to prevent their aggregation and assist in their refolding (2, 3), and were termed chaperones. Of the heat shock proteins, heat shock protein 90 (Hsp90) in particular has been the subject of intense investigation. Work over the last decade has revealed not only a general protein chaperone role for Hsp90, but also a specific chaperone role in the binding of select conformations or metastable forms of signaling proteins (clients), thereby attenuating their signaling activity (4-6). Client proteins include the targets of key cancer survival and proliferation pathways, including Akt, Bcr-Abl, Her-2, mutant EGFR, and c-Kit, many of which are the subject of individual investigation for points of therapeutic intervention. Therefore, two functions of Hsp90 exist: (i) a general protein chaperone function (protein homeostasis) and (ii) a specific function to modulate the integrity of cell-signaling pathways through the proper folding of pathway members that are Hsp90 clients.Multiple myeloma (MM) is a neoplasm of terminally differentiated B cells (plasma cells) (7). Because of the high protein secr...

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Suspected anaphylactic reaction to Cremophor EL.

Cited by 163 publications

References 4 publications

Fatal outcome of a hypersensitivity reaction to paclitaxel: a critical review of premedication regimens

Fatal outcome of a hypersensitivity reaction to paclitaxel: a critical review of premedication regimens

Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients

Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90

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