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The painful peripheral neuropathy occurring frequently during chemotherapy with paclitaxel or oxaliplatin is one of their dose-limiting factors. We reported previously that substance P is involved in the pathogenesis of pulmonary hypersensitivity reaction to paclitaxel in rats, and an antiallergic agent pemirolast reverses this reaction via the blockade of release of substance P. In the present study, we investigated the involvement of substance P in paclitaxel-induced peripheral neuropathy compared with that by oxaliplatin. In von Frey and acetone tests in rats repeated administration of paclitaxel (6 mg/kg i.p., once a week for 4 weeks) or oxaliplatin (4 mg/kg i.p., twice a week for 4 weeks) induced both mechanical allodynia and cold hyperalgesia. Paclitaxel-induced peripheral neuropathy was reversed primarily by the acute administration of pemirolast (0.1 and 1 mg/kg p.o.). Moreover, coadministration of the receptor antagonists neurokinin 1 [N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)benzylester (L-732,138), 100 μg/body i.t.] and neurokinin 2 [5-fluoro-3-[2-[4-methoxy-4-[[(R)-phenylsulphinyl]methyl]-1-piperidinyl]ethyl]-1H-indole (GR159897), 100 μg/body i.t.] strongly reversed paclitaxel-induced neuropathy. On the other hand, oxaliplatin-induced peripheral neuropathy was not reversed by pemirolast. In the in vitro study using cultured adult rat dorsal root ganglion neurons paclitaxel (1000 ng/ml) significantly increased the release of substance P, and pemirolast (100 and 1000 nM) significantly inhibited this increase of substance P release. Oxaliplatin, by contrast, did not increase the release of substance P. These results suggest that substance P is involved in paclitaxel-induced neuropathy, and the mechanism of its action is clearly different from that of oxaliplatin.

Acute renal failure is a dose-limiting factor of cisplatin chemotherapy. Here, we show the protective effect of edaravone, a recently developed radical scavenger for clinical use, against cisplatin-induced renal dysfunction in rats. A marked increase in blood urea nitrogen and creatinine in serum, and histological changes including vacuolation, necrosis and protein casts were observed in proximal renal tubules at the fourth day after cisplatin injection (5-10 mg/kg). Repeated injection of edaravone (1-10 mg/kg, i.v. twice a day for 3 days) reversed the cisplatin-induced elevation of blood urea nitrogen and creatinine, and morphological changes in a dose-dependent manner. In particular, the protective effect of edaravone was almost complete at 10 mg/kg. Moreover, the compound was still fully effective, when it was administered only at the second day after cisplatin injection. On the other hand, the glutathione content in renal tissues lowered at the fourth day after cisplatin injection, which was reversed by the late treatment with edaravone. These findings suggest that the clinically available radical scavenger edaravone is potentially useful for the prevention of cisplatin-induced renal toxicity.

Background: Neutropenia is one of the most frequent and dose-limiting toxicities in amrubicin (AMR) therapy. However, the predictive factors for the development of severe neutropenia in AMR therapy remain unknown. Methods: The subjects were 61 advanced lung cancer patients treated with AMR monotherapy. All data were retrospectively collected from the electronic medical record system. A stepwise logistic regression analysis was performed to identify risk factors for grade 3–4 neutropenia. Results: Of a total 61 patients, 50 were male and 11 were female. The median dose of AMR was 35.0 mg/m2. The incidence of grade 3–4 neutropenia during the first course was 62%. In multivariate analysis, female gender (OR = 6.68; 95% CI 1.01–134.15; p = 0.049), higher AMR doses (40 mg/m2 or more) (OR = 5.98; 95% CI 1.77–23.74; p = 0.003), and lower hematocrit values (OR = 2.04 per 5% decrease; 95% CI 1.04–4.38; p = 0.036) were significantly associated with severe neutropenia induced by AMR. Conclusion: The present results suggest that female gender, higher doses of AMR, and lower baseline hematocrit values are predictive factors associated with severe neutropenia induced by AMR in patients with advanced lung cancer. Patients who have these predictive factors should be monitored carefully and considered for early granulocyte colony-stimulating factor support.

SUMMARY Objective: To assess the usefulness of dynamic laser scattering for monitoring the stability of ampicillin after reconstitution from commercially available vials with respect to the polymer formation and potency. Methods: Polymer formation and the remaining potency of the reconstituted ampicillin solution were estimated using dynamic laser scattering and high-performance liquid chromatography. Results: The laser light-scattering submicron particle analyser was sufficiently sensitive for detecting both monomer and polymer aggregates with the average diameter of 1AE 1±0 AE2 and 7AE 3±1 AE7 nm, respectively, in the ampicillin solution. Polymer formation was dependent on both the storage temperature and the storage period, but it was detected, even when no precipitates were visible and when loss of potency was less than 10% of the initial value following storage at 4 or ‐15 � C. Conclusion: Submicron particle analysis using scanning electron microscopy, when used in combination with high-performance liquid chromatography, provides a useful method for studying polymer formation in antibiotic solutions and for the quality control of antibiotic injections during storage.