Hiroaki Ikesue

Oxaliplatin-induced neuropathy in the rat: Involvement of oxalate in cold hyperalgesia but not mechanical allodynia

ABSTRACT Oxaliplatin is a key drug in the treatment of advanced metastatic colorectal cancer, but it causes acute peripheral neuropathy (acral paresthesias triggered by exposure to cold) and chronic neuropathy (abnormal of sensory and motor dysfunction). Oxaliplatin is metabolized to oxalate and dichloro(1,2‐diaminocyclohexane)platinum (Pt(dach)Cl2). Although the chelating of Ca2+ with oxalate eliminated from oxaliplatin is thought as one of the reasons for the neuropathy, there is little behavioral evidence. In this study, we investigated the involvement of oxalate in the oxaliplatin‐induced peripheral neuropathy in rats. Oxaliplatin (4 mg/kg, i.p., twice a week) induced cold hyperalgesia/allodynia (cold‐plate and acetone tests) in the early phase, and mechanical allodynia (von Frey test) in the late phase. Oxalate (1.3 mg/kg, i.p., twice a week) induced the cold hyperalgesia/allodynia in the early phase, but did not induce the mechanical allodynia. On the other hand, Pt(dach)Cl2 (3.8 mg/kg, i.p., twice a week) induced the mechanical allodynia in the late phase, but did not induce the cold hyperalgesia/allodynia. The pre‐administration of calcium or magnesium (0.5 mmol/kg, i.v.) before oxaliplatin or oxalate prevented the cold hyperalgesia but not mechanical allodynia. However, the treatment with calcium or magnesium after the development of neuropathy could not attenuate the cold hyperalgesia or mechanical allodynia. These findings suggest the involvement of oxalate in oxaliplatin‐induced cold hyperalgesia but not mechanical allodynia, and usefulness of prophylactic treatments with calcium and magnesium on the acute peripheral neuropathy.

Ovariectomy aggravates hypersensitivity reactions to paclitaxel in rats

Hypersensitivity reactions is still a matter of serious concern during chemotherapy with paclitaxel, particularly in patients with ovarian cancer. We recently reported that intravenous injection of paclitaxel causes acute lung injury characterized by vascular hyperpermeability, edema and respiratory dysfunction in rats. In the present study, we investigated the influence of ovariectomy on the paclitaxel- induced acute lung injury in rats. Ovariectomy worsened paclitaxel- induced acute lung injury, which was reversed by 17b-estradiol. The mRNA expression for endothelial nitric oxide synthase was reduced in lungs of ovariectomized rats. To determine the role for nitric oxide, we examined the effects of several agents that modulate nitric oxide concentration on the pulmonary response to paclitaxel. In ovary- intact rats, a nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester exaggerated paclitaxel- induced acute lung injury, while nitric oxide donors such as sodium nitroprusside and isosorbide dinitrate attenuated the lung injury. Sodium nitroprusside was also effective in alleviating the paclitaxel- induced acute lung injury in ovariectomized rats. These findings suggest that ovariectomy enhances the susceptibility to paclitaxel hypersensitivity, in which decrease in estrogen and subsequent reduction in nitric oxide synthesis may be involved.

Involvement of Spinal NR2B-Containing NMDA Receptors in Oxaliplatin-Induced Mechanical Allodynia in Rats

BackgroundOxaliplatin is a platinum-based chemotherapy drug characterized by the development of acute and chronic peripheral neuropathies. The chronic neuropathy is a dose-limiting toxicity. We previously reported that repeated administration of oxaliplatin induced cold hyperalgesia in the early phase and mechanical allodynia in the late phase in rats. In the present study, we investigated the involvement of NR2B-containing N-methyl-D-aspartate (NMDA) receptors in oxaliplatin-induced mechanical allodynia in rats.ResultsRepeated administration of oxaliplatin (4 mg/kg, i.p., twice a week) caused mechanical allodynia in the fourth week, which was reversed by intrathecal injection of MK-801 (10 nmol) and memantine (1 μmol), NMDA receptor antagonists. Similarly, selective NR2B antagonists Ro25-6981 (300 nmol, i.t.) and ifenprodil (50 mg/kg, p.o.) significantly attenuated the oxaliplatin-induced pain behavior. In addition, the expression of NR2B protein and mRNA in the rat spinal cord was increased by oxaliplatin on Day 25 (late phase) but not on Day 5 (early phase). Moreover, we examined the involvement of nitric oxide synthase (NOS) as a downstream target of NMDA receptor. L-NAME, a non-selective NOS inhibitor, and 7-nitroindazole, a neuronal NOS (nNOS) inhibitor, significantly suppressed the oxaliplatin-induced pain behavior. The intensity of NADPH diaphorase staining, a histochemical marker for NOS, in the superficial layer of spinal dorsal horn was obviously increased by oxaliplatin, and this increased intensity was reversed by intrathecal injection of Ro25-6981.ConclusionThese results indicated that spinal NR2B-containing NMDA receptors are involved in the oxaliplatin-induced mechanical allodynia.

A Multi-institutional Study Analyzing Effect of Prophylactic Medication for Prevention of Opioid-induced Gastrointestinal Dysfunction

Objectives:The aim of this study was to evaluate the effectiveness of prophylactic treatment with laxatives and antiemetics on the incidence of gastrointestinal adverse reactions such as constipation, nausea and vomiting in cancer patients who received oral opioid analgesics for the first time. Methods:A multi-institutional retrospective study was carried out, in which 619 eligible hospitalized patients receiving oral opioid analgesics for cancer pain were enrolled from 35 medical institutions. The primary endpoint was the incidence of opioid-induced side effects in patients receiving prophylactic medication. Odds ratios of the incidence of adverse reactions in the absence or presence of premedication obtained from several institutions were subjected to a meta-analysis. Results:Among 619 patients, the incidence of constipation was significantly lower in patients receiving laxatives, including magnesium oxide, as premedication than in those without them (34% vs. 55%, odds ratio=0.432, 95% confidence interval=0.300-0.622, P<0.001). However, the incidence of nausea or vomiting was similar regardless of prophylactic medication with dopamine D2 blockers. The results of the meta-analysis revealed that prophylactic laxatives significantly reduced the incidence of constipation (overall odds ratio=0.469, 95% confidence interval=0.231-0.955, P=0.037), whereas dopamine D2 blockers were not effective in preventing opioid-induced nausea or vomiting. Discussion:We showed evidence for the effectiveness of premedication with laxatives for prevention of opioid-induced constipation. However, premedication with dopamine D2 blockers was not sufficient to prevent nausea or vomiting.

Involvement of glial cells in cyclosporine-increased permeability of brain endothelial cells.

AbstractSUMMARY 1. To test whether astrocytes participate in cyclosporine-induced dysfunction of the blood-brain barrier, we examined the effects of cyclosporine on the permeability of the mouse brain endothelial (MBEC4) cells cocultured with C6 glioma cells, each cell layer placed on the top and bottom of the insert membrane, respectively.2. The presence of C6 cells remarkably aggravated cyclosporine-increased permeability of MBEC4 cells to sodium fluorescein.3. In light of these findings, the possibility that astroglial cells could contribute to the occurrence of cyclosporine-induced dysfunction of the blood-brain barrier triggering neurotoxicity should be considered.

Stability of cetuximab and panitumumab in glass vials and polyvinyl chloride bags

PURPOSE The stability of cetuximab and panitumumab in glass vials and polyvinyl chloride (PVC) bags stored at 4 degrees C for up to 14 days was studied. METHODS Sixty milliliters of cetuximab was drawn directly from a commercially available vial, and 20 mL was injected into each of three sterile, empty, 100-mL PVC bags through a preattached 0.22-microm filter. Three milliliters of panitumumab and 21 mL of 0.9% sodium chloride injection were mixed, and 8 mL of the mixture was injected into each of three empty PVC bags through a preattached 0.22-microm filter. Samples were analyzed immediately after preparation and again after storage at 4 degrees C for 7 and 14 days. Cetuximab and panitumumab concentrations were measured using a modification of a previously described enzyme-linked immunosorbent assay method. Stability was defined as the mean concentrations of the test solutions being within assay variability of the initial concentration. Solution appearance and color were assessed by observing the samples against black and white backgrounds. RESULTS The percentages of initial concentration of cetuximab and panitumumab were over 90% stored at 4 degrees C after 14 days. No changes in color or turbidity were observed in any of the vials and the prepared solutions. CONCLUSION Cetuximab 2 mg/mL was stable when stored for 14 days in a glass vial and in PVC bags at 4 degrees C. Panitumumab 20 mg/mL in a glass vial and 2.5 mg/mL in 0.9% sodium chloride injection in PVC bags was also stable when stored for 14 days at 4 degrees C.

Incidence and risk factors for paclitaxel hypersensitivity during ovarian cancer chemotherapy

Hypersensitivity reaction (HSR) is still a major concern during cancer chemotherapy with paclitaxel. In the present study, we investigated retrospectively the incidence of HSRs to paclitaxel and the risk factors in 105 patients (553 courses) who received adjuvant chemotherapy (paclitaxel and carboplatin) for ovarian cancer. Moderate to severe HSRs that led to cessation or discontinuation of the chemotherapy, including respiratory distress and hypotension, were observed in 14 patients (13.3%) and 16 courses (2.9%), regardless of the use of conventional premedication with glucocorticoid, and histamine H1 and H2 antagonists. The incidence of HSRs to paclitaxel in patients with ovarian cancer seemed to be considerably higher than those reported by other investigators in patients with other carcinomas such as non-small-cell lung cancer and breast cancer. Four risk factors were identified: (1) history of mild dermal reactions such as facial flushing and urticaria in previous courses, (2) presence of respiratory dysfunction, (3) obesity (body mass index >25), and (4) postmenopausal at the time of ovariectomy. The incidence of hypersensitivity increased linearly as the number of risk factors increased (r=0.992, P=0.008). It is likely that disappearance of the estrous cycle facilitates the occurrence of HSRs to paclitaxel.

Cyclosporine enhances α1-adrenoceptor-mediated nitric oxide production in C6 glioma cells

Abstract The present study was aimed at elucidating the effect of cyclosporine on phenylephrine-evoked nitric oxide (NO) production in C6 glioma cells using direct electrochemical NO monitoring. Phenylephrine (0.1–10 μM) dose-dependently stimulated NO production (0.8–12.9 μM) and this was blocked by NO synthase inhibitor, prazosin, Ca 2+ -depletion and Xestospongin C (a blocker of the inositol 1,4,5-trisphosphate (IP 3 ) receptor), suggesting that the α 1 -adrenoceptor signaling pathway mediates NO production in C6 cells. Cyclosporine (∼10 μM) failed to evoke NO production but increased phenylephrine-evoked NO production by 20–120% of phenylephrine alone in a dose-dependent manner (1–5 μM). Xestospongin C, at a concentration which showed no effect on phenylephrine-induced NO production, significantly inhibited the cyclosporine-enhanced phenylephrine response. This finding suggests that cyclosporine may increase phenylephrine-induced NO production by accelerating IP 3 receptor function in the α 1 -adrenoceptor signaling pathway in C6 cells. This enhanced NO production in glial cells may be operative for the occurrence of cyclosporine neurotoxicity including convulsions and encephalopathy.

Increased Topical Tacrolimus Absorption in Generalized Leukemic Erythroderma

Objective To report a case of elevated blood tacrolimus concentration after application of topical tacrolimus ointment in an erythrodermic patient. Case Summary A 44-year-old man developed generalized erythroderma and itching due to infection with human T-cell lymphotropic virus. Despite application of strong glucocorticosteroid ointments, the symptoms and area of erythroderma were not alleviated. Daily topical application of tacrolimus 0.1% ointment was added and therapeutic drug monitoring was started. The dose and applied area of tacrolimus were gradually increased from 2.5 to 12.5 g/d and from 10% to 90% of body surface area, respectively. Because the trough concentration of tacrolimus in whole blood increased from 7.5 ng/mL on treatment day 9 to 15.4 ng/mL on day 13, the dose was reduced to 10 g/d. However, the concentration further elevated to 16.5 ng/mL. Therefore, the applied area was reduced to 20% of body surface area, and the tacrolimus concentration decreased gradually thereafter. Although the transient increase of blood tacrolimus concentration was observed on day 23, treatment with 20% applied area and 5 g/d were maintained. Discussion Topically applied tacrolimus was substantially absorbed with the expansion of its applied area and dose. Increased tacrolimus concentrations may have a tendency to depend on the increase of the percent of body surface area per dose. Our findings showing the elevation of blood tacrolimus concentration after application of the ointment to a large area of the body suggest that the applied area should be as narrow as possible in a barrier-disrupted condition such as erythroderma. However, the safety of tacrolimus ointment has not been established in patients with generalized erythroderma. Conclusions Tacrolimus concentrations in whole blood should be carefully monitored to prevent nephrotoxicity. Based on the results of that monitoring, the application area and dose of tacrolimus ointment should be closely adjusted, especially in generalized erythrodermic cases.

Time Course of Calcium Concentrations and Risk Factors for Hypocalcemia in Patients Receiving Denosumab for the Treatment of Bone Metastases From Cancer

Background: Severe hypocalcemia sometimes develops during denosumab treatment for bone metastases from cancer and is, therefore, an important issue. However, limited information is available on the risk factors for hypocalcemia and the appropriate interval for monitoring serum calcium concentration. Objective: The present study aimed to identify the risk factors for grade ≥2 hypocalcemia and to investigate the time course of serum calcium concentrations in patients receiving denosumab for bone metastases from cancer. Method: The medical records of 66 cancer patients treated with denosumab between April 2012 and August 2013 were retrospectively reviewed. Result: Of the 66 enrolled patients, 11, 5, and 1 developed grade 1, 2, and 3 hypocalcemia, respectively. All 4 patients with a baseline estimated glomerular filtration rate (eGFR) of <30 mL/min developed hypocalcemia. Hypocalcemia occurred in only 20%, 24%, and 15% of patients with an eGFR of 30 to 59, 60 to 89, and ≥90 mL/min, respectively. Multivariate logistic regression analysis revealed that lower eGFR values (odds ratio, 1.72 per 10 mL/min decrease, P = 0.02) were significantly associated with grade ≥2 hypocalcemia. In 11 patients who developed hypocalcemia during the first treatment course, the mean calcium concentrations decreased from 9.8 mg/dL at baseline to 8.4 mg/dL during the first week and reached a nadir of 8.1 mg/dL during the second week. Conclusion: Our results support more frequent monitoring of serum calcium concentrations at baseline and during the first 2 weeks of treatment in patients receiving denosumab, especially those with an eGFR <30 mL/min.