[Three Cases of Febrile Reactions after Using Oxaliplatin].

We report 3 cases of patients with gastrointestinal cancer who were treated with a regimen including oxaliplatin(OX). The patients were presented with fever over 38.0℃, probably due to OX. Case 1: A 73-year-old male. In the second course of bevacizumab(BEV)plus mFOLFOX6 therapy for rectal cancer and liver metastases, chills appeared 1 h and 45 min after the start of OX, and a fever of 38.0℃ appeared 2 h and 35 min after the end of OX. The body temperature dropped to 37.2℃ with a single cylinder of flurbiprofen infusion. Case 2: A 64-year-old male with sigmoid colon cancer and liver metastases treated with BEV plus mFOLFOX6. After 3 h and 10 min since completion of OX, chills and a fever of 38.5℃ appeared. The body temperature was 38.3℃ 1 h after insertion of a 25-mg diclofenac suppository but dropped to 35.4℃ 10 h later. Case 3: A 76-year-old male. In the 8th course of mFOLFOX6 therapy for gastric cancer and peritoneal dissemination, 4 h and 45 min after completion of OX, the patient developed a fever of 38.3℃ with chills. Antipyretics were not used because of the patient's refusal, but the body temperature spontaneously decreased to 35.7℃ after 15 h. Although no DLST test was performed in any of the patients, we considered this to be an adverse reaction to OX, owing to lack of symptoms of chills or fever with 5-FU plus l-LV therapy except for OX. The patient should be treated with the knowledge that hypersensitivity reactions to OX do not occur only during the course of administration of OX.

[A Case Report of Impaired Consciousness in a Patient after Receiving the Fourth Dose of Fentanyl Sublingual Tablet].

Oral transmucosal fentanyl has been indicated for the management of breakthrough pain in patients with cancer. Fentanyl sublingual tablets(FST)have been approved for use in Japan since 2013. However, the optimal use of FSTs has not been well-elucidated. In this case, a 73-year-old man with rectal cancer and third lumbar vertebral metastasis was treated with 100 µg FST and 12.5 µg/h fentanyl patch every day for the management of cancer-related breakthrough pain. After receiving the fourth dose of FST, the patient was unconscious for 2 days. However, his respiration was stable. This case shows that due care should be taken while administering FSTs to patients, specifically geriatric patients with bone metastasis and hypoalbuminemia.

Oxaliplatin-induced neurotoxicity involves TRPM8 in the mechanism of acute hypersensitivity to cold sensation.

Oxaliplatin-induced peripheral neurotoxicity (OPN) is commonly associated with peripheral hypersensitivity to cold sensations (CS) but the mechanism is unknown. We hypothesized that the transient receptor potential melastatin 8 (TRPM8), a putative cold and menthol receptor, contributes to oxaliplatin cold hypersensitivity. To determine whether the TRPM8 is involved in acute OPN, varying concentrations of menthol were topically applied to the tongues of healthy subjects (n = 40) and colorectal cancer patients (n = 36) before and after oxaliplatin administration. The minimum concentration of menthol to evoke CS at the menthol application site was determined as the CS detection threshold (CDT). In healthy subjects, the mean CDT was 0.068. Sex and age differences were not found in the CDT. In advanced colorectal cancer patients, the mean CDT significantly decreased from 0.067% to 0.028% (P = 0.0039) after the first course of oxaliplatin infusions, and this marked CS occurred in patients who had grade 1 or less neurotoxicity, and grade 2 neurotoxicity, but not in those with grade 3 neurotoxicity. Further, the mean baseline CDT in oxaliplatin-treated patients was significantly higher than that of chemotherapy-naïve patients and healthy subjects (0.151% vs. 0.066%, P = 0.0225), suggesting that acute sensory changes may be concealed by progressive abnormalities in sensory axons in severe neurotoxicity, and that TRPM8 is subject to desensitization on repeat stimulation. Our study demonstrates the feasibility of undertaking CDT test in a clinical setting to facilitate the identification of early neurotoxicity. Moreover, our results indicate potential TRPM8 involvement in acute OPN.

Oxicam structure in non-steroidal anti-inflammatory drugs is essential to exhibit Akt-mediated neuroprotection against 1-methyl-4-phenyl pyridinium-induced cytotoxicity.

In the treatment of Parkinson's disease, potent disease-modifying drugs are still needed to halt progressive dopaminergic neurodegeneration. We have previously shown that meloxicam, an oxicam non-steroidal anti-inflammatory drug (NSAID), elicits a potent neuroprotective effect against 1-methyl-4-phenyl pyridinium (MPP(+))-induced toxicity in human dopaminergic SH-SY5Y neuroblastoma cells. This cyclooxygenase-independent neuroprotection of meloxicam is mediated via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway; however, the specific chemical structure involved in inducing neuroprotection remains unresolved. In this study, we therefore investigated the structure-specific for eliciting the neuroprotective effect by examining a series of NSAIDs against MPP(+) toxicity in SH-SY5Y cells. Three oxicam-bearing NSAIDs showed potent neuroprotective effects, although none of the other 10 oxicam-nonbearing NSAIDs (3 salicylates, 6 coxibs and 1 polyphenol) or 3 piroxicam analogs (including ampiroxicam, a precursor of piroxicam) exerted any neuroprotection. Tenoxicam and piroxicam prevented MPP(+)-induced reduction of phosphorylated Akt levels in cells: a protective mechanism similar to that of meloxicam. Therefore, the oxicam structure was likely to be responsible for exhibiting the neuroprotection by sustaining survival-signaling in dopaminergic cells. The present results raise the possibility that the oxicam-bearing NSAIDs may serve as potential therapeutic drugs to retard or terminate progression of Parkinson's disease via a novel mechanism.

Topical Application of Hangeshashinto (TJ-14) in the Treatment of Chemotherapy-Induced Oral Mucositis.

BACKGROUND: The optimal treatment of chemotherapy-induced oral mucositis is not well established. A recent study showed that hangeshashinto (TJ-14) might be useful for periodontal disease via downregulating pro-inflammatory prostaglandins in the cyclooxygenase pathway in human. Our study aimed to determine whether TJ-14 is effective in the management of chemotherapy-induced oral mucositis. METHODS: Fourteen patients afflicted with chemotherapy-induced oral mucositis during mFOLFOX6 or FOLFIRI treatment for metastasis of advanced colorectal cancer were randomly assigned to topical TJ-14 treatment thrice daily for 7 days. Patients prepared a 50 ml solution with 2.5 g of TJ-14 dissolved in tap water and rinsed their oral mucosa for more than 5 seconds and then expectorated it. TJ-14 was also topically applied with a cotton pellet on the mucosal lesions. The severity of oral mucositis was evaluated using the Common Terminology Criteria for Adverse Events version 4 before and after one-week TJ-14 treatment. RESULTS: After the one-week topical treatment with TJ-14, thirteen of the fourteen patients (92.8 %) showed improvements in oral mucositis, with significantly decreased mean CTCAE grades (P = 0.0012). Compared to baseline, none of the patients' CTCAE grades worsened. The compliance of TJ-14-treatment was good and side effects from TJ-14 were not observed. CONCLUSIONS: Topical application of TJ-14 may have therapeutic effects in patients with chemotherapy-induced oral mucositis via downregulation of pro-inflammatory prostaglandins. A prospective, randomized, controlled, double-blind studies are necessary to confirm the findings of this open-label, pilot study.

Cetuximab-induced hypomagnesaemia aggravates peripheral sensory neurotoxicity caused by oxaliplatin.

Calcium and magnesium replacement is effective in reducing oxaliplatin-induced neurotoxicity. However, cetuximab treatment has been associated with severe hypomagnesaemia. Therefore, we retrospectively investigated whether cetuximab-induced hypomagnesaemia exacerbated oxaliplatin-induced neurotoxicity. Six patients with metastatic colorectal cancer who were previously treated with oxaliplatin-fluorouracil combination therapy were administered cetuximab in combination with irinotecan alone or irinotecan and fluorouracil as a second-line treatment. All patients had normal magnesium levels before receiving cetuximab. The Common Terminology Criteria for Adverse Events version 3.0 was used to evaluate the grade of neurotoxicity, hypomagnesaemia, hypocalcaemia, and hypokalemia every week. All six patients had grade 1 or higher hypomagnesaemia after starting cetuximab therapy. The serum calcium and potassium levels were within the normal range at the onset of hypomagnesaemia. Oxaliplatin-induced neurotoxicity occurred in all patients at the beginning of cetuximab therapy, with grade 1 neurotoxicity in five patients and grade 2 in one patient. After cetuximab administration, the neurotoxicity worsened in all six patients, and three progressed to grade 3. Among the three patients with grade 3 neurotoxicity, two required a dose reduction and one had to discontinue cetuximab therapy. A discontinuation or dose reduction in cetuximab therapy was associated with exacerbated oxaliplatin-induced neurotoxicity due to cetuximab-induced hypomagnesaemia in half of patients who had previously received oxaliplatin. Therefore, when administering cetuximab after oxaliplatin therapy, we suggest serially evaluating serum magnesium levels and neurotoxicity.

[Survey of oxaliplatin-associated peripheral sensory neuropathy using an interview-based questionnaire in patients with advanced colorectal cancer].

In performing FOLFOX chemotherapy (infusional 5-FU/LV with oxaliplatin) for advanced colorectal cancer, the neurotoxicity of oxaliplatin (L-OHP) is the dose-limiting factor. A retrospective study of 25 consecutive patients, receiving modified FOLFOX6 (mFOLFOX6) for advanced colorectal cancer, was conducted. From March 2006 to February 2008, we investigated the process of development of sensory neuropathy by adverse effect grading and our original interview-based intake about the afflicted regions. Neurotoxicity developed in 21 cases (84%) after 6 courses and the cumulative L-OHP dose was 410 mg/m(2) in median. In 11 cases (52%), it developed from the fingers, while in 8 cases (38%), it occurred from the fingers and toes simultaneously. It developed from the toes or tongue only in one case each. In 6 cases (55%), in which it occurred from the fingers, the symptom aggravated to grade 2 (G2) according to the Neurotoxicity Criteria of DEBIOPHARM (DEBNTC). On the other hand, in cases of coexpression of the fingers and toes, 7 cases (88%) developed G2 neuropathy, among one of whom suffered from grade 3 (G3). The coexistence of diabetes mellitus without neuropathy had no influence on the development of the neurotoxicity in the grading of DEB-NTC. One month after the last mFOLFOX6 therapy, neurotoxicity newly developed in one case, and was aggravated in two cases two months after cessation of the chemotherapy. Therefore, careful observation of the course should be continued even after the end of mFOLFOX6 therapy. Our results suggest that L-OHP neurotoxicity develops on fingers or fingers and toes simultaneously in most cases. And when it occurred on fingers and toes simultaneously, it would aggravate to G2 or G3 during the chemotherapy. The interviewed-based intake about the afflicted region, such as ours, can be used to predict the deterioration of the neurotoxicity.

[A case of neurotoxicity reduced with goshajinkigan in modified FOLFOX6 chemotherapy for advanced colon cancer].

In performing FOLFOX (infusional 5-FU/LV with oxaliplatin) for advanced colorectal cancer, neurotoxicity of oxaliplatin (L-OHP) is the serious dose limiting factor. On the other hand, goshajinkigan is recently considered as an effective agent for the neurotoxicity of taxanes in Japan. We have applied goshajinkigan (TJ 107) for a case of advanced colon cancer with mFOLFOX 6, and experienced a reduction in numbness, the adverse effect of LOHP. A 57-year-old woman with descending colon cancer (H 1, P 3, Stage IV) underwent hemicolectomy D 2, rt.colectomy, bilateral oophorectomy, cholecystectomy and transverse colonostomy. After operation, mFOLFOX 6 was applied. In order to reduce the neurotoxicity of L-OHP, TJ 107 was used together from the third course. The severities of neurotoxicity before and after administration of TJ 107 were grade 2 and 1,respectively. TJ 107 could reduce or prevent the neurotoxicity of L-OHP.

Improved high-performance liquid chromatographic detection of paclitaxel in patient's plasma using solid-phase extraction, and semi-micro-bore C18 separation and UV detection.

Although a number of analytical methods for taxanes have been published, none of them are sufficiently suitable for use in a medical setting. In this study, we established an improved analytical HPLC/UV detection method using a Sep-Pak C18 cartridge for extraction and a semi-micro-borecolumn for separation. This method employed here reduced chromatographic background signals, and allowed a more sensitive analysis of taxanes in human blood sample. The recovery of taxanes after the solid-phase extraction procedure was over 90%. Chromatographic separation of paclitaxel and docetaxel was achieved within 30 min with no interference peak by a semi-micro-bore column, packed either with C18 (Wakosil 5C18 RS) or pentafluorophenyl (Curosil/Taxol) materials. The method was reproducible with coefficients of variation less than 6%. This analytical procedure was simple and sensitive with lower quantification limit of 3 ng/ml. The improved sensitivity achieved by the popular HPLC/UV apparatus, which is available in hospitals, would vouch safer and more efficient therapy with taxane.

Tandospirone, a 5-HT1A agonist, ameliorates movement disorder via non-dopaminergic systems in rats with unilateral 6-hydroxydopamine-generated lesions.

Serotonin 1A (5-HT1A) receptors are distributed throughout the brain with their highest concentrations in the frontal cortex, subthalamic nucleus and entopeduncular nucleus as well as the dorsal and median raphe nucleus. There is growing evidence that 5-HT1A receptor agonists have an antidepressant effect in individuals with major depressive disorders. Recent clinical studies suggest that tandospirone, a highly potent and selective 5-HT1A receptor agonist used clinically as an antidepressant in Japan and China, may act as an antiparkinsonian drug. In the present study, we investigated the effect of tandospirone on contralateral rotational behavior in a unilateral hemiparkinsonian rat model produced with 6-hydroxydopamine (6-OHDA). Tandospirone, as well as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), significantly increased contralateral turnings in a dose-dependent manner (0.5-10 mg/kg). Tandospirone also remarkably potentiated the contralateral turning induced by 0.025 mg/kg of apomorphine. Pretreatment with WAY-100635, a 5-HT1A receptor antagonist, almost completely blocked the contralateral turning behavior evoked by tandospirone and 8-OHDPAT, but not that by apomorphine. SCH-23390, a selective dopamine D1 receptor antagonist, did not affect on the tandospirone-induced rotational behavior. These results suggested that tandospirone could act on postsynaptic 5-HT1A receptors and modulate excitatory amino acid pathways in the basal ganglia. Thus, tandospirone could have therapeutic potential for the treatment of Parkinson's disease by modulating neuronal activities of non-dopaminergic pathways.

Protective effects of quinaprilat and trandolaprilat, active metabolites of quinapril and trandolapril, on hemolysis induced by lysophosphatidylcholine in human erythrocytes.

We examined the effects of the angiotensin converting enzyme (ACE) inhibitors captopril, enalaprilat, quinapril, and trandolapril, and their active metabolites quinaprilat and trandolaprilat, on hemolysis induced by lysophosphatidylcholine (LPC) in human erythrocytes. LPC induced hemolysis at the concentrations above the critical micelle concentration (4 microM). Propranolol, used as a reference drug, attenuated the 50% hemolysis induced by 6 microM LPC at concentrations ranging from 100 nM to 100 microM. Similarly, quinaprilat (10 microM) and trandolaprilat (10, 100 microM) significantly attenuated the LPC-induced hemolysis, but other ACE inhibitors did not. Since propranolol possesses a membrane stabilizing action correlated with high lipophilicity, it appears that the high lipophilicity of quinaprilat or trandolaprilat is responsible for the protection from the damage induced by LPC. However, quinapril and trandolapril were not effective, although both drugs have higher lipophilicity than quinaprilat and trandolaprilat. Hence, it is suggested that the high lipophilicity alone may not contribute to the protective effects of ACE inhibitors against LPC-induced hemolysis. None of ACE inhibitors attenuated the hypotonic hemolysis (60 mM NaCl), although propranolol did. Furthermore, neither propranolol (100 microM) nor quinaprilat (50 microM) and trandolaprilat (50 microM) affected LPC micelle formation, suggesting that these drugs do not directly bind to LPC. We therefore believe that the protective effects of quinaprilat and trandolaprilat on the LPC-induced hemolysis may be related physicochemically to their highly lipophilic and ACE inhibitory structures, which probably maintain erythrocyte membrane integrity by a mechanism other than ACE inhibition, prevention of LPC micelle formation or protection against osmotic imbalance.