Multi‐walled carbon nanotube‐7 (MWCNT‐7) fibers are biopersistent and have a structure similar to asbestos. MWCNT‐7 has been shown to induce malignant mesothelioma when administered by intrascrotal or intraperitoneal injection in rats and mice, and an inhalation study demonstrated that rats exposed to respirable MWCNT‐7 developed lung tumors. MWCNT‐N, which is similar to MWCNT‐7, was shown to induce both lung tumors and malignant mesothelioma in rats when administered by trans‐tracheal intrapulmonary spraying (TIPS). The present study was performed to investigate the carcinogenicity of MWCNT‐7 when administered by the TIPS method. Ten‐week‐old male F344/Crj rats were divided into 3 groups and administered 0.5 mL vehicle, 0.250 μg/mL MWCNT‐7 or 0.250 μg/mL crocidolite once a week for 12 weeks (total doses of 1.5 mg/rat) and then observed for up to 104 weeks. Rats in the MWCNT‐7 group began to die from pathologies associated with the development of malignant mesothelioma 35 weeks after the final TIPS administration. Overall, the incidence of malignant mesothelioma in the MWCNT‐7 group was significantly higher than in the vehicle or crocidolite groups.

Bortezomib, an effective anticancer drug for multiple myeloma, often causes peripheral neuropathy which is mainly characterized by numbness and painful paresthesia. Nevertheless, there is no effective strategy to escape or treat bortezomib-induced peripheral neuropathy (BIPN), because we have understood few mechanism of this side effect. In this study, we evaluated behavioral and pathological characteristics of BIPN, and investigated pharmacological efficacy of various analgesic drugs and adjuvants on mechanical allodynia induced by bortezomib treatment in rats. The repeated administration of bortezomib induced mechanical and cold allodynia. There was axonal degeneration of sciatic nerve behind these neuropathic symptoms. Furthermore, the exposure to bortezomib shortened neurite length in PC12 cells. Finally, the result of evaluation of anti-allodynic potency, oral administration of tramadol (10 mg/kg), pregabalin (3 mg/kg), duloxetine (30 mg/kg) or mexiletine (100 mg/kg), but not amitriptyline or diclofenac, transiently relieved the mechanical allodynia induced by bortezomib. These results suggest that axonal degeneration of the sciatic nerve is involved in BIPN and that some analgesic drugs and adjuvants are effective in the relief of painful neuropathy.

Oxaliplatin, a chemotherapy medication, causes severe peripheral neuropathy. Although oxaliplatin-induced peripheral neuropathy is a dose-limiting toxicity, a therapeutic strategy against its effects has not been established. We previously reported the involvement of N-methyl-D-aspartate receptors and their intracellular signalling pathway in oxaliplatin-induced mechanical allodynia in rats. The aim of this study was to clarify the involvement of spinal glutamate transmission in oxaliplatin-induced mechanical allodynia. In vivo spinal microdialysis revealed that the baseline glutamate concentration was elevated in oxaliplatin-treated rats, and that mechanical stimulation of the hind paw markedly increased extracellular glutamate concentration in the same rats. In these rats, the expression of glutamate transporter 1 (GLT-1), which plays a major role in glutamate uptake, was decreased in the spinal cord. Moreover, we explored the potential of pharmacological therapy targeting maintenance of extracellular glutamate homeostasis. The administration of riluzole, an approved drug for amyotrophic lateral sclerosis, suppressed the increase of glutamate concentration, the decrease of GLT-1 expression and the development of mechanical allodynia. These results suggest that oxaliplatin disrupts the extracellular glutamate homeostasis in the spinal cord, which may result in neuropathic symptoms, and support the use of riluzole for prophylaxis of oxaliplatin-induced mechanical allodynia.

This study showed that the PCCT performed comprehensive assessments on referred patients and provided extra support. No patient's QOL 1 week after referral was improved with the exception of insomnia. Referring staff highly evaluated the activities of the PCCT. In the evaluation of PCCTs, further research about the variation of clinical activities of PCCTs, their applicability, and benefit is needed.

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More than 85% of cancer-related pain is pharmacologically controllable, but some patients require interventional treatments. Although audit assessment of these interventions is of importance to clarify the types of patients likely to receive benefits, there have been no multicenter studies in Japan. The primary aims of this study were (1) to clarify the frequency of neural blockade in certified palliative care units and palliative care teams, (2) determine the efficacy of interventions, and (3) explore the predictors of successful or unsuccessful intervention. All patients who received neural blockade were consecutively recruited from seven certified palliative care units and five hospital palliative care teams in Japan. Primary responsible physicians reported pain intensity on the Support Team Assessment Schedule, performance status, communication levels on the Communication Capacity Scale, presence or absence of delirium, opioid consumption, and adverse effects before and one week after the procedure on the basis of retrospective chart review. A total of 162 interventions in 136 patients were obtained, comprising 3.8% of all patients receiving specialized palliative care services during the study period. Common procedures were epidural nerve block with local anesthetic and/or opioids (n = 84), neurolytic sympathetic plexus block (n = 24), and intrathecal nerve block with phenol (n = 21). There were significant differences in the frequency of neural blockade between palliative care units and palliative care teams (3.1% vs. 4.6%, respectively, P = 0.018), and between institutions whose leading physicians are anesthesiologists or have other specialties (4.8% vs. 1.5%, respectively, P < 0.001). Pain intensity measured on the Support Team Assessment Schedule (2.9 +/- 0.8 to 1.7 +/- 0.9, P < 0.001), performance status (2.7 +/- 1.0 to 2.4 +/- 1.0, P < 0.001), and opioid consumption (248 +/- 348 to 186 +/- 288 mg morphine equivalent/day, P < 0.001) were significantly improved after interventions. There was a tendency toward improvement in the communication level measured on the Communication Capacity Scale. There was no significant improvement in the prevalence of delirium, but six patients (32%) recovered from delirium after interventions. Adverse effects occurred in 9.2%, but all were predictable or transient. No fatal complications were reported. Pain intensity was significantly more improved in patients who survived 28 days or longer than others (P = 0.002). There were no significant correlations of changes in pain intensity with the performance status or previous opioid consumption. In conclusion, neural blockade was performed in 3.8% of cancer patients who received specialized palliative care services in Japan. Neural blockade could contribute to the improvement of pain intensity, performance service status, and opioid consumption without unpredictable serious side effects.

Intratracheal instillation is the introduction of a substance directly into the trachea. Intratracheal instillation has been used to investigate the lung toxicity of several chemicals and requires the suspension or dissolution of test material in a vehicle for even dispersal throughout the lung. Importantly, the toxicities of vehicles used in intratracheal instillation studies are generally considered to be insignificant. Hence, evaluating the influence of different vehicles on the lung due to intratracheal instillation is crucial. We examined the toxic effects of pure water, saline, phosphate buffered saline (PBS), 0.5% Kolliphor ® P188 (KP188), 0.1% Tween 20 in saline, and 1.0% BSA in PBS. These vehicles were administered to male Crl:CD(SD) rats by a single intratracheal instillation. On day 3, broncho-alveolar lavage fluid (BALF) from the right lung was collected and processed for cell counting and biochemical analysis, while the left lung was used for histopathological examination. Accumulation of alveolar macrophages was observed in all vehicletreated groups but was minimal in the group administered saline, somewhat higher in the groups administered pure water, PBS, 0.1% Tween 20, and 1% BSA, and notably higher in the group administered 0.5% KP188. The results from BALF analysis indicated that intratracheal instillation of 0.5% KP188 also induced alveolar damage. Additionally, administering pure water did not appear to cause tissue damage. Eosinophil infiltration in the interstitial regions was histopathologically observed. Altogether, the results of this study are helpful for the selection of appropriate vehicles for use in intratracheal instillation studies.

The comparative dose-response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study. Anesth Analg 2000; 91: 473±9 3 Molina-Carballo A, Munoz-Hoyos A, Reiter RJ, et al. Utility of high doses of melatonin as adjunctive anticonvulsant therapy in a child with severe myoclonic epilepsy: two years' experience.