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)Cl(2)). Although the chelating of Ca(2+) 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 (4mg/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 (1.3mg/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)Cl(2) (3.8mg/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 (0.5mmol/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.

Background: Oxaliplatin 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.Results: Repeated 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.Conclusion: These results indicated that spinal NR2B-containing NMDA receptors are involved in the oxaliplatin-induced mechanical allodynia.

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. 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. 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. 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.

Since December 2019, a novel coronavirus (severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2)) infection has been rapidly spreading worldwide and causing the respiratory illness, coronavirus disease 2019 (COVID‐19). The antiretroviral drug favipiravir (FPV) has been experimentally used for COVID‐19 treatment since March 2020 in Japan. However, the pharmacokinetics of FPV in critically ill patients is unknown. We measured the serum concentration of FPV using high‐performance liquid chromatography in patients with severe COVID‐19 who were admitted to the intensive care unit and placed on mechanical ventilation. The patients were administered 1,600 mg of FPV twice daily on day 1, followed by 600 mg twice daily from day 2 to day 5 (or more if needed). Suspensions of FPV tablets were administered through a nasogastric tube. Seven patients were enrolled in this study. Forty‐nine blood samples were obtained from the eligible patients to evaluate FPV concentration. The FPV trough (after 8–12 hours) concentrations of most samples were lower than the lower limit of quantification (1 µg/mL) and half‐maximal effective concentration (9.7 µg/mL) against SARS‐CoV‐2 previously tested in vitro. FPV trough concentration in critically ill patients was much lower than that of healthy subjects in a previous clinical trial, which is a cause for great concern. Further study is required to determine the optimal strategy for treatment of patients with severe COVID‐19.

Purpose: This study aimed to evaluate the association between clinical characteristics and development of medication-related osteonecrosis of the jaw (MRONJ) in patients who underwent dental examinations before the initiation of treatment with denosumab or zoledronic acid, which are bone-modifying agents (BMAs), for bone metastases. Additionally, the clinical outcomes of patients who developed MRONJ were evaluated along with the time to resolution of MRONJ. Methods: The medical charts of patients with cancer who received denosumab or zoledronic acid for bone metastases between January 2012 and September 2016 were retrospectively reviewed. Patients were excluded if they did not undergo a dental examination at baseline. Results: Among the 374 included patients, 34 (9.1%) developed MRONJ. The incidence of MRONJ was significantly higher in the denosumab group than in the zoledronic acid (27/215 [12.6%] vs 7/159 [4.4%], P = 0.006) group. Multivariate Cox proportional hazards regression analysis revealed that denosumab treatment, older age, and tooth extraction before and after starting BMA treatments were significantly associated with developing MRONJ. The time to resolution of MRONJ was significantly shorter for patients who received denosumab (median 26.8 months) than for those who received zoledronic acid (median not reached; P = 0.024). Conclusion: The results of this study suggest that treatment with denosumab, age > 65 years, and tooth extraction before and after starting BMA treatments are significantly associated with developing MRONJ in patients undergoing treatment for bone metastases. However, MRONJ caused by denosumab resolves faster than that caused by zoledronic acid.