Masafumi Shirahama

Goshajinkigan reduces oxaliplatin-induced peripheral neuropathy without affecting anti-tumour efficacy in rodents

Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes acute and chronic neuropathies in patients. Goshajinkigan (GJG) is a Kampo medicine that is used for the treatments of several neurological symptoms including pain and numbness. More recently, GJG has been reported to prevent the oxaliplatin-induced peripheral neuropathy in clinical studies. No experimental study, however, has been conducted to date to determine the effect of GJG on pain behaviour in a rat model of oxaliplatin-induced neuropathy. Moreover, the impact on the anti-tumour effect of oxaliplatin remains unknown. In the present study, we examined the effects of GJG on the peripheral neuropathy and anti-tumour activity of oxaliplatin in rodents. Repeated administration of oxaliplatin caused cold hyperalgesia from days 3 to 37 and mechanical allodynia from days 21 to 28. Repeated administration of GJG prevented the oxaliplatin-induced cold hyperalgesia but not mechanical allodynia and axonal degeneration in rat sciatic nerve. Single administration of GJG reduced both cold hyperalgesia and mechanical allodynia after the development of neuropathy. In addition, GJG did not affect the anti-tumour effect of oxaliplatin in the tumour cells or tumour cells-implanted mice. These results suggest that GJG relieves the oxaliplatin-induced cold hyperalgesia and mechanical allodynia without affecting anti-tumour activity of oxaliplatin, and, therefore, may be useful for the oxaliplatin-induced neuropathy in clinical practice.

Optimal treatment strategy for elderly patients with hepatocellular carcinoma

Background and Aims:  The age distribution of patients with hepatocellular carcinoma (HCC) now peaks at nearly 70 years in Japan and this is continually increasing. Whether such elderly patients with HCC aged 80 years or older should be treated, and if so, how they should be selected for treatment remains uncertain. The present study was undertaken to determine any differences in the clinical characteristics and prognostic features between patients with HCC aged 80 years or older and those younger than 80 years of age. We also aimed to identify any significant variables in the prognosis of elderly patients with HCC aged 80 years or older.

Kupffer Cells May Autoregulate Interleukin 1 Production by Producing Interleukin 1 Inhibitor and Prostaglandin E2

Rat Kupffer cells stimulated with bacterial lipopolysaccharide (LPS) produced high levels of interleukin 1 (IL‐1), as determined by thymocyte proliferation assay. Indomethacin revealed a dose‐dependent augmentation in IL‐l production, in parallel with a dose‐dependent reduction in prostaglandin E2 production by Kupffer cells. The addition of exogenous prostaglandin E2, dibutyryl cAMP, or isoproterenol led to a dose‐dependent suppression of IL‐I production. The supernatant from UPS‐stimulated Kupffer cells also contained factors that Inhibited IL‐1‐induced thymocyte proliferation. Upon gel filtration, two inhibitory peaks, at apparent MW of 27,000 and 6000, were obtained. The latter but not the former fraction also affected Interleukin 2 (IL‐2)‐induced thymocyte proliferation. Increasing amounts of IL‐1 overcame the inhibitory activity derived from the 27,000 MW fraction. These results suggest to us that prostaglandin E2 and IL‐1 inhibitor released by Kupffer cells may be involved in negative self‐control in regulating IL‐1 production and its action.

Selective partial IgM deficiency:functional assessment of T and B lymphocytes in vitro

Seven patients with selective IgM deficiency (SIgMD) were studied for cell surface immunoglobulin (SmIg), T-cell subpopulations, and immunoglobulin (Ig) synthesisin vitro by peripheral blood lymphocytes (PBL). Serum IgM levels were less than 25 mg/dl, while IgA, IgG, and IgD were within normal levels. The patients had respiratory or urinary tract infections and two were diagnosed as having systemic lupus erythematosus (SLE). T/B-cell ratios in PBL were within normal ranges. Percentage ratios of B cells bearing SmIg were normal in five patients and decreased in two; however, normal values were seen after 7 days of culture in the presence of PWM. OKT4/OKT8 ratios decreased in five of seven patients, in whom two were due to a decrease in OKT4 and two to an increase in OKT8 cells. One showed a decrease in OKT4 and an increase in OKT8. Analysis of lymphocyte function for Ig synthesisin vitro, using a coculture of counterpart T and B cells from healthy individuals and patients with SIgMD, revealed that the increased function of IgM isospecific suppressor T cells (Ts) was responsible for the IgM deficiency in all seven patients.

Inhibition of Ca2+/Calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in Rats

BackgroundOxaliplatin is a key drug in the treatment of colorectal cancer, but it causes severe peripheral neuropathy. We previously reported that oxaliplatin (4 mg/kg, i.p., twice a week) induces mechanical allodynia in the late phase in rats, and that spinal NR2B-containig N-methyl-D-aspartate (NMDA) receptors are involved in the oxaliplatin-induced mechanical allodynia. In the present study, we investigated the involvement of Ca2+/calmodulin dependent protein kinase II (CaMKII), which is a major intracellular protein kinase and is activated by NMDA receptor-mediated Ca2+ influx, in the oxaliplatin-induced mechanical allodynia in rats.ResultsAn increase of CaMKII phosphorylation was found in the spinal cord (L4-6) of oxaliplatin-treated rats. This increased CaMKII phosphorylation was reversed by intrathecal injection of a selective CaMKII inhibitor KN-93 (50 nmol, i.t.) and a selective NR2B antagonist Ro 25-6981 (300 nmol, i.t.). Moreover, acute administration of KN-93 (50 nmol, i.t.) strongly reversed the oxaliplatin-induced mechanical allodynia in von Frey test, while it did not affect the oxaliplatin-induced cold hyperalgesia in acetone test. Similarly, oral administration of trifluoperazine (0.1 and 0.3 mg/kg, p.o.), which is an antipsychotic drug and inhibits calmodulin, reduced both mechanical allodynia and increased CaMKII phosphorylation. On the other hand, trifluoperazine at the effective dose (0.3 mg/kg) had no effect on the paw withdrawal threshold in intact rats. In addition, trifluoperazine at the same dose did not affect the motor coordination in rota-rod test in intact and oxaliplatin-treated rats.ConclusionsThese results suggest that CaMKII is involved in the oxaliplatin-induced mechanical allodynia, and trifluoperazine may be useful for the treatment of oxaliplatin-induced peripheral neuropathy in clinical setting.

Fulminant hepatic failure during perinatal period in a pregnant woman with Wilson's disease.

SummaryWilson’s disease associated with hepatic failure is not common and the underlying mechanism triggering the event is not known at present. We treated a 28-year-old Japanese woman with Wilson’s disease who developed hepatic failure associated with hemolytic crisis just after delivery. She was diagnosed as having Wilson’s disease at 12 years of age, at which time she started taking D-penicillamine. She had previously delivered two children without difficulty. When she found out she was pregnant this time, she stopped taking D-penicillamine in contrast to taking it faithfully during her first two pregnancies. On the day of delivery of her full-term baby, jaundice developed accompanied with severe hemolytic crisis. Plasma exchanges and blood transfusion were performed and D-penicillamine administration was started again. She gradually recovered and apparently was following a good clinical course. However, on day 30 the second hemolytic crisis occurred and subsequent liver failure led her to death on day 50. At autopsy her liver was cirrhotic and showed massive necrosis. Prophylactic oral administration of D-penicillamine and careful observation are therefore recommended to prevent hemolytic crisis during the perinatal period.

Kupffer cells modulate natural killer cell activity in vitro by producing prostaglandins

The effect of Kupffer cells on natural killer (NK) cell-mediated cytotoxicity was examined. Kupffer cells prepared from rat liver suppressed NK activity against K562 cells and other tumor cell lines through a soluble factor secreted into the culture supernatant. When human peripheral blood mononuclear cells were incubated with the Kupffer cell-culture supernatant, a significant reduction of the cytotoxic activity was observed in the 6-hr chromium-release assay. This activity was dose dependent and was evident at various effector/target cell ratios. Lipopolysaccharide stimulated generation of the suppressive factor released from Kupffer cells in a dose-dependent manner. Suppression of the NK activity was observed when the Kupffer cell-culture supernatant was present in the assay system, whereas pretreatment of effector/target cells with the supernatant had minimal inhibitory effects. Autologous monocytes in human peripheral mononuclear cells were not related to this suppression. The suppressive factor in the fraction had a molecular weight below 10,000. Indomethacin, an inhibitor of prostaglandin synthesis, ameliorated the suppressive effects. These results suggest that Kupffer cells may modulate NK activity by producing PGs (E1, E2, and F2 alpha).