Behavioral and pharmacological characteristics of bortezomib-induced peripheral neuropathy in rats.

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.

Repeated administration of amitriptyline reduces oxaliplatin-induced mechanical allodynia in rats.

Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes acute and chronic neuropathies in patients. Amitriptyline has widely been used in patients with painful neuropathy. In this study, we investigated the effect of amitriptyline on the oxaliplatin-induced neuropathy in rats. Repeated administration of amitriptyline (5 and 10 mg/kg, p.o., once a day) reduced the oxaliplatin-induced mechanical allodynia but not cold hyperalgesia and reversed the oxaliplatin-induced increase in the expression of NR2B protein and mRNA in rat spinal cord. These results suggest that amitriptyline is useful for the treatment of oxaliplatin-induced neuropathy clinically.

Inhibition of Ca2+/calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in rats.

BACKGROUND: Oxaliplatin 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-containing N-methyl-D-aspartate (NMDA) receptors are involved in the oxaliplatin-induced mechanical allodynia. In the present study, we investigated the involvement of Ca(2+)/calmodulin dependent protein kinase II (CaMKII), which is a major intracellular protein kinase and is activated by NMDA receptor-mediated Ca(2+) influx, in the oxaliplatin-induced mechanical allodynia in rats. RESULTS: An increase of CaMKII phosphorylation was found in the spinal cord (L(4-6)) 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. CONCLUSIONS: These 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.

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. METHODS: Seven hundred and four patients with HCC, diagnosed during a 12-year period from January 1989 to December 2000, were categorized into two groups as follows: (i) 36 patients aged 80 years or older at the detection of HCC were defined as the elderly group and; (ii) 668 patients younger than 80 years of age were placed in the non-elderly group. Clinical variables were analyzed and compared between the two groups, and any significant variables in the prognosis were simultaneously determined. RESULTS: Regarding sex, viral markers, concentration of serum alpha-fetoprotein, diameter and number of tumors, Child's grade, presence of portal thrombosis, histology grade of HCC and any types of treatment, no significant difference was found between the two groups. The 1-year and 3-year survival rates in the elderly group (54.1 and 28.1%, respectively) were not significantly different from those in the non-elderly group (69.9 and 43.2%, respectively; P = 0.1053). The only significant factor in the prognosis in the elderly group was the presence of portal thrombosis, although a Child's grade of B or C was almost a significant factor with a P-value of 0.063. Tumor size measuring more than 3 cm in the greatest dimension, non-solitary tumor, Child's grade of B or C, and the presence of portal thrombosis were all found to be prognostic factors in the non-elderly group using a multivariate analysis. CONCLUSIONS: An advanced stage of HCC, not advanced age, influenced the survival rate in these elderly patients. Therefore, an optimal treatment strategy should be applied for elderly patients with HCC who demonstrate less prognostic factors in the same manner as that for non-elderly patients.

Impact of hepatologists to extend survival of hepatocellular carcinoma patients with cirrhosis: a comparison with non-hepatologists.

BACKGROUND/AIMS: Whether or not generalists and specialist physicians can make an appropriate adaptation of their practice patterns when caring for their patients currently remains a matter of debate. The present study was undertaken to explore whether the clinical characteristics of hepatocellular carcinoma at its time of detection, the initial treatment options and the survival vary between patients with hepatocellular carcinoma associated with cirrhosis who were treated by hepatologists and those who were treated by non-hepatologists. METHODOLOGY: A retrospective study with 626 patients with hepatocellular carcinoma associated with cirrhosis was performed. The patients were stratified into three groups as follows; 1) a hepatologist group: 280 patients followed up and treated consistently by hepatologists, 2) a non-hepatologist group: 126 patients followed up and treated consistently by non-hepatologists, and 3) the other group: 220 patients either followed up by hepatologists and treated by non-hepatologists, or vice versa, or those identified to have tumors incidentally without any follow-up. To confirm the clear difference between generalists and specialists, the gender ratio, age, hepatitis B and C virus markers, serum alpha-fetoprotein level, tumor size, the number of tumors, Child's grade, portal thrombosis at the initial detection, the types of follow-up until the initial detection of hepatocellular carcinoma, the initial treatments chosen, and survival were compared between the hepatologist group and the non-hepatologist group. RESULTS: There were no statistically significant differences between the two groups with respect to gender ratio, age, hepatitis virus markers and the alpha-fetoprotein level. However, the tumor size, the number of tumors, Child's grade and portal thrombosis at the initial detection were more advanced in the non-hepatologist group, which was most likely due to the poorer follow-up until the detection of hepatocellular carcinoma compared with that in the hepatologist group (p value: 0.0237). Regarding therapy for hepatocellular carcinoma, intensive therapies were more often performed in the hepatologist group and, in addition, non-treated cases were less frequently found in the hepatologist group. Consequently, the 1-, 3- and 5-year survivals of the patients in the hepatologist group were 84.7, 61.1 and 35.1%, respectively, which were significantly longer than those in the non-hepatologist group, which were 80.7, 45.8 and 31.8%, respectively (p value: 0.0434). CONCLUSIONS: Hepatocellular carcinoma patients with cirrhosis who were treated by hepatologists can expect to obtain a longer survival because hepatocellular carcinoma tends to be detected at a smaller size, while such patients also usually receive more appropriate treatment modalities.

Application of color Doppler ultrasonography to ulcerative colitis.

We used color Doppler ultrasonography (US) to evaluate bowel wall thickening in ulcerative colitis and to determine the value of this modality in this application. Twelve patients (6 men and 6 women) with ulcerative colitis underwent both gray-scale and color Doppler US. Bowel wall thickness and wall echotexture were recorded by gray-scale US, and the presence of intramural color Doppler flow and arterial signal were evaluated by color Doppler US. Color Doppler flow was graded as 'weak' or 'abundant', and resistive index was calculated; clinical severity of disease activity was also graded, and serum CRP level was measured. Variation in serum CRP levels and intramural color Doppler flow according to clinical severity, and the correlations between serum CRP levels and the number of blood flow signals were statistically significant. In 10 of the 12 patients, analysis of the Doppler waveform showed an arterial blood flow signal, and mean resistive index value was determined to be 0.550. We thus conclude that information provided by gray-scale and color Doppler US is useful in evaluating bowel wall thickening in ulcerative colitis.