Milnacipran inhibits itch-related responses in mice through the enhancement of noradrenergic transmission in the spinal cord.

We investigated whether milnacipran, a serotonin-noradrenaline reuptake inhibitor, exhibits an antipruritic effect through the spinal action in mice. Intrathecal injections of milnacipran (0.1 - 10 µg/site) significantly suppressed serotonin-induced biting, which is an itch-related response. However, such an effect was not observed with fluvoxamine (10 µg/site), which is a selective serotonin reuptake inhibitor. Furthermore, an intraperitoneal injection of milnacipran (10 mg/kg) inhibited serotonin-induced biting. When phentolamine (1.0 µg/site), a non-selective α-adrenoceptor antagonist, was intrathecally injected, it inhibited the above response of milnacipran. These results suggest that milnacipran suppresses itching through the inhibition of noradrenaline reuptake in the spinal cord.

The relationship between the plasma concentration of bepridil and its efficacy in the treatment of atrial fibrillation in Japanese patients.

Bepridil hydrochloride is used for treatment of atrial fibrillation (AF) in Japan. We investigated the relationship between plasma concentrations of bepridil just before dosing (Cbep) and its clinical efficacy in Japanese patients (n=36) with AF. Patients were treated orally with 100, 150 or 200 mg/d bepridil. Cbep were measured with UV-HPLC. In the first 14 d, when 150, 200, 250 or 300 ng/mL was set as a boundary value, the efficacy of bepridil was significantly higher in all patients with Cbep above than below the boundary value (p<0.05). In the maintenance stage (3 months longer after starting therapy), the efficacy of bepridil was significantly higher in patients with Cbep above than below 300 ng/mL (p=0.04). The clinical efficacy of bepridil was closely related to Cbep. The target value of Cbep to obtain a clinical benefit was approximately 300 ng/mL. Monitoring Cbep should be useful in the treatment of patients with AF.

Correlation between leukocyte membrane lipid peroxidation and expression of Cu/Zn-superoxide dismutase mRNA in hemodialysis patients.

BACKGROUND: Previously, we reported an increase in expressions of mRNA of Cu/Zn-superoxide dismutase (SOD) in leukocytes of hemodialysis (HD) patients, and speculated that the increase is associated with oxidative stress on the leukocyte membrane due to the HD process. METHODS: Expressions of Cu/Zn-SOD mRNA in leukocytes, contents of plasma SOD, and malondialdehyde (MDA) in leukocyte and erythrocyte membranes, respectively, were examined in 25 HD patients and 14 healthy volunteers. These were also determined after using a vitamin E-coated dialyzer (VE dialyzer) for 4 weeks. RESULTS: All values were significantly higher in HD patients. A significant correlation was found between leukocyte Cu/Zn-SOD mRNA expression and membrane MDA. After using the VE dialyzer, all values were significantly lowered, showing a significant correlation between changing rate of leukocyte Cu/Zn-SOD mRNA expression and membrane MDA. CONCLUSION: In HD patients, oxidative stress is generated on the leukocyte membrane, and the level of Cu/Zn-SOD mRNA in leukocytes can be a useful oxidative stress marker.

Tonic inhibition of allergic itch signaling by the descending noradrenergic system in mice.

We investigated whether the descending noradrenergic system regulates allergic itch. Mosquito allergy of the hind paw elicited biting, an itch-related response, in sensitized mice. The biting was inhibited by intrathecal clonidine and reversed by yohimbine, an α(2)-adrenoceptor antagonist. The biting was increased by intrathecal pretreatment with the catecholaminergic neurotoxin 6-hydroxydopamine and the α-adrenoceptor antagonist phentolamine but not the serotonergic neurotoxin 5,7-dihydroxytryptamine. We propose that α(2)-adrenoceptors are involved in the inhibition of allergic itch in the spinal cord and that the descending noradrenergic system exerts a tonic inhibition on the itch signaling. The serotonergic system may not be involved.

Contribution of subcutaneous fat accumulation to insulin resistance and atherosclerosis in haemodialysis patients.

BACKGROUND: Whereas visceral fat accumulation (VFA) is related to insulin resistance and atherosclerosis in both haemodialysis (HD) patients and the general population, little is known about the role of subcutaneous fat accumulation (SFA). The purpose of the present study was to examine and confirm the relationship between abdominal fat accumulation (AFA) and various clinical parameters in HD patients. METHODS: Two hundred and thirty-three HD patients were recruited, including 120 with type 2 diabetes. Abdominal fat distribution was evaluated by computed tomography (CT) scans. Systemic atherosclerosis was assessed by intima-media thickness (IMT) using high-resolution B-mode ultrasonography. The insulin resistance was estimated by the homeostasis model assessment-insulin resistance (HOMA-IR). RESULTS: Spearman's analysis revealed that both VFA and SFA showed a significant relationship with HOMA-IR and also that SFA was correlated significantly with IMT in all HD patients. SFA was an independent risk factor associated with HOMA-IR and IMT in multiple regression analysis. Neither body mass index (BMI) nor VFA was a predominant determinant of HOMA-IR and IMT. IMT in HD patients with high SFA/low BMI groups was significantly higher than in the low SFA/high BMI groups. CONCLUSION: It appears that there is a close relationship between SFA and insulin resistance or atherosclerosis in HD patients. It was suggested that SFA plays important roles related to carbohydrate or lipid metabolism in HD patients.

Oral vitamin C supplementation in hemodialysis patients and its effect on the plasma level of oxidized ascorbic acid and Cu/Zn superoxide dismutase, an oxidative stress marker.

BACKGROUND/AIM: Oxidative stress is known to be enhanced in hemodialysis patients, and one of its useful markers is plasma copper/zinc superoxide dismutase (Cu/Zn-SOD). The increase in plasma Cu/Zn-SOD can be inhibited by orally administered lipid-soluble vitamin E. We examined the antioxidative effects of water-soluble vitamin C administered orally on Cu/Zn-SOD levels in hemodialysis patients. METHODS: Vitamin C was orally administered to 16 maintenance hemodialysis patients before each dialysis session. Doses were increased from 200 to 1,000 mg over 3 months. The levels of plasma vitamin C and Cu/Zn-SOD and its mRNA expression in leukocytes were determined 1, 2, and 3 months after the start of vitamin C administration. Furthermore, the levels of oxidized and reduced forms of plasma vitamin C were determined before the start of vitamin C administration and before and after dialysis at 1,000-mg vitamin C doses. RESULTS: Following oral administration, the plasma levels of vitamin C and its oxidized form were increased. However, significant changes in plasma Cu/Zn-SOD or its mRNA expression in leukocytes were not observed. CONCLUSION: In maintenance hemodialysis patients, vitamin C administration resulted in a significant increase in the postdialysis level of the oxidized form of vitamin C, which suggested an increase in antioxidant effect. However, water-soluble vitamin C did not significantly suppress Cu/Zn-SOD expression enhancement.

Pharmacodynamic study of the Saltz regimen for metastatic colorectal cancer in a hemodialyzed patient.

OBJECTIVE: Combination therapy with irinotecan (CPT-11), 5-fluorouracil (5-FU) and leucovorin is widely used for the treatment of metastatic colorectal cancer. However, little is known about the safety of chemotherapy of malignancies in hemodialysis (HD) patients. We encountered a patient with colorectal carcinoma on HD. We decided to administer combination chemotherapy while monitoring the pharmacodynamics of the patient. CASE REPORT: A 74-year-old male received regular HD 3 times a week because of type 1 diabetes mellitus. He was diagnosed with stage IV colorectal cancer in November 2004. After sigmoidectomy, the patient received chemotherapy: a weekly schedule of CPT-11 (50 mg/m(2)) was administered followed by l-leucovorin (10 mg/m(2)) and 5-FU (400 mg/m(2)) just after HD. During the course, the plasma concentrations of both SN-38, an active metabolite of CPT-11, and 5-FU were not increased compared with those of patients with normal renal function. Our patient presented with grade III hematological toxicity that was easily recovered by granulocyte colony-stimulating factor. CONCLUSION: These data suggest that the dose-reduced Saltz regimen can be feasible for colorectal cancer patients receiving dialysis as postoperative adjuvant chemotherapy.

Relationship between PK/PD of Cefepime and Clinical Outcome in Febrile Neutropenic Patients with Normal Renal Function.

The efficacy of cefepime (CFPM) is known to depend on the ratio of the time that the serum levels exceed the minimum inhibitory concentration (MIC) to the dosing interval (%T>MIC). The objective of this study was to clarify the relation between %T>MIC and clinical outcome of CFPM, and to identify the optimal dosage regimen. We investigated the outcome of CFPM treatment for febrile neutropenia (FN) patients with normal renal function. Treatment success was defined as the completion of FN therapy with CFPM only. And we calculated %T>MIC for each case based on population pharmacokinetic parameters. The MIC value for simulation was set as 8 µg/mL. In logistic regression analysis, treatment success was significantly associated with the elevation of %T>MIC in the group with persistent neutropenia, yielding a receiver operating characteristic curve with an optimal cutoff value of 73.1%. Next, we simulated %T>MIC for each case under various dosing regimens. For patients whose creatinine clearance (CLcr) exceeded 100 mL/min, it was found to be difficult to attain the objective under the current regimen. In contrast, it was calculated that treatment with 2 g three times a day (t.i.d.) could attain the objective for most of the patients with 3 h of infusion. These results suggest that CFPM treatment under the current regimen is ineffective for FN patients with normal or augmented renal function, and that 2 g t.i.d. is necessary in quite a lot cases, although such use is off-label.

mRNA study on Cu/Zn superoxide dismutase induction by hemodialysis treatment.

BACKGROUND/AIMS: There is little or no controversy about the increased oxidative stress of hemodialysis (HD) patients. Several reports show that the activity of superoxide dismutase (SOD), one of the major endogenous antioxidant enzymes, in plasma is elevated among HD patients. It is still unclear, however, whether this elevation is due to the promotion of SOD production or a decrease in renal excretion of SOD. This study was designed to investigate the cause of the SOD activation in HD patients, and we examined the expression of SOD mRNA levels in leukocytes of patients with chronic renal failure. METHODS: The total plasma SOD activity was determined by the nitroblue tetrazolium method, plasma SOD contents by ELISA, and SOD mRNA levels in leukocytes by RT-PCR. RESULTS: Our results demonstrated that contents and mRNA levels of Cu/Zn SOD in HD patients are 4.4 times and 2.0 times, respectively, as large as those in healthy controls. Furthermore, in contrast to nondialyzed chronic renal failure patients, we observed higher concentrations of Cu/Zn SOD in plasma and a more enhanced mRNA expression of Cu/Zn SOD in leukocytes of HD patients. CONCLUSION: Increased Cu/Zn SOD mRNA reflects enhanced antioxidant capacity of leukocytes and can be a promising oxidative stress marker in HD patients.

Association of the cardioankle vascular index and ankle-brachial index with carotid artery intima media thickness in hemodialysis patients.

The objectives of the present study are (1) to compare the cardioankle vascular index (CAVI), ankle-brachial index (ABI), and carotid artery intima-media thickness (CA-IMT) between HD patients with and without type 2 diabetes (T2D) or prevalence of cardiovascular (CV) disease and (2) also to evaluate the relationship of these indices with CA-IMT in these patients according to ABI levels. This study consisted of 132 HD patients with T2D and the same number of patients without T2D. The patients with diabetes or prevalence of CV disease had significantly higher CA-IMT and lower ABI values than those without diabetes or prevalence of CV disease, respectively. Although diabetic patients had higher CAVI than those without diabetes, CAVI did not differ between patients with or without prevalence of CV disease. In univariate analysis, CA-IMT was more strongly correlated with ABI than CAVI. However, the opposite was true in patients with an ABI value of more than 0.95. Both indices were significantly correlated with CA-IMT although ABI was a powerful determinant than CAVI. It appears that both indices are associated with CA-IMT in HD patients, especially with an ABI value of more than 0.95.

Noradrenergic regulation of itch transmission in the spinal cord mediated by α-adrenoceptors.

It has recently been shown that clonidine suppresses itch-related responses via its action on α(2)-adrenoceptors in the spinal cord, raising the possibility that the descending noradrenergic system regulates itch signaling in the spinal cord. In this study, we investigated whether the transmission of itch signals in the spinal cord is under tonic inhibition by the descending noradrenergic system. An intraplantar injection of serotonin in mice induced biting of the treated paw (an itch-related response). An intrathecal injection of 6-hydroxydopamine (catecholaminergic neurotoxin) enhanced the itch-related response. There was a significant inverse correlation between the response and noradrenaline content. An intrathecal injection of phentolamine (α-adrenoceptor antagonist) enhanced serotonin-induced biting, although prazosin (α(1)-, α(2B)-, and α(2C)-adrenoceptor antagonist) and yohimbine (α(2)-adrenoceptor antagonist) had no effects. Intrathecal injections of phenylephrine (α(1)-adrenoceptor agonist) and clonidine (α(2)-adrenoceptor agonist) inhibited serotonin-induced biting. The action of phenylephrine was antagonized by intrathecal prazosin but not 5-methylurapidil (α(1A)-adrenoceptor antagonist), cyclazosin (α(1B)-adrenoceptor antagonist), and BMY 7378 (α(1D)-adrenoceptor antagonist). mRNAs encoding α(1A)-, α(1B)-, α(2A)-, α(2B)-, and α(2C)-adrenoceptor subtypes were expressed in the dorsal root ganglion and spinal dorsal horn. These results suggest that the descending noradrenergic system exerts tonic inhibition on itch signaling in the spinal cord. Both α(1)- and α(2)-adrenoceptors may be involved in the tonic inhibition of itch signaling and the stimulation of either α-adrenoceptor subtype may result in the inhibition of itch.

Clonidine inhibits itch-related response through stimulation of α(2)-adrenoceptors in the spinal cord in mice.

The present study investigated whether clonidine - an α(2)-adrenoceptor agonist known to relieve pain - is able to suppress itch-related behavior in mice. An intraplantar injection of serotonin induced biting (an itch-related response), which was inhibited by intraperitoneal and intrathecal, but not intraplantar or intracisternal, clonidine injections. The effect of intrathecal clonidine was inhibited by intrathecal injections of phentolamine (a non-selective α-adrenoceptor antagonist) and yohimbine (a selective α(2)-adrenoceptor antagonist), but not by prazosin (a selective α(1)-adrenoceptor antagonist). The effect of intraperitoneal clonidine was also inhibited by intrathecal yohimbine. These results suggest that clonidine is an effective antipruritic agent and that the effect is mainly mediated by the stimulation of α(2)-adrenoceptors in the dorsal horn.

Comparison of effect of vitamin E-coated dialyzer and oral vitamin E on hemodialysis-induced Cu/Zn-superoxide dismutase.

BACKGROUND: We reported earlier that production of Cu/Zn-superoxide dismutase (SOD) increases markedly in hemodialysis patients but not in non-dialyzed chronic renal failure (CRF) patients. In this study, we compared the antioxidant effects of oral vitamin E supplementation (VE-PO) and vitamin E coating of a dialyzer (VE-BMD) by measuring increased Cu/Zn-SOD in hemodialysis patients. METHODS: 31 hemodialysis patients were divided into two groups: 16 hemodialysis patients underwent usual dialysis with vitamin E supplementation 600 mg/day while 15 others were dialyzed using vitamin E-coated membrane for 6 months. Total plasma SOD activity was determined by NBT method, plasma Cu/Zn-SOD contents by ELISA and Cu/Zn-SOD mRNA in leukocytes by RT-PCR. RESULTS: VE-PO and VE-BMD showed almost comparable effects on Cu/Zn-SOD contents and its mRNA levels in hemodialysis patients. VE-PO resulted in a progressive decrease of Cu/Zn-SOD content (p < 0.001). A comparable progressive decrease was observed also in VE-BMD (p < 0.0001). Both VE-PO and VE-BMD resulted in a progressive decrease of Cu/Zn-SOD mRNA (p < 0.01), which reached the level of non-dialyzed CRF patients.