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Oxaliplatin causes severe peripheral neuropathy. In this study, we examined hypomyelination in the peripheral nerve in oxaliplatin-induced neuropathy rat model. Gene expression of neuregulin 1 (NRG1), a myelination regulatory factor, is reduced in the dorsal root ganglion (DRG) in DNA microarray analysis. Oxaliplatin increased the g-ratio and reduced levels of myelin protein zero in sciatic nerve, suggesting the hypomyelination. Moreover, oxaliplatin reduced NRG1 mRNA levels in the DRG and decreased levels of cleaved NRG1 type III protein in the sciatic nerve. Our results indicate that oxaliplatin induces hypomyelination and reduced NRG1 expression.

Aims Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes acute and chronic peripheral neuropathies. We previously reported that repeated administration of neurotropin prevents oxaliplatin-induced mechanical allodynia by inhibiting axonal degeneration in rats. In the present study, we investigated the analgesic effect of a single administration of neurotropin on oxaliplatin-induced neuropathy in rats. Main methods Oxaliplatin (4 mg/kg) was administered intraperitoneally twice a week for 4 weeks. Cold hyperalgesia was assessed using the acetone test and mechanical allodynia was evaluated using the von Frey test. Key findings Repeated injection of oxaliplatin induced cold hyperalgesia on day 5 and mechanical allodynia on day 28. A single administration of neurotropin transiently relieved both pain behaviors. The analgesic effect of neurotropin was inhibited by pretreatment with 5-HT 1A , 5-HT 2 , 5-HT 3 , and α2 receptor antagonists and by monoamine depletion. Moreover, the analgesic effect of neurotropin was abolished by intrathecal injection of pertussis toxin, a G i protein inhibitor. Significance These results suggest that neurotropin is effective in relieving oxaliplatin-induced neuropathy, and that G i protein-coupled receptors in the monoaminergic descending pain inhibitory system may be involved in the analgesic effect of neurotropin. Neurotropin may have clinical potential for the treatment of oxaliplatin-induced neuropathies.

Chemotherapy-induced nausea and vomiting (CINV) is one of the most challenging symptoms associated with cancer treatment. To maintain quality of life and enable patients to complete therapy, it is very important to control CINV with the appropriate use of antiemetics.1 Dexamethasone in combination with a 5-hydroxytryptamine 3 (5-HT3) receptor antagonist represents the standard of care in CINV associated with high-dose conditioning regimens for hematopoietic stem cell transplantation (HSCT).2–4 Although the combination of dexamethasone plus a 5-HT3 receptor antagonist is often used prior to HSCT, vomiting is not controlled in as many as 80–93% of patients.5–13 Since the neurokinin-1 receptor antagonist aprepitant was approved, the use of triple combination antiemetic therapy (i.e., dexamethasone, 5-HT3 receptor antagonist, and aprepitant) has resulted in further improvements in the control of CINV in non-HSCT patients with solid tumors who are treated with moderate to highly emetogenic chemotherapy.14–16 In addition, aprepitant has been recently reported to prevent CINV associated with high-dose preparative regimens followed by HSCT.17–21 However, there is still limited information on the safety and efficacy of aprepitant in the setting of allogeneic HSCT (allo-HSCT). Confounding factors that may lead to overlap of acute and delayed CINV in allo-HSCT include the use of calcineurin inhibitors for the control of graft-versus-host disease (GVHD), antibiotics and antifungal agents for infection prophylaxis, total body irradiation (TBI), and high-dose multiday administration of anticancer drugs.13, 22 Further, many regimens contain drugs such as cyclophosphamide and busulfan that are metabolized by cytochrome (CYP) 3A4. Aprepitant inhibits CYP 3A4,23 and concomitant use with CYP3A4 substrates may alter the pharmacokinetic properties of these drugs.24–29 Thus there is a need to evaluate the antiemetic efficacy and safety of aprepitant in conditioning regimens for allo-HSCT. In 2010, our institution began using aprepitant as part of the antiemetic prophylaxis strategy for patients undergoing allo-HSCT. The purpose of this study was to evaluate retrospectively the safety and efficacy of aprepitant in allo-HSCT patients.

Purpose Antiemetic effectiveness and safety of aprepitant in patients with he-matologic malignancy receiving multiday chemotherapy were evaluated. Methods All data were retrospectively collected from the Kyushu University Hospital’s electronic medical record system. Patients age 20 years or older with hematologic malignancies who received multiday chemotherapy were included in the study. All patients received 3 mg of granisetron i.v. 30 minutes before chemotherapy administration. Patients in the aprepitant group received 125 mg of aprepitant orally 60–90 minutes before administration of the first moderately to highly emetogenic chemotherapy (day 1). On day 2 or thereafter, an 80-mg oral dose of aprepitant was administered in the morning for up to five days. The primary endpoint was the percentage of patients who achieved complete response (CR). Results A total of 42 patients were treated with aprepitant and granisetron as antiemetic prophylaxis between April and December 2010 (aprepitant group), and 40 patients were treated with only granisetron between March 1, 2009, and March 31, 2010, before the introduction of aprepitant. The percentage of patients who achieved CR in the aprepitant group was significantly higher than that in the control group ( p = 0.01). Factors that were significantly associated with non-CR included the prophylactic use of aprepitant and chemotherapies containing ≥4 g/m2/day of cytarabine. The rates of adverse drug events (ADEs) did not significantly differ between groups. Conclusion The addition of aprepitant to granisetron increased the antiemetic effect without influencing ADEs in patients treated with moderately to highly emetogenic multiday chemotherapy for hematologic malignancies. Am J Health-Syst Pharm. 2013; 70:343-9

Intravenous injection of bendamustine often causes venous irritation and also deteriorates the patient's quality of life. Thus, we evaluated the risk factors associated with venous irritation induced by bendamustine in patients with follicular lymphoma or mantle cell lymphoma. We also evaluated the effectiveness of intervention of changing the preparation procedure for bendamustine. All data were retrospectively collected from the electronic medical record system. In the initial analysis of the total 43 courses of bendamustine therapy, most patients (88%) were administered bendamustine with 250 mL of diluent according to the bendamustine package insert in Japan. The median concentration of bendamustine solution (0.56 mg/mL vs. 0.24 mg/mL) and the incidences of venous irritation (66% vs. 0%, p=0.01) were significantly different between the patients receiving bendamustine at 250 mL and 500 mL of diluent. Based on this result, we proposed changing the final volume of bendamustine dissolution from 250 to 500 mL, which is recommended in other countries. After this intervention, the incidence of venous irritation was significantly reduced from 58 to 20% (p=0.02). The incidence of venous irritation increased in a concentration-dependent manner (≤0.40 mg/mL: 6%; 0.41-0.60 mg/mL: 62%, p0.001;0.60 mg/mL: 75%, p0.001). We conclude that a high concentration bendamustine solution is a risk factor for venous irritation and that 500 mL of diluent is ideal. To further reduce the incidence of venous irritation, the concentration of bendamustine solution is recommended to be 0.40 mg/mL or less.

Obsessive-compulsive disorder (OCD) is characterized by recurrent unwanted thoughts (obsessions), usually accompanied by repetitive behaviors (compulsions) intended to alleviate anxiety. Marble-burying behavior is a pharmacological model for study of OCD.In the present study, we examined the effects of mood stabilizers on marble-burying behavior in mice, as well as the role of GABA receptors in this behavior.The effects of treatment with valproate, carbamazepine, lithium carbonate, lamotrigine, muscimol and baclofen on marble-burying behavior in mice were evaluated.Valproate (10, 30 and 100 mg/kg, i.p.) and carbamazepine (30 and 100 mg/kg, p.o.) significantly reduced marble-burying behavior without affecting total locomotor activity in ICR mice. Lamotrigine (30 mg/kg, i.p.) also significantly reduced marble-burying behavior in ddY mice. On the other hand, lithium carbonate (10, 30 and 100 mg/kg, i.p.) reduced total locomotor activity without affecting marble-burying behavior in ddY mice. The selective GABA(A) receptor agonist muscimol (1 mg/kg) significantly reduced marble-burying behavior without affecting total locomotor activity, whereas the selective GABA(B) receptor agonist baclofen (3 mg/kg) reduced total locomotor activity without affecting marble-burying behavior. Moreover, the selective GABA(A) receptor antagonist bicuculline (3 mg/kg) significantly counteracted the decrease in marble-burying induced by the administration of muscimol (1 mg/kg) and valproate (100 mg/kg).These results suggest that GABAergic mechanism is involved in marble-burying behavior, and that valproate, carbamazepine and lamotrigine reduce marble-burying behavior. Moreover, valproate reduces marble-burying behavior via a GABA(A) receptor-dependent mechanism.

The purpose of this study was (i) to determine the optimal dosage of teicoplanin for each patient group stratified by renal function and weight based on a population pharmacokinetic model and observed distribution of patient characteristics and (ii) to develop new simplified dosing regimens designed to achieve 15-30 μg/mL. Patient data were collected retrospectively from routine therapeutic drug monitoring files of adult patients who were given the standard loading dose regimen of teicoplanin (400 mg twice on Day 1, followed by 400 mg once daily for 2 days) and whose trough concentration was measured just before administration on Day 4. Monte Carlo simulation was conducted to estimate the trough concentration at 72 h after the initial loading dose (C(min)(72 h)) and at steady state (C(ss)(min)). The percentage of observed C(min)(72 h) in patients who received the standard loading dose regimen outside the non-parametric 90% prediction interval (from 5th to 95th percentile) of the simulated C(min)(72 h) was10%. Simplified loading dose and maintenance dose regimens for each group stratified by renal function and weight were created to achieve C(min)(72 h) and C(ss)(min) of 15 μg/mL and 20-25 μg/mL, respectively. The percentage of C(min)(72 h) and C(ss)(min) in the range 15-30 μg/mL was 43-65% and 61-82% across each renal function and weight strata, respectively. These new simplified dosing regimens of teicoplanin could be helpful in individual adjustment of the loading and maintenance doses to achieve 15-30 μg/mL.

Vancomycin chloride (VCM), a glycopeptide antibiotic, is widely used for the therapy of infections caused by methicillin-resistant Staphylococcus aureus. However, nephrotoxicity is a major adverse effect in VCM therapy. In this study, we investigated the cellular mechanisms underlying VCM-induced renal tubular cell injury in cultured LLC-PK1 cells. VCM induced a concentration- and time-dependent cell injury in LLC-PK1 cells. VCM caused increases in the numbers of annexin V-positive/PI-negative cells and TUNEL-positive cells, indicating the involvement of apoptotic cell death in VCM-induced renal cell injury. The VCM-induced apoptosis was accompanied by the activation of caspase-9 and caspase-3/7 and reversed by inhibitors of these caspases. Moreover, VCM caused an increase in intracellular reactive oxygen species production and mitochondrial membrane depolarization, which were reversed by vitamin E. In addition, mitochondrial complex I activity was inhibited by VCM as well as by the complex I inhibitor rotenone, and rotenone mimicked the VCM-induced LLC-PK1 cell injury. These findings suggest that VCM causes apoptotic cell death in LLC-PK1 cells by enhancing mitochondrial superoxide production leading to mitochondrial membrane depolarization followed by the caspase activities. Moreover, mitochondrial complex I may play an important role in superoxide production and renal tubular cell apoptosis induced by VCM.

We examined the role of 5-hydroxytryptamine(2C) (5-HT(2C)) receptors in marble-burying behavior in mice. When administered alone, the selective 5-HT(2C) agonist WAY161503 (3 mg/kg) inhibited marble-burying behavior. Moreover, the selective 5-HT(2C) antagonist SB242084 (3 mg/kg) reversed the inhibition of marble-burying behavior by 2,5-dimethoxy-4-iodoamphetamine (DOI) (1 mg/kg) or WAY161503 (3 mg/kg). Similarly, SB242084 (1 mg/kg) reversed the inhibition of marble-burying behavior by fluvoxamine (30 mg/kg) or paroxetine (3 mg/kg). These results suggest that 5-HT(2C) receptors play a role in marble-burying behavior in mice.

In the present study, we examined the effect of N-acetyl-L-cysteine (NAC), a glutamate-modulating agent, on marble-burying behavior in mice. Fluvoxamine (30 mg/kg, p.o.) and mirtazapine (3 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity. Similarity, NAC (150 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity. On the other hand, the antioxidant α-tocopherol (10, 30, and 100 mg/kg, p.o.) had no effect on the marble-burying behavior. These results suggest that the glutamatergic system is involved in the marble-burying behavior, and NAC may be useful for treatment of OCD.

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. Keywords:: oxaliplatin, amitriptyline, peripheral neuropathy

The purposes of this study were to evaluate the effect of implementation of institutional guidelines for low emetic risk chemotherapy with docetaxel and estimate the cost saving for all low emetic risk chemotherapies. We examined the clinical effect of preparing and implementing institutional antiemetic guidelines for the breast cancer patients receiving adjuvant docetaxel therapy. Although the antiemetic medication for such patients used to be ondansetron 4 mg plus dexamethasone 8 mg (OND + DEX), it was changed to dexamethasone (DEX) 12 mg alone after implementation of the institutional guidelines. The effectiveness and adverse effects of DEX alone (56 patients, 205 courses) were compared with those of OND + DEX (41 patients, 151 courses). The cost saving was calculated from the antiemetic costs in both groups. The annual cost saving was estimated from the number of all low emetic risk chemotherapies in a year. The incidences of nausea (19.5% versus 16.1%), vomiting (2.4% versus 0%), constipation (34.1% versus 30.4%), and insomnia (17.1% versus 17.9%) were not significantly different between the OND + DEX group and DEX alone group. In all low emetic risk chemotherapies, US $78,883 of potential cost saving was estimated in the first year after changing the antiemetic treatment. The present results suggest that DEX alone is equally effective for preventing nausea and vomiting and less expensive compared with a 5-HT3 receptor antagonist plus DEX in low emetic risk chemotherapy with docetaxel.

Cannabis is a widely used illicit substance. ∆(9)-Tetrahydrocannabinol (THC), the major psychoactive component of cannabis, is known to induce cognitive deficits that closely resemble the impairment observed in schizophrenic patients. We previously reported that THC (6 mg/kg) impairs spatial memory in the eight-arm radial maze, and that this memory disturbance was reversed by the cannabinoid CB(1) receptor antagonist rimonabant (0.1 mg/kg), suggesting that the effect of THC is mediated through cannabinoid CB(1) receptors.The present study was designed to examine the possible involvement of opioid receptors in the THC-induced impairment of spatial memory.The effects of treatment with the nonselective opioid receptor antagonist naloxone (0.3 and 1 mg/kg), the μ-opioid receptor antagonist β-funaltrexamine (0.3 and 1 mg/kg), the δ-opioid receptor antagonist naltrindole (1 and 3 mg/kg), and the κ-opioid receptor antagonist nor-binaltorphimine (0.03 and 0.1 mg/kg) on the impairment of spatial memory induced by THC were evaluated using the eight-arm radial maze.The nonselective opioid receptor antagonist naloxone, the μ-opioid receptor antagonist β-funaltrexamine, and the κ-opioid receptor antagonist nor-binaltorphimine, but not the δ-opioid receptor antagonist naltrindole, attenuated THC-induced cognitive deficits, suggesting an involvement of μ- and κ-opioid receptors in this behavioral response.These results demonstrate that the endogenous opioid system is involved in the regulation of the acute short-term and working memory deficits induced by cannabis.

Emesis is the most feared side effect in patients who are undergoing cancer chemotherapy. In particular, cisplatin causes severe acute and delayed emesis. Although early vomiting is well controlled by 5-hydroxytryptamine 3 (5-HT(3)) receptor antagonists, delayed-phase vomiting is not sufficiently controlled. Substance P is thought to be involved in the development of emesis, and tachykinin NK(1) receptor antagonists can inhibit delayed vomiting. We previously have reported that substance P is involved in the paclitaxel-induced hypersensitivity reaction in rats, and anti-allergic agent pemirolast reduces these reactions via inhibition of substance P release. In the present study, we investigated the effect of pemirolast on cisplatin-induced kaolin intake, which is an index of nausea/vomiting in the rat. Cisplatin (5 mg/kg, i.p.) induced kaolin intake and reduced normal feed intake from days 1 to 5 after injection. Cisplatin-induced kaolin intake was significantly reduced by co-administration of ondansetron (2 mg/kg, i.p.), a 5-HT(3) receptor antagonist, and dexamethasone (2 mg/kg, i.p.) from days 1 to 5. Similarly, pemirolast (10 mg/kg, p.o.) and the tachykinin NK(1) receptor antagonist aprepitant (10 and 30 mg/kg, p.o.) significantly reduced cisplatin-induced kaolin intake on days 3 and 4. Moreover, pemirolast at the same dose significantly reversed the cisplatin-induced increase in the cerebrospinal fluid level of substance P in rats. These results suggest that substance P is involved in cisplatin-induced kaolin intake in rats, and pemirolast reduces kaolin intake by inhibition of substance P release.

The painful peripheral neuropathy occurring frequently during chemotherapy with paclitaxel or oxaliplatin is one of their dose-limiting factors. We reported previously that substance P is involved in the pathogenesis of pulmonary hypersensitivity reaction to paclitaxel in rats, and an antiallergic agent pemirolast reverses this reaction via the blockade of release of substance P. In the present study, we investigated the involvement of substance P in paclitaxel-induced peripheral neuropathy compared with that by oxaliplatin. In von Frey and acetone tests in rats repeated administration of paclitaxel (6 mg/kg i.p., once a week for 4 weeks) or oxaliplatin (4 mg/kg i.p., twice a week for 4 weeks) induced both mechanical allodynia and cold hyperalgesia. Paclitaxel-induced peripheral neuropathy was reversed primarily by the acute administration of pemirolast (0.1 and 1 mg/kg p.o.). Moreover, coadministration of the receptor antagonists neurokinin 1 [N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)benzylester (L-732,138), 100 μg/body i.t.] and neurokinin 2 [5-fluoro-3-[2-[4-methoxy-4-[[(R)-phenylsulphinyl]methyl]-1-piperidinyl]ethyl]-1H-indole (GR159897), 100 μg/body i.t.] strongly reversed paclitaxel-induced neuropathy. On the other hand, oxaliplatin-induced peripheral neuropathy was not reversed by pemirolast. In the in vitro study using cultured adult rat dorsal root ganglion neurons paclitaxel (1000 ng/ml) significantly increased the release of substance P, and pemirolast (100 and 1000 nM) significantly inhibited this increase of substance P release. Oxaliplatin, by contrast, did not increase the release of substance P. These results suggest that substance P is involved in paclitaxel-induced neuropathy, and the mechanism of its action is clearly different from that of oxaliplatin.

In the present study, we investigated the effect of the Kampo medicine Yokukansan (YKS) on pentobarbital-induced sleep in group-housed and socially isolated mice. Socially isolated mice showed shorter sleeping time than the group-housed mice. YKS (300 mg/kg, p.o.) prolonged the pentobarbital-induced sleeping time in socially isolated mice without affecting pentobarbital sleep in group-housed mice. The prolongation of sleeping time by YKS was reversed by bicuculline (3 mg/kg, i.p.) and flumazenil (3 mg/kg, i.p.), but not WAY100635. These findings suggest that the GABAA – benzodiazepine receptor complex, but not 5-HT1A receptors, is involved in the reversal effect of YKS on the decrease of pentobarbital sleep by social isolation. Keywords:: sleep, social isolation, Yokukansan

Nanoparticle albumin–bound paclitaxel (nab-paclitaxel) is delivered to tumors and increases antitumor activity compared with solvent-based paclitaxel. However, in a clinical trial, higher and lower rates of peripheral neuropathy and neutropenia were observed. In this study, we compared the effects of nab-paclitaxel and standard paclitaxel on pain behaviors in rats. Repeated administration of nab-paclitaxel dose-dependently induced both mechanical and cold allodynia, and the effects of nab-paclitaxel on pain behaviors tended to be stronger than that of standard paclitaxel at the doses used clinically. These results suggest that closer attention must be paid to the neuropathy when administering nab-paclitaxel in clinical settings. Keywords:: nanoparticle albumin–bound paclitaxel, paclitaxel, peripheral neuropathy

We previously reported that 21-day (14-day pre-ischemic and 7-day post-ischemic) treatment with Kangen-karyu (KGKR) improved spatial memory impairment and hippocampal neuronal death induced by repeated cerebral ischemia (2 x 10-min, 1-h interval) in rats. In the present study, we examined the effect of single and 14-day pre-ischemic KGKR treatment on neuronal damage in the same repeated cerebral ischemia model. Additionally, to determine the mechanisms of neuroprotection by KGKR at glutamatergic neurons, we examined the effects of KGKR on glutamate release induced by repeated cerebral ischemia in vivo, and on cell damage induced by both glutamate and kainate in primary cultured hippocampal neurons in vitro. The 14-day pre-ischemic KGKR (300 mg/kg, oral administration (p.o.)) treatment reduced neuronal damage and astrocyte expression induced by repeated cerebral ischemia. No effect was observed after single pre-ischemic KGKR treatment. Both single and 14-day KGKR treatment decreased glutamate release in the hippocampal CA1 region in intact rats; however, neither pre-ischemic KGKR treatment altered glutamate release during cerebral ischemia. In vitro, KGKR (100-1000 microg/mL) dose-dependently suppressed hippocampal neuronal damage induced by both glutamate (100 microM) and kainate (1 mM). These data suggest neuroprotection with KGKR requires continuous pre-ischemic treatment, and that the mechanisms of protection may be involved in inhibiting the glutamatergic receptors of the post-synaptic neurons.

Vinorelbine (VNR), a vinca alkaloid anticancer drug, often causes vascular injury such as venous irritation, vascular pain, phlebitis, and necrotizing vasculitis. The purpose of this study was to identify the mechanisms that mediate the cell injury induced by VNR in porcine aorta endothelial cells (PAECs). PAECs were exposed to VNR for 10 min followed by further incubation in serum-free medium without VNR. The exposure to VNR (0.3-30 microM) decreased the cell viability concentration and time dependently. The incidence of apoptotic cells significantly increased at 12 h after transient exposure to VNR. At the same time, VNR increased the activity of caspases. Interestingly, VNR rapidly depleted intracellular glutathione (GSH) and increased intracellular reactive oxygen species (ROS) production. Moreover, VNR depolarized the mitochondrial membrane potential and decreased cellular ATP levels. These VNR-induced cell abnormalities were almost completely inhibited by GSH and N-acetylcysteine. On the other hand, L-buthionine-(S,R)-sulfoximine, a specific inhibitor of GSH synthesis, aggravated the VNR-induced loss of cell viability. These results clearly demonstrate that VNR induces oxidative stress by depleting intracellular GSH and increasing ROS production in PAECs, and oxidative stress plays an important role in the VNR-induced cell injury.

近年，がん化学療法の有用性が高まってきたが，タキサン系抗がん剤であるパクリタキセルや白金系抗がん剤であるオキサリプラチンは，末梢神経障害を高頻度で発現し，身体的苦痛から患者の生活の質（Quality of Life: QOL）を著しく低下させるだけでなく，がん治療の変更や中止を余儀なくさせることから，臨床上大きな問題となっている．無作為化二重盲検臨床試験において，オキサリプラチンの末梢神経障害に対しては，カルシウム/マグネシウム静脈内投与，グルタチオンおよびキサリプロデンの有用性が報告されているが，いろいろな理由により臨床現場ではほとんど用いられておらず，パクリタキセルの末梢神経障害に対しては明らかに有用な効果を示す薬物はない．抗がん剤による末梢神経障害動物モデルでは，パクリタキセルは坐骨神経の変性に伴い機械的アロディニアならびに低温知覚異常を発現する．オキサリプラチンは急性期より低温知覚異常を，その後遅発的に機械的アロディニアを発現するが，前者はオキサレート基で後者は白金を含む部分の化合物で発現される．今後は，末梢神経障害の発現機序を明らかにして，予防策や治療法の確立には発現機序に基づいた取り組みが重要である．

The neuroprotective effects of Hericium erinaceum (H. erinaceum) were studied in mice subjected to middle cerebral artery (MCA) occlusion. Infarct volumes were markedly reduced in mice receiving 14 days of H. erinaceum (300 mg/kg) treatment prior to 4-hr MCA occlusion. Moreover, 14-day pre-ischemic H. erinaceum treatment significantly increased the levels of nerve growth factor (NGF) in both the cortex and striatum of mice subjected to 4-hr MCA occlusion. However, pre-ischemic H. erinaceum treatment had no effect on cerebral blood flow (CBF) in the cortex of mice subjected to MCA occlusion. Treatment with H. erinaceum for 1 day prior to MCA occlusion-induced ischemia had no effect on infarct volume or NGF level. These results suggest that 14 days of treatment with H. erinaceum prior to MCA occlusion protected against focal cerebral ischemia, by increasing NGF levels. This implies that H. erinaceum and its components could be useful for preventing cerebral infarction.

Starch is often used as a pharmaceutical diluent in dispensing.However,starch is susceptible to large errors in dividing weight because of its low fluidity.In the present study,we prepared granulated starch and a potato starch containing a stearic acid magnesium salt (St-starch) to improve the dispensing of powder medicines with starch diluent.These 2 starch diluents caused no problems in dispensing powder medicines in terms of pharmaceutical characteristics.In a dividing test,the coefficients of variation (C.V.) of the granulated starch and St-starch were much less than for potato starch,and met the dispensing criteria.In addition in the evaluation of ease of handling,St-starch was the best.Furthermore,the time for preparing the St-starch was much shorter (20 minutes for 2 persons) than that for granulated starch (3.5 hours).These results clearly show that St-starch is a useful starch diluent and enhances efficiency in the preparation of powder medicines with starch.

Oxaliplatin is a platinum-based chemotherapy drug characterized by the development of acute and chronic peripheral neuropathies. Mexiletine, an orally available Na+-channel blocker, has widely been used in patients with chronic painful diabetic neuropathy. In the present study, we examined the effect of mexiletine on oxaliplatin-induced neuropathic pain in rats. Mexiletine (100, but not 10 and 30, mg/kg, p.o.) completely reversed both mechanical allodynia and cold hyperalgesia induced by oxaliplatin (4 mg/kg, i.p., twice a week). Lidocaine (30, but not 3 and 10, mg/kg, i.p.) also significantly relieved both pain behaviors. These results suggest that mexiletine may be effective in relieving the oxaliplatin-induced neuropathic pain clinically. Keywords:: mexiletine, oxaliplatin, neuropathic pain

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.