The Chemo Sero Therapeutic Research Institute Kaketsuken

Kikuchi, Japan

The Chemo Sero Therapeutic Research Institute Kaketsuken

Kikuchi, Japan
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Kato K.,Kyoto Sangyo University | Akaike N.,Kumamoto Health Science University | Kohda T.,Osaka Prefecture University | Torii Y.,The Chemo Sero Therapeutic Research Institute KAKETSUKEN | And 5 more authors.
Toxicon | Year: 2013

Temporal lobe epilepsy often shows pharmacoresistance, and well-known anti-convulsants sometimes are not effective for blocking chronic seizures. Botulinum neurotoxins are metalloproteases that act on presynaptic proteins and inhibit neurotransmitter release in both the peripheral and central nerve systems. That is why neurotoxins may elicit an effect for the restraint of the seizures. Meanwhile, it has been suggested that a property and the stability of neurotoxin activities differ among the types A-G, in which type A neurotoxin (ANTX) is, especially, the most stable and can continue having activity for a long term. The present study therefore investigated the effects of hippocampal injections of A2NTX on seizures derived in TLE model mice, received repeated kindling stimulations in the amygdala. The injections induced complete disappearance of grand mal seizures in half of the population of amygdala kindled mice for 4 days. The injections also induced reduction of the evoked seizure level significantly for at least 18 days after injections. Taken together, these results suggest that A2NTX prevents from epileptic seizures, proposing that A2NTX is available as a new antiepileptic reagent. © 2013 Elsevier Ltd.


Torii Y.,The Chemo Sero Therapeutic Research Institute KAKETSUKEN | Kiyota N.,The Chemo Sero Therapeutic Research Institute KAKETSUKEN | Sugimoto N.,Molecular Therapeutics | Mori Y.,The Chemo Sero Therapeutic Research Institute KAKETSUKEN | And 6 more authors.
Toxicon | Year: 2011

Botulinum toxin type A is used as a therapeutic agent for some spastic neurological disorders. Type A organisms have been classified into four subtypes (A1 to A4) based on the amino acid sequence variability of the produced neurotoxin. At present, commercially available preparations of the toxin belong to subtype A1. To date, no study has compared the characteristics of the biological activity of toxins from different subtypes. We compared the efficacy of A1 toxin (LL toxin or neurotoxin: NTX) with that of A2 toxin (NTX) employing the twitch tension assay using the mouse phrenic nerve hemidiaphragm and grip strength test in rats. The inhibitory effects on neuromuscular transmission of A2NTX at pH 7.4 and pH 6.8 were 1.95 and 3.73 times more potent than those of A1LL, respectively. The 50% effective doses for the administered limb, the dose which caused a 50% reduction in grip strength, i.e. ED50, of A1LL, A1NTX, and A2NTX were calculated as 0.087, 0.060, and 0.040 U/head, respectively. These doses for the contralateral limb, i.e. TD50, of A1LL, A1NTX, and A2NTX were calculated as 6.35, 7.54, and 15.62 U/head, respectively. In addition, the time required for A2NTX-injected rats to recover the grip strength of the contralateral limb was 17 days, while that for rats injected with A1LL was 35 days. The results indicated that A2NTX is a more potent neuromuscular blocker than A1 toxins, and suggested that A2NTX will provide a preferentical therapeutic agent for neurological disorders. © 2010 Elsevier Ltd.


Torii Y.,The Chemo Sero Therapeutic Research Institute KAKETSUKEN | Torii Y.,Osaka University | Goto Y.,The Chemo Sero Therapeutic Research Institute KAKETSUKEN | Nakahira S.,The Chemo Sero Therapeutic Research Institute KAKETSUKEN | And 3 more authors.
Basic and Clinical Pharmacology and Toxicology | Year: 2015

The adverse events caused by botulinum toxin type A (subtype A1) product, thought to be after-effects of toxin diffusion after high-dose administration, have become serious issues. A preparation showing less diffusion in the body than existing drugs has been sought. We have attempted to produce neurotoxin derived from subtype A2 (A2NTX) with an amino acid sequence different from that of neurotoxin derived from subtype A1 (A1NTX). In this study, to investigate whether A2NTX has the potential to resolve these issues, we compared the safety of A2NTX, a progenitor toxin derived from subtype A1 (A1 progenitor toxin) and A1NTX employing the intramuscular lethal dose 50% (im LD50) in mice and rats and the compound muscle action potential (CMAP) in rats. Mouse im LD50 values for A1 progenitor toxin and A2NTX were 93 and 166 U/kg, respectively, and the rat im LD50 values were 117 and 153 U/kg, respectively. In the rat CMAP test, the dose on the contralateral side, which caused a 50% reduction in the CMAP amplitude, that is, CMAP-TD50, was calculated as 19.0, 16.6 and 28.7 U/kg for A1 progenitor toxin, A1NTX and A2NTX, respectively. The results indicate that A2NTX is safer than A1 progenitor toxin and A1NTX. © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).


Koizumi H.,Tokushima University | Goto S.,Tokushima University | Okita S.,Tokushima University | Morigaki R.,Tokushima University | And 6 more authors.
Frontiers in Neurology | Year: 2014

Because of its unique ability to exert long-lasting synaptic transmission blockade, botulinum neurotoxin A (BoNT/A) is used to treat a wide variety of disorders involving peripheral nerve terminal hyperexcitability. However, it has been a matter of debate whether this toxin has central or peripheral sites of action. We employed a rat model in which BoNT/A1 or BoNT/A2 was unilaterally injected into the gastrocnemius muscle. On time-course measurements of compound muscle action potential (CMAP) amplitudes after injection of BoNT/A1 or BoNT/A2 at doses ranging from 1.7 to 13.6 U, CMAP amplitude for the ipsilateral hind leg was markedly decreased on the first day, and this muscle flaccidity persisted up to the 14th day. Of note, both BoNT/A1 and BoNT/A2 administrations also resulted in decreased CMAP amplitudes for the contralateral leg in a dose-dependent manner ranging from 1.7 to 13.6 U, and this muscle flaccidity increased until the fourth day and then slowly recovered. Immunohistochemical results revealed that BoNT/A-cleaved synaptosomal-associated protein of 25 kDa (SNAP-25) appeared in the bilateral ventral and dorsal horns 4 days after injection of BoNT/A1 (10 U) or BoNT/A2 (10 U), although there seemed to be a wider spread of BoNT/A-cleaved SNAP-25 associated with BoNT/A1 than BoNT/A2 in the contralateral spinal cord. This suggests that the catalytically active BoNT/A1 and BoNT/A2 were axonally transported via peripheral motor and sensory nerves to the spinal cord, where they spread through a transcytosis (cell-to-cell trafficking) mechanism. Our results provide evidence for the central effects of intramuscularly administered BoNT/A1 and BoNT/A2 in the spinal cord, and a new insight into the clinical effects of peripheral BoNT/A applications. © 2014 Koizumi, Goto, Okita, Morigaki, Akaike, Torii, Harakawa, Ginnaga and Kaji.


Yokote H.,The Chemo Sero Therapeutic Research Institute Kaketsuken | Shinmura Y.,The Chemo Sero Therapeutic Research Institute Kaketsuken | Kanehara T.,The Chemo Sero Therapeutic Research Institute Kaketsuken | Maruno S.,The Chemo Sero Therapeutic Research Institute Kaketsuken | And 3 more authors.
Vaccine | Year: 2015

Background: Attenuated vaccinia virus strain, LC16m8, defective in the B5R envelope protein gene, is used as a stockpile smallpox vaccine strain in Japan against bioterrorism: the defect in the B5R gene mainly contributes to its highly attenuated properties. Methods: The protective activity of LC16m8 vaccine against challenge with a lethal dose of vaccinia Western Reserve strain was assessed in wild-type and immunodeficient mice lacking CD4, MHC class I, MHC class II or MHC class I and II antigens. Results: The immunization with LC16m8 induced strong protective activity comparable to that of its parent strain, Lister (Elstree) strain, in wild-type mice from 2 days to 1 year after vaccination, as well as in immunodeficient mice at 2 or 3 weeks after vaccination. These results implicated that the defect in the B5R gene hardly affected the potential activity of LC16m8 to induce innate, cell-mediated and humoral immunity, and that LC16m8 could be effective in immunodeficient patients. Conclusion: LC16m8 with truncated B5 protein has an activity to induce immunity, such as innate immunity and subsequent cell-mediated and humoral immunity almost completely comparable to the activity of its parental strain Lister. © 2015 The Authors.


PubMed | The Chemo Sero Therapeutic Research Institute KAKETSUKEN, Nissan Tamagawa Hospital and The Study Group for Pneumothorax and Cystic Lung Diseases
Type: Journal Article | Journal: PloS one | Year: 2016

Spontaneous pneumothorax is a major and frequently recurrent complication of lymphangioleiomyomatosis (LAM). Despite the customary use of pleurodesis to manage pnenumothorax, the recurrence rate remains high, and accompanying pleural adhesions cause serious bleeding during subsequent lung transplantation. Therefore, we have developed a technique of total pleural covering (TPC) for LAM to wrap the entire visceral pleura with sheets of oxidized regenerated cellulose (ORC) mesh, thereby reinforcing the affected visceral pleura and preventing recurrence.Since January 2003, TPC has been applied during video-assisted thoracoscopic surgery for the treatment of LAM. The medical records of LAM patients who had TPC since that time and until August 2014 are reviewed.TPC was performed in 43 LAM patients (54 hemithoraces), 11 of whom required TPC bilaterally. Pneumothorax recurred in 14 hemithoraces (25.9%) from 11 patients (25.6%) after TPC. Kaplan-Meier estimates of recurrence-free hemithorax were 80.8% at 2.5 years, 71.7% at 5 years, 71.7% at 7.5 years, and 61.4% at 9 years. The recurrence-free probability was significantly better when 10 or more sheets of ORC mesh were utilized for TPC (P = 0.0018). TPC significantly reduced the frequency of pneumothorax: 0.544 0.606 episode/month (mean SD) before TPC vs. 0.008 0.019 after TPC (P<0.0001). Grade IIIa postoperative complications were found in 13 TPC surgeries (24.1%).TPC successfully prevented the recurrence of pneumothorax in LAM, was minimally invasive and rarely caused restrictive ventilatory impairment.


Niimi N.,Tokyo Metropolitan Institute for Neuroscience | Kohyama K.,Tokyo Metropolitan Institute for Neuroscience | Kamei S.,The Chemo Sero Therapeutic Research Institute Kaketsuken | Matsumoto Y.,Tokyo Metropolitan Institute for Neuroscience
Neuropathology | Year: 2011

Although intravenous immunoglobulin (IVIG) has been reported to improve the status of expanded disability status scale (EDSS) of multiple sclerosis (MS) patients and reduce the annual relapse rate, some studies did not find its beneficial effects. In the present study, using an animal model for MS, we found that prophylactic, but not therapeutic, treatment successfully suppressed the disease development. During the search for factors involved in the disease suppression by IVIG, we obtained evidence suggesting that IVIG exerts its function, at least in part, by suppressing activation of matrix metalloproteinases (MMP)-2 and -9. Gelatin zymography revealed that gelatinase activities were suppressed by IVIG treatment in the spinal cord, but not in plasma. This finding raises the possibility that IVIG blocks MMP activities at the interface between the blood stream and CNS. With in situ zymography, we also observed that gelatinase activities were expressed mainly in astrocytes in the inflamed spinal cord of control rats and that this expression was attenuated by the treatment. These findings provide useful information to set optimal conditions for IVIG treatment of MS and to obtain more beneficial effects. © 2010 Japanese Society of Neuropathology.


PubMed | The Chemo Sero Therapeutic Research Institute Kaketsuken, Tokyo University of Agriculture, Osaka Prefecture University and Japan National Institute of Infectious Diseases
Type: | Journal: Toxicon : official journal of the International Society on Toxinology | Year: 2016

Japanese botulinum antitoxins have been used for more than 50 years; however, their safety and therapeutic efficacy are not clear. In order to analyze the available data on botulinum antitoxin therapy in Japan, we surveyed published reports about botulism cases in which botulinum antitoxins were used, and retrospectively analyzed the safety and efficacy of the therapy. A total of 134 patients administered botulinum antitoxins were identified from published reports. Two cases of side effects (1.5%) were detected after antitoxin administration, both not fatal. The fatality rate was 9.4%, and more than 70% of the patients showed improvement in their symptoms and better clinical conditions than those not treated with antitoxins. These data suggest that the therapy with Japanese antitoxins is safe and highly effective.


Chisada S.-I.,Kyushu University | Chisada S.-I.,Japan National Research Institute of Fisheries And Environment of Inland Sea | Shimizu K.,Kyushu University | Shimizu K.,The Chemo Sero Therapeutic Research Institute KAKETSUKEN | And 5 more authors.
FEMS Microbiology Letters | Year: 2013

Vibrios, distributed in marine and brackish environments, can cause vibriosis in fish and shellfish under appropriate conditions. Previously, we clarified by thin-layer chromatography (TLC) overlay assay that 35S-labeled Vibrio trachuri adhered to GM4 isolated from red sea bream intestine. However, whether GM4 actually functions on epithelial cells as an attachment site for vibrios still remains to be uncovered. We found that six isolates, classified as V. harveyi, V. campbellii, and V. splendidus, from intestinal microflora of red sea bream adhered to GM4 but not galactosylceramide (GalCer) by TLC-overlay assay. Tissue-overlay assays revealed that V. harveyi labeled with green fluorescent protein (GFP) adhered to epithelial cells of red sea bream intestine where GM4 and GalCer were found to be distributed on the top layer of actin filaments by immunohistochemical analysis using corresponding antibodies. The number of adhering vibrios was diminished by pretreatment with anti-GM4 antibody, but not anti-GalCer antibody. These results clearly indicate that vibrios adhere to epithelial cells of red sea bream intestine utilizing GM4 as an attachment site. © 2013 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd.


Tanaka R.,Kumamoto University | Ishima Y.,Kumamoto University | Enoki Y.,Kumamoto University | Kimachi K.,The Chemo Sero Therapeutic Research Institute KAKETSUKEN | And 5 more authors.
Frontiers in Immunology | Year: 2014

Reactive oxygen species (ROS) are the primary pathogenic molecules produced in viral lung infections. We previously reported on the use of a recombinant human serum albumin (HSA)-thioredoxin 1 (Trx) fusion protein (HSA-Trx) for extending the half-life Trx, an endogenous protein with anti-oxidant properties. As a result, it was possible to overcome the unfavorable pharmacokinetic and short pharmacological properties of Trx. We hypothesized that HSA-Trx would attenuate the enhanced ROS production of species such as hydroxyl radicals by neutrophils during an influenza viral infection. The levels of 8-hydroxy-2'-deoxyguanosine and 3-nitrotyrosine were used as indices of the anti-oxidant activity of HSA-Trx. In addition, the cytoprotective effects of HSA-Trx were examined in PR8 (H1N1) influenza virus-induced lung injured mice. The findings show that HSA-Trx reduced the number of total cells, neutrophils, and total protein in BALF of influenza virus-induced lung injured mice. The HSA-Trx treatment significantly decreased the level of 8-hydroxy-2'-deoxyguanosine and 3-nitrotyrosine, but failed to inhibit inducible nitric oxide synthase expression, in the lungs of the virus-infected mice. On the other hand, Tamiflu® treatment also significantly suppressed the production of inflammatory cells and neutrophil infiltration, as well as the protein level in BALF and lung histopathological alterations caused by the influenza virus. The suppressive effect of Tamiflu® was slightly stronger than that of HSA-Trx. Interestingly, Tamiflu® significantly decreased virus proliferation, while HSA-Trx had no effect. These results indicate that HSA-Trx may be of therapeutic value for the treatment of various acute inflammatory disorders such as influenza-virus-induced pneumonia, by inhibiting inflammatory-cell responses and suppressing the overproduction of NO in the lung. © 2014 Tanaka, Ishima, Enoki, Kimachi, Shirai, Watanabe, Chuang, Maruyama and Otagiri.

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