Dainippon Pharmaceutical Research Articles

1038-P: Exposures to Hyperglycemia in the Embryonic Period and to Breast Milk from Mothers with Hyperglycemia Affect Glucose Tolerance with Higher Glucagon-Like Peptide-1 Secretion

Exposure to hyperglycemia during pregnancy results in diabetes in offspring. However, its underlying mechanisms are unclear. We therefore focused on the glucose metabolism of the offspring who were exposed to hyperglycemia in uterus or who were breast-fed from mothers with hyperglycemia. ICR female mice received single intraperitoneal injection (i.p.) of streptozotocin at six weeks old as the model of mother with diabetes (MD) . An additional group of mice received citric acid buffer injection, instead, as the model of mother with normal glycemia (MNG) . We established the model exposed to hyperglycemia in the uterus (EHU) by switching offspring from MD to MNG right after birth. As the model exposed to the breast milk of mothers with hyperglycemia (EBM) , the offspring from MNG were moved to MD right after birth. To eliminate the effects of cross fostering, offspring from MNG were fostered by another MNG as the control group. In intraperitoneal glucose tolerance test (IPGTT) at P60, EHU and EBM didn’t show increase of blood glucose level (BG) nor decrease of plasma insulin level but showed in oral glucose tolerance test (OGTT) at P50 (AUC of BG: p < 0.in EHU, p < 0.00in EBM, AUC of plasma insulin level per BG: <0.00in EHU and EBM) . From these conflicting results, we suspected the participation of glucagon-like peptide-1 (GLP-1) . However, the AUC of plasma total GLP-1 and active GLP-1 levels were higher in OGTT. Since we didn’t observe any difference in beta cell area per whole pancreas section by immunostaining, EHU and EBM might have GLP-1 resistance. Disclosure K.Ishii: None. M.Odawara: Other Relationship; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo, Daiichi Sankyo, Dainippon Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk, Omnipod, ONO PHARMACEUTICAL CO., LTD., Sanofi K.K., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Co.,Ltd., Teijin Pharma Limited. R.Suzuki: Consultant; Novo Nordisk A/S, Other Relationship; Daiichi Sankyo, Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Research Support; Boehringer Ingelheim Japan, Inc., LifeScan, Mitsubishi Tanabe Pharma Corporation. J.Sasaki: None. K.Sugai: None. M.Ito: None. H.Iwasaki: None. N.Hara: None. M.Aierken: n/a. G.Li: None. H.Suwanai: None.

The Birth and Development of Dainippon Pharmaceutical Company Based on “Wagasha Gojunen no Ayumi (Fifty Years of Our Company)”

The Birth and Development of Dainippon Pharmaceutical Company Based on “Wagasha Gojunen no Ayumi (Fifty Years of Our Company)”

Correction to: Histologic transformation of t(11;18)-positive MALT lymphoma presented with aberrant T-cell marker expression.

M. Nishikori receives honoraria from Eisai and funding from Eisai and Sumitomo Dainippon Pharmaceutical.

Regulators of Chronic Inflammation, Cytokines, and Neural Stimulation

Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan. Reprints: Masaaki Murakami, DVM, PhD, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan (e-mail: [email protected]). Supported by research grants from Kakenhi; Takeda Science Foundation; Institute for Fermentation, Osaka; Mitsubishi Foundation; Tokyo Medical Research Foundation; Uehara Memorial Foundation; Akiyama Life Science Foundation; Chugai Pharmaceutical Co Ltd; Takeda Pharmaceutical Co Ltd; Shionogi Co Ltd; and Sumitomo Dainippon Pharmaceutical Co Ltd. Ono Pharmaceutical Co Ltd, Gene Techno Science, Timelapse Vision/Sanofi, AMED-SICP, and JAXA-JSF to M. Murakami. M. Murakami has received consultation fees from Takeda Pharmaceutical Co Ltd and funding for research from Chugai Pharmaceutical Co Ltd, Takeda Pharmaceutical Co Ltd, Shionogi Co Ltd, Sumitomo Dainippon Pharmaceutical Co Ltd, Ono Pharmaceutical Co Ltd, Gene Techno Science, and Timelapse Vision/Sanofi.

Increases in Bioavailability of Poorly Absorbed Drug by Acylcarnitine

We examined the effect of acylcarnitines on the in situ bioavailability of lucifer yellow (LY) from the loops of small and large intestines of rats. The area under the blood concentration of LY versus time curve (AUC) from the jejunum was significantly increased by the treatments of the loop with 100 µM lauroylcarnitine (LC) or 100 µM palmitoylcarnitine (PC) (fourfold and 17-fold, respectively). No marked change in the expression of claudin-4 protein was observed by the treatments. On the contrary, the expression of P-glycoprotein (P-gp) was decreased by the treatment, more greatly by PC than by LC, suggesting that increases in the bioavailability of LY by LC and PC are associated with the decreased expression of P-gp in jejunum. The increase in the bioavailability was also observed for colon by the treatment of LC, but not that of PC. LC decreased the expression of claudin-4 protein, whereas PC decreased the expression of P-gp in colon. Therefore, LC and PC appear to have different impact on the intestinal transporters depending on the site (i.e., jejunum and colon).

Novel mutations of the lipoprotein lipase gene associated with hypertriglyceridemia in members of type 2 diabetic pedigrees

Increased plasma triglyceride and free fatty acid levels are frequently associated with type 2 diabetes mellitus (T2DM). To test the hypothesis that LPL gene mutations contribute to the hypertriglyceridemia observed in members of T2DM pedigrees, we screened the LPL gene in 53 hypertriglyceridemic members of 26 families. Four known and three novel mutations were identified. All three novel mutations, Lys312insC, Thr361insA, and double mutation Lys312insC + Asn291Ser, are clinically associated with hypertriglyceridemia. In vitro mutagenesis and expression studies confirm that these variants are associated with a significant reduction in LPL activity. The modeled structures displaying the Lys312insC and Thr361insA mutations showed loss of the activity-related C-terminal domain in the LPL protein. Another novel double mutation, Lys312insC + Asn291Ser, resulted in the loss of the catalytic ability of LPL attributable to the complete loss of the C-terminal domain and alteration in the heparin association site. Thus, these novel mutations of the LPL gene contribute to the hypertriglyceridemia observed in members of type 2 diabetic pedigrees.

A Protein Toxin from the Sea Anemone Phyllodiscus semoni Targets the Kidney and Causes a Severe Renal Injury with Predominant Glomerular Endothelial Damage

Envenomation by the sea anemone Phyllodiscus semoni causes fulminant dermatitis and, rarely, acute renal failure in humans. Here, we investigated whether the venom extracted from the nematocysts (PsTX-T) was nephrotoxic when administered intravenously in rats and whether PsTX-T induced activation of the complement system. Although small dose of PsTX-T induced acute tubular necrosis in rats resembling pathology seen in patients, kidneys displayed glomerular injury with glomerular endothelial damage, thrombus formation, mesangiolysis, and partial rupture of glomerular basement membrane, accompanied by severe tubular necrosis at 24 hours after administration of 0.03 mg of PsTX-T per animal, similar to the glomerular findings typical of severe hemolytic uremic syndrome. The early stage injury was accompanied by specific PsTX-T binding, massive complement C3b, and membrane attack complex deposition in glomeruli in the regions of injury and decreased glomerular expression of complement regulators. A pathogenic role for complement was confirmed by demonstrating that systemic complement inhibition reduced renal injury. The isolated nephrotoxic component, a 115-kd protein toxin (PsTX-115), was shown to cause identical renal pathology. The demonstration that PsTX-T and PsTX-115 were highly nephrotoxic acting via induction of complement activation suggests that inhibition of complement might be used to prevent acute renal damage following envenomation by P. semoni.

Depletion of High‐density Lipoprotein and Appearance of Triglyceride‐rich Low‐density Lipoprotein in a Japanese Patient With FIC1 Deficiency Manifesting Benign Recurrent Intrahepatic Cholestasis

Lipoprotein metabolism in FIC1 deficiency due to ATP8B1 mutations has never been studied sufficiently. This study was performed to investigate the detailed lipoprotein metabolism in benign recurrent intrahepatic cholestasis (BRIC) caused by FIC1 deficiency. Lipoprotein profile and major lipoprotein regulators such as lecithin:cholesterol acyltransferase (LCAT), hepatic triglyceride lipase (HTGL), lipoprotein lipase, and cholesteryl ester transfer protein in a Japanese patient with BRIC were serially examined during a bout of cholestasis. Liver expression of farnesoid X receptor (FXR), which suppresses high-density lipoprotein (HDL) generation, was also examined. Hypercholesterolemia and lipoprotein X accumulation were never observed throughout this study. When the cholestasis was severe, triglyceride-rich low-density lipoprotein (LDL) accounted for most of the plasma lipoproteins whereas HDL was hardly detectable. Concurrently, activities of all regulators were decreased, together with decreases of the serum parameter for liver protein synthesis. In particular, suppressions of LCAT and HTGL activities were severe and greatly contributed to the appearance of triglyceride-rich LDL. As the cholestasis improved, this LDL gradually transformed into normal LDL with the recoveries of LCAT and HTGL activities. The activities of all regulators for the last 1 to 2 months were normal but HDL remained depleted. His liver showed low FXR expression compared with control livers. The present study showed an appearance of triglyceride-rich LDL due to suppressions of LCAT and HTGL activities and a depletion of HDL that is not able to be explained by lipoprotein regulators or FXR in our patient.

Transcriptional Regulation of ATP2C1 Gene by Sp1 and YY1 and Reduced Function of its Promoter in Hailey–Hailey Disease Keratinocytes

Hailey-Hailey disease (HHD) is a blistering skin disease caused by malfunction of the Ca2+-dependent ATPase, ATP2C1. In this study, key regulatory regions necessary for the expression of the gene encoding human ATP2C1 were investigated. The transient reporter assay demonstrated that region +21/+57 was necessary for activation of the ATP2C1 promoter, and the electrophoretic mobility shift assay demonstrated that the region was recognized by the transcription factors, Sp1 and YY1. In accordance with this result, when Sp1 or YY1 was overexpressed in keratinocytes, an obvious increase in ATP2C1 promoter activity was observed, which was in contrast with the case where a mutant promoter lacking the binding sites for Sp1 and YY1 was used as the reporter. Ca2+-stimulation signal increased nuclear Sp1 proteins and ATP2C1 mRNA levels in normal keratinocytes. In contrast, both these increases were suppressed in keratinocytes from HHD patients. These results indicate that Sp1 and YY1 transactivate the human ATP2C1 promoter via cis-enhancing elements and that incomplete upregulation of ATP2C1 transcription contributes to the keratinocyte-specific pathogenesis of HHD. This is a report describing the regulation of the expression of ATP2C1.

Critical Roles of Threonine 187 Phosphorylation in Cellular Stress-induced Rapid and Transient Activation of Transforming Growth Factor-β-activated Kinase 1 (TAK1) in a Signaling Complex Containing TAK1-binding Protein TAB1 and TAB2

Transforming growth factor-beta-activated kinase 1 (TAK1) mitogen-activated protein kinase kinase kinase has been shown to be activated by cellular stresses including tumor necrosis factor-alpha (TNF-alpha). Here, we characterized the molecular mechanisms of cellular stress-induced TAK1 activation, focusing mainly on the phosphorylation of TAK1 at Thr-187 and Ser-192 in the activation loop. Thr-187 and Ser-192 are conserved among species from Caenorhabditis elegans to human, and their replacement with Ala resulted in inactivation of TAK1. Immunoblotting with a novel phospho-TAK1 antibody revealed that TNF-alpha significantly induced the phosphorylation of endogenous TAK1 at Thr-187, and subsequently the phosphorylated forms of TAK1 rapidly disappeared. Intermolecular autophosphorylation of Thr-187 was essential for TAK1 activation. RNA interference and overexpression experiments demonstrated that TAK1-binding protein TAB1 and TAB2 were involved in the phosphorylation of TAK1, but they regulated TAK1 phosphorylation differentially. Furthermore, SB203580 and p38alpha small interfering RNA enhanced TNF-alpha-induced Thr-187 phosphorylation as well as TAK1 kinase activity, indicating that the phosphorylation is affected by p38alpha/TAB1/TAB2-mediated feedback control of TAK1. These results indicate critical roles of Thr-187 phosphorylation in the stress-induced rapid and transient activation of TAK1 in a signaling complex containing TAB1 and TAB2.

Review of zonisamide development in Japan

Zonisamide is a benzisoxazole-based compound first synthesized in the early 1970s by the research laboratories of Dainippon Pharmaceutical Company in Osaka, Japan. Identified as an anticonvulsant during exploratory research, zonisamide has since been characterized as having broad-spectrum antiepilepsy and neuroprotective effects. Early clinical studies in Japan demonstrated that zonisamide has a long elimination half-life and is well tolerated; Phase II and III clinical trials established the drug’s efficacy and safety for the treatment of partial and generalized seizures. In 1989, zonisamide was approved and marketed in Japan under the trade name of Excegran ®. Data from postmarketing surveillance studies and clinical observations over 10 years of use have continued to support zonisamide’s efficacy and safety, identified its usefulness as monotherapy, and characterized its effectiveness for various seizure types and epilepsy syndromes.

Chicken leukemia inhibitory factor maintains chicken embryonic stem cells in the undifferentiated state.

Mouse embryonic stem (ES) cells can be maintained in an undifferentiated state in the presence of leukemia inhibitory factor (LIF), a member of the interleukin-6 cytokine family. In other mammals, this is not possible with LIF alone. Chicken ES-like cells (blastodermal cells) have only been cultured with mouse LIF because chicken LIF was not available. However the culture system is imperfect and chicken ES-like cells equivalent to mouse ES cells were not observed. In the present study, we cloned the cDNA-encoding chicken LIF using mRNA subtraction and RACE methodology. The chicken LIF cDNA encodes a protein with approximately 40% sequence identity to mouse LIF. It has 211 amino acids including a putative N-terminal signal peptide of 24 residues. Chicken blastodermal cells were cultured in the presence of bacterially expressed chicken LIF or mouse LIF. The expression of alkaline phosphatase and embryonal carcinoma cell monoclonal antibody-1 and stage-specific embryonic antigen-1 and the activation of STAT3 were examined, all of which are indices of the undifferentiated state. Exposure in the blastodermal cells to recombinant chicken LIF but not to mouse LIF maintained the expression of these various markers. After 9 days of incubation, the blastodermal cells formed cystic embryoid bodies in the presence of mouse LIF but not in the presence of recombinant chicken LIF. We conclude that chicken LIF is able to maintain chicken ES cell cultures in the undifferentiated state.

ACAT inhibitor F-1394 prevents intimal hyperplasia induced by balloon injury in rabbits

Acyl-CoA:cholesterol acyltransferase (ACAT) is thought to contribute significantly to lipid deposition in macrophages, which subsequently leads to the initiation and progression of atherosclerosis. The aim of the present study was to examine the influence of hypercholesterolemia on arterial hyperplasia induced by endothelial denudation and the direct effect of ACAT inhibition on lesion formation. Rabbits were fed either a cholesterol diet or a regular diet for 4 weeks, and then the left common carotid arteries were denuded of endothelium. After the operation, all rabbits were kept on the regular diet for 2;-6 weeks. Two weeks after the denudation, the degree of intimal thickening and the number of proliferating cells (which were immunohistologically identified to be smooth muscle cells) were similar in hypercholesterolemic and normolipidemic rabbits. After that, both parameters progressively increased in hypercholesterolemic rabbits but declined in normolipidemic rabbits. Macrophages were apparent in the lesions only in hypercholesterolemic rabbits. Next, the effect of the ACAT inhibitor, (1S,2S)-2-[3-(2,2-dimethylpropyl)-3-nonylureido] cyclohexane-1-yl 3-[(4R)-N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionate (F-1394), on neointimal formation in hypercholesterolemic rabbits was examined. Oral administration of F-1394 significantly reduced neointimal thickening and the extent of macrophages in lesions without affecting serum cholesterol levels. These results suggest that hypercholesterolemia causes macrophage-derived foam cell accumulation in lesions, and that the progression of lesions is accelerated by the presence of macrophages. Moreover, the study shows that F-1394 prevents neointimal formation even in the presence of hypercholesterolemia, indicating that F-1394 may be useful for treating restenosis after percutaneous translumenal coronary angioplasty in hyperlipidemic patients.

Changes in Serum Phenytoin Concentrations in Epileptic Patients Produced by Changing Phenytoin Preparation from Granular Form to a Novel 10% Powder.

Purpose: It is well known that there is a significant difference in the bioavailability of different preparations of phenytoin (PHT). A novel 10 % powder formulation of PHT (Aleviatino‐10 % powder), which was believed to have equivalent bioavailability to the tablet and granular formulations, was developed by Dainippon Pharmaceutical Co., LTD. in 1997. This lead us to switch 12 outpatients with epilepsy from the granular preparation of PHT (Aleviatino‐granules) to the novel 10 96 powder. Here, we report that changing the PHT formulation from the granular to the novel powder form produced a significant change in hioavailability. Methods: Subjects consisted of 8 men and 4 women with epilepsy; mean age, 32.7 years; range, 21–58 years; 2 generalized epilepsies and 10 localization‐related epilepsies recruited from the outpatient clinics. The dose of the granular form of PHT was 90‐390 mg/day (mean, 258.3 mg/day). Four patients received only PHT and the remaining patients received PHT and at least 1 other AED. The serum PHT concentrations were determined prior to and more than 2 weeks after changing the formulations. We used the same dose for each preparation, and the dose of any other anticonvulsant drug taken by the patients was not changed during the study. Results: The mean serum PHT level was significantly elevated from 9.66 to 19.51 pg/ml after switching the patients to the 10% powder formulation (p < 0.01). The mean ratio of serum PHT concentrations (S, pg/ml) to dose (D, mgikgiday), i.e. S/D ratio, was also increased significantly from 2.1 to 4.3 after switching preparations (p < 0.01). A decrease in the dose (mean, 85 %) was required in 6 patients. There was a significant positive correlation between extent of the elevation of serum PHT concentration after switching to the 10 % powder and serum PHT concentration before the switch (r = 0.86, p c 0.0003). Furthermore, the elevation of serum PHT levels in the patients receiving only PHT was significantly greater than that in the patients receiving 1 or more other anticonvulsants (p < 0.05). Cuncbsion: These results suggest that the 10% powder formulation of PHT (Aleviatino‐10% powder) has a significantly greater bioavailability than the granular form (Aleviatino‐granules). Therefore, one must be vigilant when switching patients from one formulation of PHT to another, particularly in patients receiving only PHT. In addition, upon switching, one should consider adjusting the dose to decrease the likelihood of adverse effects and interactions between PHT and other anticonvulsants.

Detection of a new compound heterozygote (del G 916/G1401A) for lipoprotein lipase deficiency and a comparative haplotype analysis of the mutant lipoprotein lipase gene from Japanese patients

A patient with early-onset chylomicronemia from a non-consanguineous family to be a compound heterozygote for two different mutations in the lipoprotein lipase (LPL) gene has been demonstrated. Reports on compound heterozygotes for LPL deficiency have been limited. The patient, a 2-month-old Japanese boy, was admitted to Urayasu Hospital because of hyperlipidemia. He showed eruptive exanthomas on his face and buttocks, but had no signs of pancreatitis or hepatosplenomegaly. The patient’s plasma triglyceride (TG) and total cholesterol (TC) concentrations were 14 183 and 763 mg/dl, respectively (Table 1). The apolipoprotein (apo) CII concentration was a predictable value for plasma TG levels from a previous study [1]. LPL activity, assayed as described elsewhere [2], and mass, determined with a sandwich enzyme-linked immunosorbent assay (ELISA) kit (Dai-nippon Pharmaceutical, Japan) [3], in the patient’s postheparin plasma were virtually undetectable. The father’s plasma lipid levels were within the normal range, whereas the mother exhibited moderate hypertriglyceridemia shortly after the delivery. The LPL activities of the parents were nearly normal, but their LPL masses were approximately half the normal value. Informed consent for molecular analysis was obtained from the parents. Nucleotide sequence analysis of the patient’s LPL gene showed two separate point mutations: a single guanosine deletion at nucleotide 916 (del G) in exon 5, leading to premature termination at codon 224 by a frameshift; and a G-to-A transition at nucleotide 1401 (G1401A) in exon 8, resulting in a substitution of tryptophan (TGG) at codon 382 by a stop codon (TGA). Southern blot hybridization was performed first, as described previously [4], but showed no major rearrangements (data not shown). The polymerase chain reaction (PCR) was then carried out as previously described [4]. PCR products were directly inserted into a plasmid vector pCRII (Invitrogen, USA), and the nucleotide sequence of subcloned plasmids were determined in both directions by dideoxy termination with an AmpliTaq cycle sequencing kit (Perkin-Elmer, USA) * Corresponding author. Tel.: +81-3-3588-1111; fax: +81-3-35827068. E-mail address: QFG00550@nifty.ne.jp (M. Okubo) 1 Present address: Department of Medicine, Urayasu Hospital, Juntendo University, Chiba 279, Japan.

The Clinical Effect of Sparfloxacin for the Treatment of Acute Respiratory Infection

Sparfloxacin is a new synthetic quinolone antimicrobial developed at the Research Laboratories of Dainippon Pharmaceutical Co, Ltd. To evaluate the efficacy and safety of sparfloxacin in acute pulmonary infection, we administered sparfloxacina(100mg) twice in a day to 30 patients who had signs and symptoms of acute pulmonary infectious diseases regardless of their underlying lung disease for 7 days. The results were as follows: 1) A total 30 patients were enrolled in the trial. Among them, 24 cases(80%) had underlying lung problems such as chronic obstructive pulmonary disease(36.4%), bronchiectasis(36.4%), bronchial asthma(3.3%), or lung cancer(3.3%). 2) In 26 cases(86.6%), we observed effective improvement, and 4 cases(13.4%) show mildly effective improvement of symptoms and signs of respiratory infection. 3) In 23 cases(73.4%), we observed bacteriological eradication in culture or decreased the number of bacteria by Gram stain which found dominantly in previous Gram stain. 4) The significant side effect was not noted. The above results suggested that sparfloxacin was effective as a first line therapy in patients with acute respiratory infection.

全自動ＥＬＩＳＡシステムによるゾニサミドおよびハロペリドールの血しょう中濃度測定

A fully automated enzyme immunoassay system, Omni (BIO-TEK Co.) (ELISA system), using Markit-M Excegran and Markit-M Haloperidol (Dainippon Pharmaceutical Co.) was evaluated to determine the concentrations of zonisamide (ZNS) and haloperidol (HP) in human plasma. At first, the within-run (ZNS: n=8, HP: n=10) and the between-run (4 days) precisions of ZNS and HP were examined.The coefficient of the variations in both the within-run and the between-run precisions of HP were below 5.0 and 7.0%, respectively. In contrast, the some values of ZNS were below 6.5 and 8.4%, respectively. A good correlation was observed between this ELISA system and HPLC (r=0.917), which was used to determine the plasma ZNS concentration. In the case of HP, a good correlation was seen between this ELISA system and the manual ELISA method (r=0.978).This method was thus used to monitor the serum levels in patients receiving ZNS or HP therapy. The relationship was observed between the daily dose (mg/kg) and the plasma concentration of the trough level for ZNS and HP, respectively (r=0.750 p<0.001, r=0.669 p<0.001). However, the ratio of the plasma concentration of ZNS and the daily dose increased significantly with aging.

5376639 Treatment of sarcoma with interleukin 1 alpha polypeptides : Yamada Masaak; Furutani Yasuj; Yamayoshi Michiko; Notake Mitsue; Yamagishi Junichi Kyoto, Japan Assigned to Dainippon Pharmaceutical Co Ltd

5376639 Treatment of sarcoma with interleukin 1 alpha polypeptides : Yamada Masaak; Furutani Yasuj; Yamayoshi Michiko; Notake Mitsue; Yamagishi Junichi Kyoto, Japan Assigned to Dainippon Pharmaceutical Co Ltd

5043271 DNA encoding Rabbit TNE, vector having said DNA inserted thereinto, host transformed with said vector, rabbit TNF polypeptide, and process for production thereof: Masaak Yamada, Yasuj Furutani, Nitsue Notake, Kyoto, Japan assigned to Dainippon Pharmaceutical Co Ltd

5043271 DNA encoding Rabbit TNE, vector having said DNA inserted thereinto, host transformed with said vector, rabbit TNF polypeptide, and process for production thereof: Masaak Yamada, Yasuj Furutani, Nitsue Notake, Kyoto, Japan assigned to Dainippon Pharmaceutical Co Ltd

Substitution of the 151st amino acid of human interleukin-1α converted it into a partial agonist or an antagonist: [formula omitted] Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Enoki 33–94, Suita/Osaka, 564 Japan

Substitution of the 151st amino acid of human interleukin-1α converted it into a partial agonist or an antagonist: [formula omitted] Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Enoki 33–94, Suita/Osaka, 564 Japan