Nippon Kayaku Research Articles

Survival improvement in patients (pts) with small cell lung cancer (SCLC): A historical comparison before and after amrubicin (AMR) approval in Japan.

e18105 Background: AMR is a totally synthetic anthracycline and a potent topoisomerase II inhibitor. Recent phase II trials demonstrated that AMR provided promising response rates. AMR was approved for the treatment of lung cancer in December 2002 in Japan. We retrospectively investigated the clinical outcome in pts with SCLC, comparing overall survival before and after AMR approval. Methods: The medical records of SCLC pts who received treatment at the National Cancer Center Hospital East between July 1992 and December 2007 were reviewed. A total of 712 pts received chemotherapy as an initial treatment. 110 pts received AMR. Among them, 107 pts received an initial chemotherapy after 2002. The 712 pts were divided into two groups: group A included pts received an initial chemotherapy between 1992 and 2001 (n=364), and group B included after 2002 (n=348). Results: Pts characteristics including age, gender, PS, and stage (limited or extensive) had no statistical difference among group A and B. Survival was not significantly different in pts with limited disease (LD) between group A and B; however, group B tended to have better survival in pts with extensive disease (ED) (p=0.069). Multivariate analyses in pts with ED demonstrated that group B had significantly longer survival (hazard ratio: 0.783, 95% confidence interval [CI]: 0.624-0.982). Conclusions: After approval of AMR, survival has been improved especially in pts with ED-SCLC. n Median survival time (months) 95% CI 2- year survival rate (%) 3-year survival rate (%) 5-year survival rate (%) Group A (1992-2001) 364 11.8 10.5-13.1 21 14 9 LD 176 19.4 17.2-21.6 35 24 16 ED 188 9.3 8.36-10.3 8 4 2 Group B (2002-2007) 348 13.9 12.7-15.2 23 16 10 LD 195 17.5 15.0-19.9 32 24 15 ED 153 10.2 8.52-11.8 9 5 3 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Nippon Kayaku

Monitoring of Urinary L-Type Fatty Acid-Binding Protein Predicts Histological Severity of Acute Kidney Injury

The present study aimed to evaluate whether levels of urinary L-type fatty acid-binding protein (L-FABP) could be used to monitor histological injury in acute kidney injury (AKI) induced by cis-platinum (CP) injection and ischemia reperfusion (IR). Different degrees of AKI severity were induced by several renal insults (CP dose and ischemia time) in human L-FABP transgenic mice. Renal histological injury scores increased with both CP dose and ischemic time. In CP-induced AKI, urinary L-FABP levels increased exponentially even in the lowest dose group as early as 2 hours, whereas blood urea nitrogen (BUN) levels increased at 48 hours. In IR-induced AKI, BUN levels increased only in the 30-minute ischemia group 24 hours after reperfusion; however, urinary L-FABP levels increased more than 100-fold, even in the 5-minute ischemia group after 1 hour. In both AKI models, urinary L-FABP levels showed a better correlation with final histological injury scores and glomerular filtration rates measured by fluorescein isothiocyanate-labeled inulin injection than with levels of BUN and urinary N-acetyl-D-glucosaminidase, especially at earlier time points. Receiver operating characteristic curve analysis demonstrated that urinary L-FABP was superior to other biomarkers for the detection of significant histological injuries and functional declines. In conclusion, urinary L-FABP levels are better suited to allow the accurate and earlier detection of both histological and functional insults in ischemic and nephrotoxin-induced AKI compared with conventional renal markers.

Cisplatin‐conjugated Gelpart: initial study in vitro

In Japan, Gelpart (Nippon Kayaku, Tokyo, Japan) is commercially available as an embolic agent made of gelatin for hepatocellular carcinoma. The object of this study was to develop cisplatin-conjugated Gelpart, confirm its bonding capability and confirm cisplatin-release from it in vitro. Gelpart (80 mg) were immersed in 50 mL of the cisplatin solution (0.3 mg/mL) at 38 degrees C for 1 hour to allow conjugation to cisplatin. Half of them were washed with double distilled water and centrifuged seven times to remove the uncombined cisplatin from Gelpart. Five mg of washed Gelpart and 5 mg unwashed Gelpart were freeze-dried and the platinum concentrations in these Gelpart were analyzed. In an in vitro release test, 30 mg of each cisplatin-conjugated Gelpart were placed in 10 mL of phosphate buffered salts (PBS) containing 0.01 wt.% Tween 80 and the system was shaken reciprocally at 72 strokes/min at 38 degrees C. At different time intervals (1, 3, 6, 12 and 24 hours), 5 mL of the supernatant was pipetted out and immediately after that the same volume of PBS was added. The platinum concentration of the solutions sampled was measured and the release rate from cisplatin-conjugated Gelpart was calculated. The platinum concentrations (microg/g) of unwashed Gelpart and washed Gelpart were, respectively, 9563.5 +/- 101.1 and 6396.5 +/- 14.8. The release rates (%) from unwashed Gelpart and from washed Gelpart were, respectively, 43.1, 56.3, 56.5, 58.5, 60.9 and 5.8, 6.7, 8.5, 11.0, 12.0. Gelpart had a bonding capability to cisplatin and an ability of sustained release from it. Cisplatin-conjugated Gelpart might become a simple embolic agent with drug delivery systems.

Efficacy of deoxyspergualine for antibody-mediated rejection and proteinuria after kidney transplantation

A patient showing antibody-mediated rejection (AMR) with severe vasculitis, and massive proteinuria after kidney transplantation was treated with deoxyspergualine (DSG, Spanidin((R)), Nippon Kayaku). DSG showed marked efficacy for this patient's symptoms. We report on a patient for whom DSG was effective against AMR after renal transplantation.

A phase I dose-escalation study of NK012

2538 Background: NK012 is a micelle-forming macromolecular prodrug of EHC (7-ethyl-10-hydroxycamptothecin), also known as SN-38 the active metabolite of irinotecan, bound to an amphiphilic block copolymer. NK012 accumulates as nanoparticles in tumors where it gradually releases EHC by chemical hydrolysis under neutral conditions. Accumulation and sustained release of EHC could result in increased efficacy of the drug. Methods: Patients with previously treated advanced solid tumors and acceptable organ function were administered NK012 as a 30-minute infusion every 21 days without premedications. UGT1A1 genotype screening was performed prior to enrollment, and UGT1A1*28/*28 homozygotes were treated at a reduced dose level with the potential for dose escalation based on toxicities. At least three patients were treated and evaluated for dose-limiting toxicities at each dose level prior to dose escalation. Pharmacokinetic samples were obtained during cycles 1 and 2 of treatment. Results: Eighteen patients have received 54 cycles of treatment across 5 dose levels ranging from 9 - 28 mg/m2. Four homozygous patients have also been enrolled at dose levels ranging from 4.5 - 10.5 mg/m2 and received a total of 16 cycles. Three of the 22 patients previously received irinotecan. No dose-limiting toxicities were reported at dose levels 1–4. One patient at dose level 5 (28 mg/m2) experienced uncomplicated grade 4 neutropenia lasting > 7 days, which was a dose-limiting toxicity per protocol. As a result, this level has been expanded to a total of 6 patients. Hematologic toxicities have consisted of transient grade 3 neutropenia (1 pt), grade 4 neutropenia (4 pts), and grade 3 thrombocytopenia (1 pt) with 3 patients requiring dose delays due to neutropenia. Nonhematologic toxicities have been minimal. Two partial responses have been reported in patients with previously treated breast cancer and small cell lung cancer, respectively. Ten patients have experienced stable disease as best response (range 3–10 cycles), four patients experienced disease progression, two were inevaluable, and 4 are too early to evaluate. Conclusions: NK012 is well tolerated and has demonstrated antitumor activity in patients with refractory tumors. Phase II trials are warranted in patients with tumor types demonstrating sensitivity to irinotecan. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Nippon Kayaku Co, Ltd Nippon Kayaku

Randomized phase II study comparing docetaxel plus cisplatin, docetaxel plus carboplatin, and paclitaxel plus carboplatin in patients with advanced or recurrent endometrial carcinoma: Japanese Gynecologic Oncology Group trial (JGOG2041)

16526 Background: The purpose of this study is to assess the efficacy and safety of treatment with taxane plus platinum in combination therapies for advanced or recurrent endometrial carcinoma. Methods: The study planned to administer docetaxel (70 mg/m2) plus cisplatin (60 mg/m2) (DP), docetaxel (60 mg/m2) plus carboplatin (AUC 6) (DC), or paclitaxel (180 mg/m2) plus carboplatin (AUC 6) (TC) every 3 weeks until disease progression or adverse effects prohibited further therapy. Eligibility criteria of this study allowed for entry of patients with measurable disease derived from histologically confirmed stage III/IV or recurrent endometrial carcinoma and/or patients having had a treatment-free interval following cytotoxic chemotherapy, radiotherapy, or hormonal therapy of at least 6 months, 4 weeks or 2 weeks, respectively. Among these regimens the study compared the tumor response rate as the primary endpoint as well as toxicity. An independent review committee assessed the tumor response for each patient according to RECIST. Results: Ninety patients were enrolled. Of the enrolled patients, 88 were eligible and consequently 29, 29, and 30 patients were randomly assigned to DP, DC, and TC, respectively. Regarding the frequency of the main toxicities, the following were observed: grade 3 and 4 neutropenia in 83.3, 90.0, and 76.6%; febrile neutropenia in 10.0, 6.7, and 3.3%; thrombocytopenia in 6.7, 10.0, and 10.0%; diarrhea in 13.3, 3.3, and 0%, respectively; and grade 2 neurotoxicity in 13.3% of TC group. These toxicity profiles were not significantly different; however, diarrhea and neurotoxicity tended to be more frequent in DP and TC, respectively. Tumor response rates were 51.7% (0 CR, 15 PR; 95% C.I.; 32.5–70.6), 48.3% (4 CR, 10 PR; 29.4–67.5), and 60.0% (2 CR, 16 PR; 40.6–77.3) in DP, DC, and TC, respectively (P = 0.65). Conclusions: Toxicity of taxane plus platinum combination therapies was confirmed to be tolerable. The efficacy was similar in each arm and their potential efficacy will allow us to choose an experimental arm for a phase III trial to confirm a survival benefit of taxane plus platinum for endometrial carcinoma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb, Kyowa Hakko Kogyo, Nippon Kayaku, Pfizer Japan, sanofi-aventis

Randomized phase III trial of conventional paclitaxel and carboplatin (c-TC) versus dose dense weekly paclitaxel and carboplatin (dd-TC) in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: Japanese Gynecologic Oncology

5506 Background: Tri-weekly administration with paclitaxel and carboplatin (c-TC) is considered the standard of care for treatment of ovarian carcinoma. We compared the c-TC with dose dense weekly administration with TC (dd-TC) as first-line chemotherapy for stage II-IV epithelial ovarian, fallopian tube or primary peritoneal cancer. Methods: We randomly assigned patients to receive carboplatin to an area under the plasma concentration-time curve of 6 with either paclitaxel at 180 mg/m2 on day 1 or paclitaxel at 80 mg/m2 on days 1, 8, and 15. The treatments were repeated every 3 weeks for six cycles; in responding patients, additional three cycles were administered. Primary endpoint was progression-free survival (PFS) to be compared by log-rank test. Assuming 300 eligible patients in each arm, the study had 0.8 power to detect 5 months increase in median PFS at 0.05 two-sided alpha. Results: Of 637 patients who underwent randomization, 631 were eligible. After median follow-up of 29 months, median duration of PFS in the c-TC group and dd-TC group was 17.1 and 27.9 months, respectively (P=0.0014 by the log-rank test), and overall survival at 2 years was 77.7% and 83.6%, respectively (P=0.05). Among 282 patients with measurable disease, objective response rates were 53.3% and 55.8% in the c-TC and dd-TC groups respectively (P=0.91). Grade 3 and 4 anemia was reported more frequently in the dd-TC group, and other toxicities were similar in both groups. Conclusions: The dd-TC improves PFS as compared with c-TC in patients with advanced epithelial ovarian cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Aska, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Kyowa Hakko Kogyo, Mochida, Nippon Kayaku, Pfizer Oncology, sanofi-aventis, Yakult Bristol-Myers Squibb, Yakult

Which factors will make the duration short between last palliative chemotherapy and death?

20575 Background: There are no standard criteria for physician to quit palliative chemotherapy (PC) in order to switch into best supportive care only. While vignettes study (C.G.Koedoot et al, 2004) previously provided trends of preference for PC from the point of physicians and patients (pts), there is no report in clinical practice to identify the specific factors which affects the indication of PC in near-the- end-of-life (NEL) setting. Methods: We retrospectively analyzed 383 deceased pts who received PC in our division from 2002 to 2006. There are 244 pts whose date of last PC and death were available. Univariate and multivariate analysis were performed to examine the factors affecting the duration between last PC and death. Results: The variety and numbers of the cancer were Breast/Gynecological/unknown primary/others and 133/77/24/20, respectively. Median duration between last PC and death was 100 days (range; 5 to 1206). Thirty two pts (12.6 %) and 82 pts (32.3 %) died within 30 and 60 days after PC, respectively. Twenty one pts (8.1 %) were symptomatic when PC started. Two hundred four pts (83.6 %) were referred to hospice. The factors to have short duration between last PC and death by univariate analysis were male sex, young age, attending doctor, good ECOG performance status (PS), expected high response rate (RR), cancer type, symptomatic pts and previous informed consent (IC) without introduction to hospice. The strong factor which affected the duration between last PC and death the most was the IC without introducing about hospice (P<0.0001). Other factors such as young age, good PS, good RR and symptomatic pts are also significantly correlated to short duration between PC and death. Conclusions: Young pts who were symptomatic, in good PS and also expected to achieve good response by chemotherapy tend to choose PC instead of visiting hospice till the very NEL stage. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers, Kyowa Hakko, Nippon Kayaku, Pfizer, sanofi-aventis

Poster 031: Evaluation of the Type of Cell Death Induced by Mitomycin C in Human Oral Squamous Cell Carcinoma Cell Lines

Poster 031: Evaluation of the Type of Cell Death Induced by Mitomycin C in Human Oral Squamous Cell Carcinoma Cell Lines

Binding of ADAM28 to P-selectin Glycoprotein Ligand-1 Enhances P-selectin-mediated Leukocyte Adhesion to Endothelial Cells

ADAMs (a disintegrin and metalloproteinases) are a recently discovered gene family of multifunctional proteins with the disintegrin-like and metalloproteinase domains. To analyze the biological functions of ADAM28, we screened binding molecules to secreted-type ADAM28 (ADAM28s) by the yeast two-hybrid system and identified P-selectin glycoprotein ligand-1 (PSGL-1). Binding between the disintegrin-like domain of ADAM28s and the extracellular portion of PSGL-1 was determined by yeast two-hybrid assays, binding assays of the domain-specific recombinant ADAM28s species using PSGL-1 stable transfectants and leukocyte cell lines expressing native PSGL-1 (HL-60 cells and Jurkat cells), and co-immunolocalization and co-immunoprecipitation of the molecules in these cells. Incubation of HL-60 cells with recombinant ADAM28s enhanced the binding to P-selectin-coated wells and P-selectin-expressing endothelial cells. In addition, intravenous injection of ADAM28s-treated HL-60 cells increased their accumulation in the pulmonary microcirculation and alveolar spaces in a mouse model of endotoxin-induced inflammation. These data suggest a novel function that ADAM28s promotes PSGL-1/P-selectin-mediated leukocyte rolling adhesion to endothelial cells and subsequent infiltration into tissue spaces through interaction with PSGL-1 on leukocytes under inflammatory conditions.

15-Deoxyspergualin Primarily Targets the Trafficking of Apicoplast Proteins in Plasmodium falciparum

15-Deoxyspergualin, an immunosuppressant with tumoricidal and antimalarial properties, has been implicated in the inhibition of a diverse array of cellular processes including polyamine synthesis and protein synthesis. Endeavoring to identify the mechanism of antimalarial action of this molecule, we examined its effect on Plasmodium falciparum protein synthesis, polyamine biosynthesis, and transport. 15-Deoxyspergualin stalled protein synthesis in P. falciparum through Hsp70 sequestration and subsequent phosphorylation of the eukaryotic initiation factor eIF2alpha. However, protein synthesis inhibition as well as polyamine depletion were invoked only by high micromolar concentrations of 15-deoxyspergualin, in contrast to the submicromolar concentrations sufficient to inhibit parasite growth. Further investigations demonstrated that 15-deoxyspergualin in the malaria parasite primarily targets the hitherto underexplored process of trafficking of nucleus-encoded proteins to the apicoplast. Our finding that 15-deoxyspergualin kills the malaria parasite by interfering with targeting of nucleus-encoded proteins to the apicoplast not only exposes a chink in the armor of the malaria parasite, but also reveals new realms in our endeavors to study this intriguing biological process.

Development of a novel lepidopteran insect control agent, chromafenozide

Chromafenozide is a novel dibenzoylhydrazine insecticide that was developed in the collaborative research project between Nippon Kayaku Co., Ltd., and Sankyo Co., Ltd., and is categorized to be an insect hormone-ecdysone agonist. Two formulations of chromafenozide and one combination formulation with silafluofen are available in Japan under the trade names of MATRIC® FL, MATRIC® DL and MATRICJOKER® DL, respectively. Chromafenozide is found to be significantly potent against various lepidopterous insects, but at the same time almost non-toxic to non-lepidopterous species, including pollinators, predators and parasitoids. As chromafenozide has a low toxicity profile in mammals and non-target organisms described above, and has minimum impact on the environment, it would be an ideal agent for integrated pest management (IPM). © Pesticide Science Society of Japan

Development of a novel Lepidopteran insect control agent, chromafenozide

Chromafenozide is a novel dibenzoylhydrazine insecticide that was developed in the collaborative research project between Nippon Kayaku Co., Ltd., and Sankyo Co., Ltd., and is categorized to be an insect hormone-ecdysone agonist. Two formulations of chromafenozide and one combination formulation with silafluofen are available in Japan under the trade names of MATRIC® FL, MATRIC® DL and MATRICJOKER® DL, respectively. Chromafenozide is found to be significantly potent against various lepidopterous insects, but at the same time almost non-toxic to non-lepidopterous species, including pollinators, predators and parasitoids. As chromafenozide has a low toxicity profile in mammals and non-target organisms described above, and has minimum impact on the environment, it would be an ideal agent for integrated pest management (IPM). © Pesticide Science Society of Japan

Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (CTX), sterol 27-hydroxylase (CYP27A1) deficiency, is associated with markedly reduced chenodeoxycholic acid (CDCA), the most powerful activating ligand for farnesoid X receptor (FXR). We investigated the effects of reduced CDCA on FXR target genes in humans. Liver specimens from an untreated CTX patient and 10 control subjects were studied. In the patient, hepatic CDCA concentration was markedly reduced but the bile alcohol level exceeded CDCA levels in control subjects (73.5 vs. 37.8 +/- 6.2 nmol/g liver). Cholesterol 7alpha-hydroxylase (CYP7A1) and Na+/taurocholate-cotransporting polypeptide (NTCP) were upregulated 84- and 8-fold, respectively. However, small heterodimer partner (SHP) and bile salt export pump were normally expressed. Marked CYP7A1 induction with normal SHP expression was not explained by the regulation of liver X receptor alpha (LXRalpha) or pregnane X receptor. However, another nuclear receptor, hepatocyte nuclear factor 4alpha (HNF4alpha), was induced 2.9-fold in CTX, which was associated with enhanced mRNA levels of HNF4alpha target genes, CYP7A1, 7alpha-hydroxy-4-cholesten-3-one 12alpha-hydroxylase, CYP27A1, and NTCP. In conclusion, the coordinate regulation of FXR target genes was lost in CTX. The mechanism of the disruption may be explained by a normally stimulated FXR pathway attributable to markedly increased bile alcohols with activation of HNF4alpha caused by reduced bile acids in CTX liver.

Vinblastine [Exal; Nippon Kayaku] for injection has been approved for an additional indication in Japan.

Vinblastine [Exal; Nippon Kayaku] for injection has been approved for an additional indication in Japan.

The Case Study on the Costing System of Nippon Kayaku Co., Ltd : Final Report of Internship Program 2003 JCAA

The Case Study on the Costing System of Nippon Kayaku Co., Ltd : Final Report of Internship Program 2003 JCAA

KMPR Photoresist Process Optimization Using Factorial Experimental Design

MicroChem Corp. and Nippon Kayaku Co., Ltd. have jointly developed a new, photoimageable coating composition for use in fabricating a wide variety of micro-electromechanical systems (MEMS) and optical MEMS. This chemically amplified thick-film photoresist, known as KMPR, has many of the same high-aspect ratio photo imaging properties as solvent developable SU-8, but can be developed in a conventional aqueous alkaline developer (TMAH) and readily stripped from the wafer.Single-factor experimental methods rarely find the optimum performance of a photoimageable coating efficiently and often fail to detect the interactions so common in complicated photochemical systems. By combining the settings of several factors simultaneously in an array (experimental design), it is possible to separate out the main effects and their interactions.1This paper presents the optimization of KMPR for contact alignment and near diffraction-limited, thick film reduction stepper applications. A Sequence of Taguchi style, half-factorial experimental designs was used to evaluate the process parameters for a 5 and 50 Mm thick film exposed on a contact aligner followed by a third half-factorial design for a 10 Mm thick film of KMPR photoresist exposed on a 365 nm, 0.40 N.A. stepper. Independent factors, such as: soft bake time, focus, exposure dose, initiator activation time (post-exposure bake time), developer time and delay time were evaluated

Reactive dyes containing a 4- m-carboxypyridinium-1,3,5-triazine-2-oxide reactive group: exhaust dyeing of cotton under alkaline and neutral fixation conditions

Two sulphonated reactive dyes, each carrying a 4- m-carboxypyridinium-1,3,5-triazine-2-oxide (triazinyl betaine) reactive group, were applied to cotton under both alkaline and neutral exhaust dyeing conditions and the dyeings compared to those of related chlorotriazinyl and β-sulphatoethylsulphonyl based products. The novel reactive dyes displayed good colour yields under alkaline fixation conditions, but unexpectedly performed very poorly under neutral dyeing conditions. The latter result runs counter to the dyeing performance of commercially available dyes of closely related structure ( Kayacelon React; Nippon Kayaku). The exceptionally poor neutral dyeing behaviour is believed to be due to low substantivity at elevated temperature, a reactive group of low selectivity in acid medium at high temperature, and in part, to an acid labile dye–fibre bond.

The Development of Environmental Consciousness with Regard to the Use of Dyes and Pharmaceuticals in the Paper Pulp Industry

Although environmental problems have been a major concern for a number of years, it is only comparativelyrecently that many companies have deemed it a matter of course to make an appropriate responseto environmental problems.Since its foundation in 1916, Nippon Kayaku has enthusiastically promoted such causes throughoutits 80-year history, using as its basic philosophy the following dual concepts. The company believes increating products that will benefit mankind and contribute to an improvement in global living standards, paying particular attention to the effect on health. Secondly, the company promises to respectthe environment and to guarantee the quality as well as the safety of its products.The paper industry was particularly prompt in dealing with environmental issues. There has beena considerable expansion in the use of fluorescent whiteners as well as colorful dyestuffs in general. NipponKayaku has been able to supply such dyestuffs to meet the expectations of the paper industry andhas introduced a new recyclable series of dyestuffs with excellent decoloration properties. Additionally, a new series of liquid fluorescent whiteners requiring only water as their solvent has been put on themarket. It is also necessary to speak of the positive effect that removing the luminosity from bleached paper by means of fluorescence-removing agents has on the environment.

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