Influence of Hydrocarbon Moiety of DMMP on Flame Propagation in Lean Mixtures.

Phosphorus-containing compounds (PCCs) have been found to be significantly more effective than CF3Br for reducing burning velocity when added to stoichiometric hydrocarbon-air flames. However, when added to lean flames, DMMP (dimethylmethylphosphonate) is predicted to increase the burning velocity. The addition of DMMP to lean mixtures apparently increases the equivalence ratio (fuel/oxidizer) and the combustion temperature, as a result of hydrocarbon content of DMMP molecule. Premixed flames studies with added DMMP, OP(OH)3, and CF3Br are used to understand the different behavior with varying equivalence ratio and agent loading. Decrease of the equivalence ratio leads to the decrease of inhibition effectiveness of PCCs relative to bromine-containing compounds. For very lean mixtures CF3Br becomes more effective inhibitor than PCCs. Calculations of laminar burning velocities for pure DMMP/air mixtures predict the maximum burning velocity of 10.5 cm/s at 4.04 % of DMMP in air and at an initial temperature of 400 K. Adiabatic combustion temperature is 2155 K at these conditions.

Quality-of-life outcomes from a randomized phase III trial of dose-dense weekly paclitaxel and carboplatin compared with conventional paclitaxel and carboplatin as a first-line treatment for stage II-IV ovarian cancer: Japanese Gynecologic Oncology Group Trial (JGOG3016).

BACKGROUND: Dose-dense weekly paclitaxel (Taxol) and carboplatin (dd-TC) improved survival compared with conventional tri-weekly paclitaxel and carboplatin (c-TC) as a first-line chemotherapy for newly diagnosed stage II-IV ovarian cancer in the Japanese Gynecologic Oncology Group 3016 trial. We report the quality-of-life (QoL) results from this trial. PATIENTS AND METHODS: A total of 637 patients were randomly assigned to receive c-TC or dd-TC (c-TC, n = 319; dd-TC, n = 312) and were asked to complete a QoL assessment at baseline, just after the third and sixth chemotherapy cycles, and at 12 months after randomization. QoL was assessed using Functional Assessment of Cancer Therapy (FACT)-general (FACT-G), FACT-taxane subscale (FACT-T), and FACT-ovary subscale (FACT-Ov). The overall QoL and that according to each subscale were analyzed using mixed-effects models adjusted for treatment and time. RESULTS: Baseline QoL assessment was completed by 204 out of 319 (63.9%) and 200 out of 312 (64.1%) patients in the c-TC and dd-TC groups, respectively. In these groups, the compliance rates with regard to QoL assessment were 74.5% and 73.0%, respectively, after three chemotherapy cycles; 86.8% and 86.9%, respectively, after six chemotherapy cycles; and 74.2% and 71.6%, respectively, at 12 months after randomization. The overall QoL did not differ significantly between the two treatment groups up to 12 months after randomization (P = 0.46). However, QoL according to the FACT-T subscale was significantly lower in the dd-TC group than in the c-TC group (P = 0.02). CONCLUSION: dd-TC does not decrease overall QoL compared with c-TC.

Randomized trial of preoperative docetaxel with or without capecitabine after 4 cycles of 5-fluorouracil­ epirubicin­cyclophosphamide (FEC) in early-stage breast cancer: exploratory analyses identify Ki67 as a predictive biomarker for response to neoadjuvant chemotherapy.

This randomized, multicenter study compared the efficacy of docetaxel with or without capecitabine following fluorouracil/epirubicin/cyclophosphamide (FEC) therapy in operable breast cancer and investigated the role of Ki67 as a predictive biomarker. Patients were randomized to 4 cycles of docetaxel/capecitabine (docetaxel: 75 mg/m2 on day 1; capecitabine: 1,650 mg/m2 on days 1­14 every 3 weeks) or docetaxel alone (75 mg/m2 on day 1 every 3 weeks) after completion of 4 cycles of FEC (5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 every 3 weeks). The primary endpoint was the pathological complete response (pCR) rate. Predictive factor analysis was conducted using clinicopathological markers, including hormone receptors and Ki67 labeling index (Ki67LI). A total of 477 patients were randomized; the overall response in the docetaxel/capecitabine and docetaxel groups was 88.3 and 87.4 %, respectively. There were no significant differences in the pCR rate (docetaxel/capecitabine: 23 %; docetaxel: 24 %; p = 0.748), disease-free survival, or overall survival. However, patients with mid-range Ki67LI (10­20 %) showed a trend towards improved pCR rate with docetaxel/capecitabine compared to docetaxel alone. Furthermore, multivariate logistic regression analysis showed pre-treatment Ki67LI (odds ratio 1.031; 95 % CI 1.014­1.048; p = 0.0004) to be a significant predictor of pCR in this neoadjuvant treatment setting. Docetaxel/capecitabine (after 4 cycles of FEC) did not generate significant improvement in pCR compared to docetaxel alone. However, exploratory analyses suggested that assessment of pre-treatment Ki67LI may be a useful tool in the identification of responders to preoperative docetaxel/capecitabine in early-stage breast cancer.

Ovulation compensatory function after unilateral ovariectomy in dogs.

As a step towards elucidation of the timing and mechanism of the determination of the number of ovulated ova in dogs, we excised one ovary 2, 5 and 8 days after the beginning of vulval bleeding and examined whether the lost ovulation function, assessed by estimating the number of ovulated oocytes, would be compensated for by the remaining ovary. The number of ovulated ova was maintained by the remaining ovary in the group that underwent unilateral ovariectomy 2 days after the beginning of vulval bleeding. However, in the groups ovariectomized 5 or 8 days after the beginning of vulval bleeding, no compensation for the number of ova that would have been ovulated from the lost ovary was observed; ova were ovulated only from the follicles 3 mm or greater in diameter observed in the remaining ovary at unilateral ovariectomy. Thus, in dogs, the number of ovulated ova is considered to be determined within 5 days after the beginning of vulval bleeding.

Enhanced removal of sodium salts supported by in-situ catalyst synthesis in a supercritical water oxidation process.

For practical applications of supercritical water oxidation to wastewater treatment, the deposition of inorganic salts in supercritical phase must be controlled to prevent a reactor from clogging. This study investigated enhanced removal of sodium salts with titanium particles, serving as a salt trapper and a catalyst precursor, and sodium recovery by sub-critical water. When Na(2)CO(3) was tested as a model salt, sodium removal efficiency was higher than theoretically maximum efficiency defined by Na(2)CO(3) solubility. The enhanced sodium removal resulted from in-situ synthesis of sodium titanate, which could catalyse acetic acid oxidation. The kinetics of sodium removal was described well by a diffusion mass-transfer model combined with a power law-type rate model of sodium titanate synthesis. Titanium particles showed positive effect on sodium removal in the case of NaOH, Na(2)SO(4) and Na(3)PO(4). However, they had negligible effect for NaCl and negative effect for Na(2)CrO(4), respectively. More than 99% of trapped sodium was recovered by sub-critical water except for Na(2)CrO(4). In contrast, sodium recovery efficiency remained less than 50% in the case of Na(2)CrO(4). Reused titanium particles showed the same performance for enhanced sodium removal. Enhanced salt removal supported by in-situ catalyst synthesis has great potential to enable both salt removal control and catalytic oxidation.

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

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. PATIENTS AND METHODS: Patients with measurable disease derived from histologically confirmed stage III/IV or recurrent endometrial carcinoma were randomly assigned to receive docetaxel plus cisplatin (DP), docetaxel plus carboplatin (DC), or paclitaxel plus carboplatin (TC) every 3 weeks until disease progression or adverse events prohibited further therapy. Among these regimens, the study evaluated the tumor response rate as the primary end point as well as toxicity. RESULTS: Ninety patients were enrolled. Of them, 88 were eligible and consequently 29, 29, and 30 patients were randomly assigned to DP, DC, and TC, respectively. Tumor response rates were 51.7%, 48.3%, and 60.0% in DP, DC, and TC, respectively (P = 0.65). The following toxic effects were observed: grade 3/4 neutropenia in 83.3%, 90.0%, and 76.6%; febrile neutropenia in 10.0%, 6.7%, and 3.3%; grade 3/4 thrombocytopenia in 6.7%, 10.0%, and 10.0%; grade 3/4 diarrhea in 13.3%, 3.3%, and 0%, respectively; and grade 3 neurotoxicity in 10.0% of TC. These toxicity profiles were not significantly different. CONCLUSION: The taxane plus platinum combination therapies could be candidates in further phase III trials for endometrial carcinoma.

Prolonged duration of fertility of dog ova.

The fertile period for natural mating in dogs extends from before ovulation until day 5 post ovulation (PO) and involves a delay in oocyte maturation until 2-3 days PO and viability of secondary oocytes for 48-60 h or more. Spermatozoa do not enter the uterus after vaginal insemination in late oestrus. Cervical closure appears to occur on average 5 days PO, but conception may occur following intrauterine artificial insemination (IUAI) up to 8 days PO. Therefore, the present study was conducted to clarify the duration of fertility of canine ova. Using IUAI at 6, 7, 8 and 9 days PO (n = 5 bitches each) conception rates were 100%, 71.4%, 37.5% and 0%, respectively, with an average litter resorption rate of 30.8%, and with mean litter sizes and times to delivery PO being 4.3 +/- 1.6 and 64.3 +/- 0.3 days, 4.0 +/- 1.4 and 66.3 +/- 0.4 days, and 2.5 and 68 days for IUAI at 6, 7 and 8 days, respectively. The high pregnancy rates with IUAI at 6 and 7 days PO confirm that many canine oocytes are fertile at 4-5 days after maturation. The high rate of resorption was presumably because of aging of ova or asynchrony between embryonic development and the intrauterine environment.

Accurate dose assessment system for an exposed person utilising radiation transport calculation codes in emergency response to a radiological accident.

A system has been developed to assess radiation dose distribution inside the body of exposed persons in a radiological accident by utilising radiation transport calculation codes-MCNP and MCNPX. The system consists mainly of two parts, pre-processor and post-processor of the radiation transport calculation. Programs for the pre-processor are used to set up a 'problem-dependent' input file, which defines the accident condition and dosimetric quantities to be estimated. The program developed for the post-processor part can effectively indicate dose information based upon the output file of the code. All of the programs in the dosimetry system can be executed with a generally used personal computer and accurately give the dose profile to an exposed person in a radiological accident without complicated procedures. An experiment using a physical phantom was carried out to verify the availability of the dosimetry system with the developed programs in a gamma ray irradiation field.

Application of the Self- Assembling Peptide P11-4 for Prevention of Acidic Erosion.

The aim of this study was to use ultrasonography to evaluate the effect of the self-assembling peptide P11-4 on acid erosion prevention. Curodont Repair (CR), which includes peptide P11-4, was used. Rectangular prisms of bovine enamel (4×1×1 mm) were immersed in pure orange juice for a period of 5 minutes six times per day for 28 days. These samples were divided into four groups of six specimens each and treated differently for an additional period of 28 days: 1) baseline group specimens were stored in artificial saliva; 2) CR group specimens were exposed to curodont without acid challenge; 3) NCRA (no curodont+acid challenge) specimens were treated with orange juice without curodont exposure; and 4) CRA (CR+acid challenge) specimens were treated with curodont before treatment with orange juice. The propagation time of longitudinal ultrasonic velocity (UV) was measured. Ultrastructural observation of each tested enamel surface was carried out using field-emission scanning electron microscopy (SEM). The UV data were analyzed using two-way analysis of variance with time and treatment as confounding factors. Post hoc pairwise tests among groups were performed using the Tukey honestly significant difference test. The average UV in intact bovine enamel for the baseline group ranged from 4,483 to 4,549 m/s and did not vary significantly within the test period. The average ultrasonic velocity (UV) in all samples decreased after the initial erosion. The UV in NCRA decreased further over time. Increased UVs were found for CR and CRA. For CR and CRA, there was no significant difference in UV at the end of the experiment from the initial value before erosion. In the results of SEM observation, the CR and CRA groups had similar morphologic features in that etching patterns were not clearly due to precipitation between the enamel rods. From the results of this in vitro study, it might be concluded that applying enamel matrix derivatives and self-assembling peptides on erosive lesions can improve remineralization.

Isolation and characterization of a colonic autoantigen specifically recognized by colon tissue-bound immunoglobulin G from idiopathic ulcerative colitis.

Patients with idiopathic ulcerative colitis (UC) have a colonbound antibody (CCA-IgG) that reacts with colon tissue extracts. We have partially characterized a colonic protein that is specifically recognized by CCA-IgG. CCA-IgG was eluted from operative colon specimens from 10 patients with UC. A colon tissue-bound IgG was similarly eluted from six patients with Crohn's colitis, two with ischemic colitis, and one with diverticulitis. Purified serum IgG from patients with Crohn's disease, from normal subjects and a patient with myeloma were also used as additional controls. For detection of antigen(s), tissue extracts were prepared from 26 specimens of colon (UC, 12; Crohn's disease, 6; normal, 4; other controls, 4), 8 specimens of human normal stomach, duodenum, ileum, and liver (2 each). Tissue extracts were also prepared from rats and mice, including germ-free rat colons and rat's fetal colons. Immunorecognition of CCA-IgG to the tissue extracts was examined by affinity-column chromatography and by transblot analysis. Tissue-extracted proteins were electrophoresed in SDS-polyacrylamide gel, transferred to nitrocellulose sheet, and probed with iodinated CCA-IgG, colonic IgG from other inflammatory bowel disease patients, UC serum IgG, and control serum IgG. Although many proteins were present in colon tissue extracts, 9 of 10 CCA-IgG consistently recognized a protein of 40 kD. None of the nine IgG preparations from colon specimens of patients with Crohn's colitis and other colonic inflammatory diseases reacted with the 40-kD protein. Five of six symptomatic UC serum IgG and none of eight control serum IgG reacted with the 40-kD protein. The 40-kD protein was present in all colon specimens and it appeared to be organ specific. It was absent in mouse and rat tissues, including colon. The 40-kD protein is not actin and nor a part of the Ig molecule. These results suggest that the 40-kD protein is a colonic "autoantigen" that may initiate a specific IgG antibody response in UC.

Numerical system utilising a Monte Carlo calculation method for accurate dose assessment in radiation accidents.

A system utilising radiation transport codes has been developed to derive accurate dose distributions in a human body for radiological accidents. A suitable model is quite essential for a numerical analysis. Therefore, two tools were developed to setup a 'problem-dependent' input file, defining a radiation source and an exposed person to simulate the radiation transport in an accident with the Monte Carlo calculation codes-MCNP and MCNPX. Necessary resources are defined by a dialogue method with a generally used personal computer for both the tools. The tools prepare human body and source models described in the input file format of the employed Monte Carlo codes. The tools were validated for dose assessment in comparison with a past criticality accident and a hypothesized exposure.

Photoelectrolysis using chlorophyll electrodes.

By the conversion of sunlight to chemical energy, photoelectrolysis was carried out using two different chlorophyll-redox compound lining electrodes. These electrodes were prepared by covering platinum plates with chlorophyll and naphthoquinone or anthrahydroquinone and a conducting adhesive. These electrodes exhibit a photoexciting property. The potential was found to shift to a less noble state when the system of the chlorophyll-naphthoquinone electrode was inserted into NAD solution with illumination. On the other hand, the photoexcitation of the system of the chlorophyll-anthrahydroquinone electrode inserted into ferrocyanide solution made the potential more noble. (If the potential in the dark is in the dark is in the positive region of the scheme and the potential moves in the positive direction when the light is turned on, it can be said to be more positive region, it can be said to become less noble, but it is not suitable to say that it becomes more negative.) To make the potential difference between two electodes as big as possible, various factors such as intensity of illumination, molar ratio of chlorophyll to naphthoquinone or anthrahydroquinone and concentration of redox compound in electrolyte were examined. A cell was set up by combining the system of the chlorophyll-naphthoquinone electrode in NAD solution with that of the chlorophyll-anthrahydroquinone electode in ferrocyanide solution, and photoelectrolysis was carried out by closing the external circuit with illumination. The photovoltage between the two electrodes was 0.25 V and the current density was 8 muA/cm2. It was found that NAD was reduced to form NADH at the chlorophyll-naphthoquinone electrode and ferrocyanide was oxidized to form ferricyanide at the chlorophyll-anthrahydroquinone electrode.

Modulation of the plasma cholesteryl ester transfer by stachybotramide.

Plasma cholesteryl ester transfer protein (CETP), which mediates the transfer and exchange of neutral lipids (cholesteryl esters (CE) and triglycerides (TG) and phospholipids between plasma lipoproteins, plays an essential role in reverse cholesterol transport system. We have found that a fungal metabolite, stachybotramide, modulates the activity of CETP. Stachybotramide stimulated the [14C]CE transfer from high density lipoprotein (HDL) to very low density lipoprotein (VLDL) and low density lipoprotein (LDL) by 1.3- to 1.5-fold at 0.2-0.5 mM. This stimulation was abolished in the presence of anti-CETP antibody. On the other hand, the transfer of [14C]CE from LDL and VLDL to HDL was slightly reduced by stachybotramide at 0.5 mM. Unlike the transfer of [14C]CE, the transfer of [3H]TG from HDL was not significantly affected by stachybotramide. These results suggest that stachybotramide preferentially stimulate the CETP-mediated transfer of CE from HDL to both VLDL and LDL.

Structure and expression of hedgehog, a Drosophila segment-polarity gene required for cell-cell communication.

The complete nucleotide sequence of the coding region of hedgehog (hh), a segment-polarity gene in Drosophila melanogaster, was determined. The gene was found to include three exons which would encode a 421- (or 471-) amino acid (aa) polypeptide with a long hydrophobic stretch. The hh mRNA was about 2.3 kb long and expressed throughout development. The hh expression in an embryo occurred in stripes, while that in imaginal discs occurred in the posterior compartment. As a whole, the spatial expression pattern of hh mRNA was very similar to that of engrailed (en), a homeobox gene required for the formation of the anterior-posterior compartment boundary. Unlike en, no hh expression was observed in the central nervous system.

Difference of (Ca2+)i movements in platelets stimulated by thrombin and TRAP: the involvement of alpha(IIb)beta3-mediated TXA2 synthesis.

This study investigated the difference of [Ca2+]i movement in platelets in response to thrombin and TRAP. The involvement of alpha(IIb)beta3 in this signaling was also studied. Stimulation of platelets with thrombin at 0.03 U/ml caused platelet aggregation and a two-peak increase in [Ca2+]i. The second peak of [Ca2+]i, but not the first peak was abolished by the inhibition of platelet aggregation with alpha(IIb)beta3 antagonists or by scavenging endogenous ADP with apyrase. A cyclooxygenase inhibitor, aspirin, and a TXA2 receptor antagonist, BM 13505, also abolished the second peak of [Ca2+]i but not the first peak, although these regents did not inhibit aggregation. Under the same assay conditions, measurement of TXB2 demonstrated that alpha(IIb)beta3 antagonists and aspirin almost completely inhibited the production of TXB2. In contrast to thrombin-stimulation, TRAP caused only a single peak of [Ca2+]i even in the presence of platelet aggregation, and a high level of [Ca2+]i increase was needed for the induction of platelet aggregation. The inhibition of aggregation with alpha(IIb)beta3 antagonists had no effect on [Ca2+]i change and TXB2 production induced by TRAP. Inhibition studies using anti-GPIb antibodies suggested that GPIb may be involved in the thrombin response, but not in the TRAP. Our findings suggest that low dose thrombin causes a different [Ca2+]i response and TXA2 producing signal from TRAP. Endogenous ADP release and fibrinogen binding to alpha(IIb)beta3 are responsible for the synthesis of TXA2 which results in the induction of the second peak of [Ca2+]i in low thrombin- but not TRAP-stimulated platelets.

Differential osteopontin expression in lung cancer.

Osteopontin (OPN) is a phosphorylated glycoprotein with diverse functions including cancer development, progression and metastasis. Its expression is induced by a variety of stimuli such as TNF-alpha and Ras proto-oncogene. However, differential OPN expression and its regulation in each histologic type of lung cancer are not well established. In this study, we assessed expression of OPN in lung cancer tissues with immunohistochemical analysis. OPN was predominantly expressed in tumor cells of non-small cell lung cancer (NSCLC) tissues: 11 of 16 cases (68.8%) of squamous cell carcinoma (SCC), five of 24 cases (20.8%) of adenocarcinoma (AD), but only two of 18 cases (11%) of small cell lung cancer (SCLC). Expectedly, OPN was principally expressed in NSCLC cell lines (H322 cells and HL460 cells) but not in SCLC cell line (H69 cells) by Western blotting and Northern blotting. Interestingly, Ras-p21 was specifically co-expressed with OPN staining in eight of eight cases with SCC (100%), whereas it was demonstrated in three of ten cases (30%) with AD and only one of 18 cases (5%) with SCLC. Collectively, these results suggest that OPN is mainly expressed in NSCLC, especially among SCC. OPN expression may be tightly regulated by Ras oncogene, and its concomitant induction with Ras activation may play a crucial role in the development of SCC.

Characterization of cytochrome b(5) in the ascidian Polyandrocarpa misakiensis and budding-specific expression.

A cDNA for cytochrome b(5) was cloned from a cDNA library of buds of the ascidian, Polyandrocarpa misakiensis, by a hybridization method involving a digoxigenin-labeled cDNA probe of human soluble cytochrome b(5). The nucleotide sequence of the cDNA for the ascidian cytochrome b(5) (Pmb5) consisted of about 1,800 base pairs including 5'- and 3'-noncoding regions, and a coding sequence of 405 base pairs. The amino acid sequence of 135 residues deduced from the coding nucleotide sequence exhibited 54% identity and 76% similarity to chicken cytochrome b(5). A highly conserved amino acid sequence was observed in the amino-terminal domain of 96 residues containing two heme-binding histidine residues. The putative soluble form of the recombinant Pmb5 expressed in Escherichia coli was purified to homogeneity by column chromatographies on an anion-exchanger and gel filtration. The purified Pmb5 showed the typical absorption spectrum of cytochrome b(5) with an asymmetric peak at 556 nm and a shoulder at 560 nm upon reduction with NADH and NADH-cytochrome b(5) reductase. The low temperature spectrum of the dithionite-reduced form of the protein contained the split peaks at 551 and 555 nm, this spectrum being very similar to that of mammalian liver cytochrome b(5). Expression of Pmb5 in the ascidian was examined immunohistochemically with a monoclonal antibody against the Pmb5. Apparently high level expression of Pmb5 was found in the developing buds, but the levels of cytochrome b(5) in the parents and juvenile adults were very low. This is the first report on the characterization of Pmb5, and the increased expression of Pmb5 in the ascidian.

Analysis of phospho- and phosphonosphingolipids by high-performance liquid chromatography.

A simple and efficient method for the separation of phosphosphingolipids including phosphonosphingolipids by high-performance liquid chromatography is described. A mixture of authentic lipids consisting of sphingomyelin, ceramide phosphorylethanolamine, ceramide 2-aminoethylphosphonate, and ceramide N-methylaminoethylphosphonate was completely separated using a silica gel (Zorbax SIL) column with acetonitrile-methanol-water 72:40:10 (v/v) as eluting solvent. The elution of these sphingolipids was monitored directly with an ultraviolet spectromonitor at 207 nm. The practical limit of detection of each sphingolipid was about 0.2 microgram or 0.3 nmol. Using this method, we found that from one to four different phosphono- and/or phosphosphingolipids in fresh-water shellfish can be routinely identified and reproducibly quantified.

Effect of alpha-methyl-p-tyrosine and an antiserum to rat growth hormone (GH)-releasing factor (GRF) on plasma GH secretory profile during a continuous infusion of human GRF in rats.

The effects of alpha-methyl-p-tyrosine (alpha-MT) and an antiserum specific to rat growth hormone-releasing factor (GRF) on growth hormone (GH) secretory profile during a 6-h continuous infusion of human GRF(1-44) NH2 were observed in unrestrained adult male Wistar rats. All rats were provided with two indwelling cannulae; one in the right atrium for undisturbed blood collection and the other in the inferior vena cava for 0.9% NaCl or GRF infusion. GRF was administered by an infusion pump at a dose of 50 ng/kg b.wt./min ma GH levels during baseline period were low with little fluctuation. GH secretion was augmented significantly during continuous GRF infusion in control rats but interpeak intervals remained unaltered. When an antiserum specific to rat GRF was administered, episodic GH secretion was abolished. In these rats, pulsatile GH secretion indistinguishable from that of control rats was observed in the continuous presence of human GRF. Although alpha-MT inhibited episodic GH secretion, alpha-MT-treated rats exhibited high-frequency, low-amplitude episodic GH secretion and elevated baseline levels during the stimulation. There were no differences in the amount of GH secreted during GRF infusion between rats that had received either alpha-MT or antiserum to rat GRF. Since GH secretion to GRF is determined largely by somatostatin, the results suggest that phasic release of somatostatin plays an important role in determining the rhythmicity of episodic GH secretion, and that it is modulated by alpha-MT but not by the immunoneutralization of GRF.

Safety and kinetic properties of a humanized antibody to human interleukin-6 receptor in healthy non-human primates.

A monoclonal antibody, hPM-1, was constructed by grafting the complementarity determining regions to human interleukin-6 (IL-6) receptor, raised in mouse, onto a human antibody backbone (humanized antibody). It is expected to be useful as a therapeutic agent for IL-6-related diseases such as multiple myeloma. To investigate the toxicological and kinetic properties of hPM-1 preliminarily, normal cynomolgus monkeys, which showed cross-reactivity with hPM-1, were intravenously administered with hPM-1 at doses of 0 (vehicle), 4 or 40 mg/kg once a week for 13 weeks. Upon toxicological examination, there were no changes in clinical signs, food consumption, body weights, urinalyses, body temperatures, electrocardiograms, hematological and biochemical parameters including blood platelet counts, serum levels of immunoglobulin G and C-reactive protein, and pathological findings. In a kinetic study, serum concentrations of hPM-1 showed a linearity between doses of 4 and 40 mg/kg. The serum concentrations, even at a dose of 4 mg/kg, were maintained at a high enough level to inhibit the IL-6 functions throughout the period of the study. Concentrations of hPM-1 in bone marrow were almost equal to those in serum. The antibodies against hPM-1 were detected only in one of four monkeys receiving hPM-1. This study suggests that blockage of the IL-6 receptor by hPM-1 does not induce any influence on a healthy living body, and hPM-1 is not toxic under the conditions of this investigation.