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Phase ii study of pentostatin in patients with corticosteroid-refractory chronic graft-versus-host disease.

Amina Hamed Ahmad AlObaidi, AbdulGhani Mohamed Ali AlSamarai Abdul Monem Hamad Majed AlSamarai From Departments of Biochemistry and Medicine College of Medicine, Tikrit University, Tikrit, Iraq Email: aminahamed2006 yahoo H Received: February 27, 2007 Accepted: May 13, 2007 ABSTRACT Objective: To study the effect of the organic substances on adenosine deaminase ADA ; activity in normal and abnormal cerebrospinal fluid CSF ; . Methods: Various concentrations of 2-mercaptopurine, Ame"tycine, Adenosine analogues Guanine, Thymine ; and ATP were tested to see their effect on ADA activity in normal and abnormal CSF. Results: ADA activity in normal and abnormal CSF was remarkably decreased with the increasing of concentrations of substances tested. Conclusion: These effects may have important therapeutic implications. Rawal Med J 2007; 32: 146-149 ; . Key words: Adenosine deaminase, CSF, Organic inhibitors, ATP, AMP. INTRODUCTION Several inhibito6s of adenosine deaminase ADA ; have been developed with a goal of to develop inhibitors of ADA for use in combination chemotherapy.1 The antibiotic coformycin is well known as a potent inhibitor of ADA, however, it was found to have the highest inhibitory effect on erthrocytic ADA.2 But the inhibition of ADA in humans induced nausea, vomiting, impaired hepatic and renal functions, central nervous system toxicity and hemolysis.3 On the other hand, the cytotoxic and cytostatic effects of adenosine and deox adenosine are generally potentiated by inhibitors of ADA.4 Inhibition of the enzyme ADA seems an attrative approach to immunosuppressive therapy3 and used for treatment of diseases like T-cell leukemia, advanced malignancies, hairy cell leukemia and chronic lymphocytic leukemia.5 2 deoxy-coformycin Pentostatin ; has striking antitumor activity in several lymphoid neoplasms6 and inhibitors of ADA display antiviral activity.7 The aim of this study was to evaluate the effects of various agents on CSF ADA activity!

The authors thank Drs. James L. Ferguson and H. Bruce Bosmann for discussion of results and review of this manuscript. This work was funded by the University of Illinois at Chicago College of Medicine and Supergen. Pentostatin was a generous gift from Supergen. REFERENCES 1. Arvidsson S, Falt K, and Haglund U. Feline E. coli bactere miaeffects of misoprostol scavengers of methylprednisolone on hemodynamic reactions and gastrointestinal mucosal injury. Acta Chir Scand 156: 215221, 1990. Barankiewicz J and Cohen A. Purine nucleotide metabolism in resident and activated rat macrophages in vitro. Eur J Immunol 15: 627631, 1985. Brackett LE, Shamim MT, and Daly JW. Activities of caffeine, theophylline, and enprofylline analogs as tracheal relaxants. Biochem Pharmacol 39: 18971904, 1990. Brogden RN and Sorkin EM. Pentostatin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in lymphoproliferative disorders. Drugs 46: 652 677, Broner CW, Shenep JL, Stidham GL, Stokes DC, Fairclough D, Schonbaum GR, Rehg JE, and Hildner WK. Effect of antioxidants in experimental Escherichia coli septicemia. Circ Shock 29: 7792, 1989. Castillo M, Toledo-Pereyra LH, Gutierrez R, Prough D, and Shapiro E. Peritonitis after cecal ligation perforation. An experimental model to study the therapeutic role of antibiotics associated with allopurinol and catalase. Surg 57: 313316, 1991. Cronstein BN, Levin RI, Philips M, Hirschhorn R, Abramson SB, and Weissmann G. Neutrophil adherence to endothelium is enhanced via adenosine A1 receptors and inhibited via adenosine A2 receptors. J Immunol 148: 22012206, 1992. Cronstein BN, Naime D, and Firestein G. The antiinflammatory effects of an adenosine kinase inhibitor are mediated by adenosine. Arthritis Rheum 38: 10401045, 1995. Daly JW, Padgett W, Shamim MT, Butts LP, and Waters J. 1, 3-Dialkyl-8- p-sulfophenyl ; xanthines: potent water-soluble antagonists for A1- and A2-adenosine receptors. J Med Chem 28: 487492, 1985. Dziki AJ, Lynch WH, Ramsey CB, and Law WR. Betaadrenergic-dependent and -independent actions of naloxone on perfusion during endotoxin shock. Circ Shock 39: 2938, 1993. Eigler A, Greten TF, Sinha B, Haslberger C, Sullivan GW, and Endres S. Endogenous adenosine curtails lipopolysaccharide-stimulated tumour necrosis factor synthesis. Scand J Immunol 45: 132139, 1997. Firestein GS, Boyle D, Bullough DA, Gruber HE, Sajjadi FG, Montag A, Sambol B, and Mullane KM. Protective effect of an adenosine kinase inhibitor in septic shock. J Immunol 152: 58535859, 1994.

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Novartis institutes of biomedical research, horsham research centre, wimblehurst road, horsham, west sussex rh12 5ab, uk. Focus on cerebrovascular disease. Ideally, the ED physicians should be board certified. They should meet with the CSC director at least semiannually and review care issues. Other aspects of the integration of the ED EMS personnel with a stroke center are reviewed in the PSC recommendations.3. We are not allowed to speak in favor of our specialties codes under review, other than to offer points of information. All political activity on the part of RUC members is forbidden at the table and peppermint.

Publications Aytac, U., Sato, K., Yamochi, T., Yamochi, T., Ohnuma, K., Mills, GB., Morimoto, C., Dang, NH. Effect of CD26 dipeptidyl peptidase IV on Jurkat sensitivity to G 2 ; arrest induced by topoisomerase II inhibitors. Br J Cancer. 88: 455-62, 2003. Ouchida, R., Kusuhara, M., Shimizu, N., Hisada, T., Makino, Y., Morimoto, C., Handa, H., Ohsuzu, F., Tanaka, H. Suppression of NFkappaB-dependent gene expression by a hexamethylene bisacetamide-inducible protein HEXIM1 in human vascular smooth muscle cells. Genes Cells. 8: 95-107, 2003. Ishii, T., Ohnuma, K., Murakami, A., Takasawa, N., Yamochi, T., Iwata, S., Uchiyama, M., Dang, NH., Tanaka, H., Morimoto, C. SSA Ro 52, an autoantigen involved in CD28mediated IL-2 production. J. Immunol. 170: 3656-36, 2003. Miyake-Nishijima, R., Iwata, S., Saijo, S., Kobayashi, H., Kobayshi, S., Souta-Kuribara, A., Hosono, O., Kawasaki, H., Tanaka, H., Ikeda, E., Okada, Y., Iwakura, Y., Morimoto, C. Role of Crk-associated substrate lymphocyte type in pathophysiology of rheumatoid arthritis in tax transgenic mice and humans. Arthr. And Rheum. 48: 1890-900, 2003. Dang, NH., Aytac, D., Sato, K., U Brien, S., Melenhorst, J., Morimoto, C., Barrett, A J., Molldrem, JJ. T-LGL lymphoproliferative disordedr: expression of CD26 as a marker of clinically aggressive disease and characterization of narrow inhibition. Brt.J.Hematol. 121: 857-65, 2003. Kodama, T., Shimizu, N., Yoshikawa, N., Makino, Y., Ouchida, R., Okamoto, K., Hisada, T., Nakamura, H., Morimoto, C., Tanaka, H. Role of the glucocorticoid receptor for regulation of hypoxia-dependent gene expression. J Biol Chem. 278: 33384-91, 2003. Sato, K., Aytac, U., Yamochi, T., Ohnuma, K., McKee, KS., Morimoto, C., Dang, NH. CD26 dipeptidyl peptidase IV enhances expression of topoisomerase II alpha and sensitivity to apoptosis induced by topoisomerase II inhibitors. Br J Cancer. 89: 1366-74, 2003. Dang, NH., Hagemeister, FB., Duvic, M., Romaguera, JE., Younes, A., Jones, D., Samuels, B., Fayad, LE., Pro, B., Samaniego, F., Sarris, A., Goy, A., McLaughlin, P., Tong, AT., Walker, PL., Tiongson, LP., Smith, T.L, Huh, YO., Morimoto, C., Rodriguez, MA. Pentostatin in T-non-Hodgkin's lymphomas: efficacy and effect on CD26 + T lymphocytes. Oncol Rep. 10: 1513-8, 2003. Nori, M., Iwata, S., Munakata, Y, . Kobahashi, H., Kobayashi, S., Umezawa, Y., Hosono, O., Kawasaki, H., Dang, NH., Tanaka, H., Shiohara, H., Morimoto, C. Ebastine inhibits T cell migration, production of Th2-type cytokines and proinflammatory cytokines. Clin Exp. Allergy. 33: 1544-54, 2003. Makino, Y., Nakamura, H., Ikeda, E., Ohnuma, K., Yamaguchi, K., Yabe, Y., Poellinger, L., Okada, Y., Morimoto, C., Tanaka, H. Hypoxia -inducible factor regulates survival of antigen receptor-driven T cells. J. Immunol. 171: 653440, 2003. Matsumoto, M., Makino, Y., Tanaka, T., Tanaka, H., Ishizaka, N., Noiri, E., Fujita, T., Nangaku, M. Induction of renoprotective gene expression by cobalt ameliorates ischemic injury of the kidney in rats. J Soc Nephrol. 14: 1825 -32, 2003. Hosono, O., Ohnuma, K., Dang, NH., Morimoto, C. CD26: a key molecule in immune regulation and autoimmune diseases. Mod. Rheumatol. 13: 199-204, 2003. Kobayashi, S., Ohnuma, K., Uchiyama, M., Iino, K., Iwata, S., Dang, NH., Morimoto, C. Association of CD26 with CD45RA outside lipid rafts attenuates cord blood T-cell activation. Blood. 103: 1002-1010, 2004. Kobayashi, H., Hosono, O., Iwata, S., Kawasaki, H., Kuwana, M., Tanaka, H., Dang, NH., Morimoto, C. Preferential expression of CD9 on human CD4 + CD45RA + nave T cell population responsive to beta2-glycoprotein I. Clin. Exp. Immunol. In press.

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Until 1991, nicotine gum was the only FDA-approved pharmacotherapy for the treatment of tobacco dependence to aid smoking cessation, and it was available by prescription only in the 2-mg dose and in one flavor. Today, nicotine gum, patches, and lozenges are available OTC in two doses and several flavor variations. Additional nicotine replacement and percodan!

[23] J. Teichman and L. Mahadevan. The viscous catenary. J. Fluid Mech. 2003 ; , vol. 478, pp. 71-80 [24] Y.C. Fung, Biomechanics, second edition, "Chapter 9: Skeletal Muscle", pp. 399.
MODULATION OF RAS-MAPK PATHWAY PROVIDES SURVIVAL BENEFIT IN CONDITIONAL CARDIAC SPECIFIC HRAS-V12 MOUSE MODEL OF HUMAN CARDIOMYOPATHY. P. L. Martin, E. Spehalski, M. J. Hoenerhoff, S. Hoover, J. M. Rozenburg, C. Vinson, R. M. Simpson. Comparative Molecular Pathology Unit and Laboratory of Metabolism, National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD and pergolide!

Sterylizacja radiacyjna na tle innych metod wyjalawiania Radiation sterilization as compared with other sterilization methods ; W. Stachowicz Institute of Nuclear Chemistry and Technology, Warszawa, Poland ; Podstawy oddzialywania promieniowania jonizujcego z materi Fundamentals of interaction of ionizing radiation with matter ; P.P. Panta Institute of Nuclear Chemistry and Technology, Warszawa, Poland ; Mikrobiologiczne aspekty sterylizacji radiacyjnej Microbiological aspects of radiation sterilization ; D. Lachiewicz Balton Ltd., Warszawa, Poland ; , M. Jakowska Balton Ltd., Warszawa, Poland ; Okrelanie dawki sterylizacyjnej Sterilization dose determination ; I. Kaluska Institute of Nuclear Chemistry and Technology, Warszawa, Poland ; Przegld rozwiza konstrukcyjnych akceleratorw stosowanych w technice i technologii radiacyjnej Review of the technical solutions of accelerators applied in radiation technology ; Z. Zimek Institute of Nuclear Chemistry and Technology, Warszawa, Poland ; Izotopowe rdla promieniowania w sterylizacji radiacyjnej Isotopic sources of radiation used for radiation sterilization ; W. Bogus Technical University of Ld, Poland.
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Michael G Dodds 1 ; , Paolo Vicini 1 ; , Jennifer E Visich 2 ; and Mark Rogge 2 ; 1 ; Department of Bioengineering, University of Washington, Seattle, Washington, USA 2 ; ZymoGenetics Inc., Seattle, Washington, USA poster Purpose: To develop a population pharmacokinetic model to describe the fate of recombinant FXIII-A2 rA2 ; subunit administered to patients congenitally deficient CD ; in Factor XIII A2 subunit. The model incorporates the rate and extent of complexation of recombinant A2 rA2 ; with available endogenous FXIIIB subunit to form the heterotetramer, rA2B2. Circulating FXIII is activated by calcium and thrombin, and the A2 subunit is liberated, activated and is responsible for cross-linking fibrin and stabilizing clots. Methods: Previously, a three-compartment, nonlinear population PK model was implemented in NONMEM V, and then used to analyze data from randomized, double-blind, placebo controlled Phase I studies of rA2 in healthy volunteers. Immunoassay data included plasma levels for FXIII activity and A2B2, total A2 and free B concentrations. This model was extended to include a genetic covariate FXIII A subunit deficient or normal ; and differences in assay matrix composition. Phase I studies in CD subjects were then assessed using this model. Results: The half-life of FXIII was found to be similar in healthy volunteers and CD subjects. Endogenous production rates of FXIII-B subunit were unchanged, but endogenous production of A2 in patients was estimated to be very small, as expected. Assay scale factors, in the form of volume of distribution, were found to be different in CD subjects. Conclusions: The model well described immunoassay data prior to and following single- and multiple-dose administration of rA2 and its subsequent incorporation into rA2B2 in both healthy and CD subjects. This mechanistic model can be used for prospective simulation of other dosing schemes and modified to account for both congenital and potentially acquired FXIII deficiencies.

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