Experimental and clinical
`endocrinology 8. diabetes : official
`journal. German Society of.
`DUP - General Colieclion
`-N1 EX464
`v. 108. no. 1
`
`|uu\.I inology
`
`Founded in 1928
`
`Official Journal
`
`society of
`Endocrinology
`
`‘
`
`g :% PROPERTY OF THE
`
`LIBRARY OF
`LIBRARYOF
`>4 MEDICINE
`Editors-In--L.nn.-.-n.
`
`K. Voigt, Marburg - H. Schatz, Bochum
`
`Editors of Volume:
`
`R. Renner, Miinchen
`
`C. J. Strasburger, Miiinchen
`
`Abstracts of Oral Presentations
`
`and Posters
`
`44th Symposion of the German
`Society of Endocrinology (DGE) and
`
`35. Jahrestagung der Deutschen
`Diabetes-Gesellschaft (DDG)
`
`Munich, May 31st—June 3rd, 2000
`
`EXPER I HENTHL RND CL I N I CHL ENDOCRINOLOGY
`HND D I HBETES ~ SUPPLEMENTS
`
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`Subject US Copyright Laws
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`AstraZeneca Exhibit 2160
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`Page 1 of 3
`
`

`
`Experimental and Clinical
`
`Endocrinology
`& Diabetes
`
`Supplement 1, Vol. 108, 2000
`
`Editors-in-Chief:
`
`K. Voigt, Marburg - H. Schatz, Bochum
`
`Editors of Volume:
`
`R. Renner, Mijnchen
`C. J. Strasburger, Miinchen
`
`Abstracts of Oral Presentations
`
`and Posters
`
`44th Symposion of the
`German Society
`of Endocrinology (DGE) and
`
`35. Jahrestagung der
`Deutschen Diabetes-Gesellschaft (DDG)
`
`Munich, May 31st—June 3rd, 2000
`
`Homepage: http:llwww.eced.org
`
`Johann Ambrosius Barth
`Heidelberg
`
`Page 2 of3
`
`Page 2 of 3
`
`

`
`pFr1t)5
`
`K. Glund', r. Hoffmartn', H.-U. Demuth', J. Banke-Bochitaz, K.L. Rostz, H.
`Fuderz,
`
`iProbiodrug Research GmbH, Halle/Saale and ZPAREXEL Institute of Clinical
`Phannacology, Berlin, Germany
`
`Single dose-escalation study to investigate the safety and tolerability ofthe
`DP IV inhibitor P32/98 in healthy volunteers
`
`The DP IV inhibitor Di-[3N-((2S,3S)-2—amino-3-methyl-pentanoyl) l,3-thiazoli-
`dine]
`fumarate (P32/98)
`improves glucose tolerance (GT) by an incretin-
`mediated enhanced insulin response in normal and diabetic rodents [1,2].
`A monocenter, randomized and double-blind phase I study in healthy volunteers
`Was designed to investigate the safety and tolerability of P32/98. Healthy male
`Volunteers (n=36, age 18-45, with normal oral glucose tolerance test results)
`received two single oral ascending doses of 7.5, 15, 30, 60, I20 and 240 mg of
`1332/98 or placebo (tablets containing 7.5 mg or 60 mg P32/98 or placebo).
`Drug administration (t=0) was followed by an oral glucose tolerance test (glucose
`solution of 75g at t=l0 min). Safety laboratory, vital signs, 12-lead ECG,
`telemetry and adverse events were recorded. No serious adverse events were
`observed. Eight adverse events (5): mild headache, Ix mild nausea, Ix common
`cold and Ix micro-haematuria) did not appear to be drug related as they either
`occurred within volunteers on placebo or were reported long time after the
`preceeding dose. No adverse event occurred at
`the highest 240-mg dose. No
`clinically significant changes
`in
`routine
`laboratory, vital
`signs or ECG
`assessments were observed.
`From these data it can be concluded, that single doses of P32/98 up to 240 mg
`were well tolerated. Plasma DP IV was inhibited in a dose-dependent manner. In
`parallel
`to the decreased DP IV-activity in the circulation a dose-dependent
`Increase in the half life of the active GLP-l7._~,(, was observed from plasma
`Samples
`
`I. Pederson, RA, White, HA, Schlenzig, D, Pauly, RP, Mclntosh, CHS, Demuth,
`H~U (1998) Diabetes 47(8): 1253-1258
`2. Pauly, RP, Demuth, H-U, Rosche, F, Schmidt, J, White, HA, Lynn, F,
`Mclntosh, CHS., Pederson, RA (1999) Metabolism 48(3): 385-389.
`
`pFr107
`ttir die HOE 901f3001-Study group,
`Standl E,
`Institut iiir Diabetestorschung , Miinchen
`randomislerten 28-
`Titel: Ergebnisse einer internationalen, multizentrischen,
`Wochen Studie zum Vergleich von Insulin Glargin (HOE 901) und NPH- insulin in
`der lntensivierten Therapie (ICT) von Typ 1 Diabetikern
`Ziel : Untersuchung der l/Viksamkeit und Vertraglichkeit von HOE 901. HOE 901 ist
`ein langwirksames Insulin-Analogon mit einem flachen Wirkprofil ohne dstinkte
`Aktivllatsspitzen. Methodik:
`in einer randomisierten Studie erhielten 585 Typ 1
`Diabetiker fiber 28 Wochen entweder HOE 901 oder NPH als Basalinsulin ( HOE 901
`292; NPH 293). 55% waren Manner, das miltlere Alter war 39 Jamie, die miltlere
`Diabetesdauer betrug 16 Jahre und der miltlere BMI 25 kg/m?. Vor der Slude wurde
`das Basalinsulin bei 49% der Patienten mindestens 2x am Tag injizien, Zu Beginn der
`Studio war der GHb 7.9 %, der NBZ 9.3 mmol/l (Mittelwerte). Beide Gruppen hatten
`vergleichbare Ausgangswerte. HOE 901 wurde
`1x/Tag
`(beim Zubettgehen)
`verabreicht, NPH 1x/Tag (beim Zubettgehen) oder 2x/Tag (morgens und beim
`Zubetigehen), je nach Vortherapie. Zu den Mahlzeiten wurde Normalinsulin gegeben.
`Die Abenddosis HOE 901 bzw. NPH sollte so gewahlt werden, dais der NBZ unter
`Venneidung von nachtlichen Hypoglykamien 5 120mg/dl
`(6.7mmol/l)
`lag. Beim
`Wechsel zu HOE 901 bei mit 1><NPH vorbehandelten Patienten blieb die Dosis des
`Basalinsulins nahezu unverandert; bei Patienten, die mehr als txNPH/Tag injiziert
`hatten, wurde verglichen mit der letzten NPH-Tagesdosis die HOE 901-Dosis um ca,
`20% reduziert und teilweise mit einer Erhohung des Nonnalinsulins kompensiert.
`Ergebnisse: Der GHb blieb in belden Behandlungsgruppen nahezu unverandert (HOE
`901 0.21%; NPH 0.10%), der NBZ nahm deutlich ab (HOE 901 -1.17 mmo|Il;NPH —
`0.89 mmol/l, adjusted means).
`lm Vergleich mit 2><NPH/Tag wurde der NBZ in der
`HOE 901 Gruppe signifikant mehr
`reduziert
`(HOE 901 -1.38 mmol/l; NPH -
`0.72 mmolll; p<0.05), ohne dais vermehrt nachtliche Hypoglykamien beiichtet wurden.
`lm Vergleich mit 1xNPH/Tag wurde der NBZ in beiden Gruppen gleicherrnaflen
`reduziert
`(-1.0mmolIl; adjusted means), wobei
`in der HOE 901 Gruppe weniger
`Patienten nachtliche Hypoglykamien (49% vs. 56%) oder schwere Hypoglykamien (9%
`vs. 16%) berichteten. Nach 28 Wochen hatten mehr HOE 901 (26%) als NPH
`Patienten (20%) einen NBZ _<_ 120mg/dl erreicht. Die Auswertung der Sicherheitsdaten
`ergab
`keinen
`relevanten Unlerschied
`zwischen
`den Behandlungsgruppen
`Schlulliolgerung: lm Vergleich mit NPH tretem unter HOE 901 im Rahmen der ICT
`weniger Hypoglykamien bei gleich guten Blutzuckerwenen auf bzw. es konnen bessere
`Blutzuckerwerte ohne vermehrtes Risiko erreicht werden.
`
`pFrl06
`Konrad T., Usadel K.-H.
`Medical Clinic l, Centre for Internal Medicine, Frankfurt am Main
`
`Effects of short-term treatment with the insulin sensitizer Pioglitazone
`(PIO) in a severely immobile type 2 diabetic on ICT
`
`Study obective: To investigate the short-term effects of 45 mg PIO in a
`metabolically well controlled, quadriplegic, insulin-resistant type 2 diabetic
`on ICT. Method: Case history. Results: Patient K.M., 46 y., quadriplegia
`since 1988 after a road accident with C3/4 damage, type 2 diabetes since
`1991, highly compliant with treatment and diet, treated with OAD since
`1994, BMI 24.8 kg/m2, consistently for years no endogenous C-peptide
`secretion detectable in fasting and postprandial tests. HbA1c consistently
`between 5.5% and 5.6% until 6/99 with 30 |.U. NPH and a mean of 20
`l.U. short-acting ins., then a slow increase to 6.6% by 11/99 when the
`insulin dose was increased.
`
`Daily blood sugar profiles show isolated hypoglycaemlc episodes which
`made it necessary to reduce the insulin dose. Conclusions: The increase
`in insulin dose, despite continued dietary compliance and no detectable
`endogenous insulin secretion,
`is occasioned by the patient's insulin
`resistance (IR). Owing to concomitant illness, there is no possibility of
`improving the IR by muscular exertion.
`PIO reduces the daily insulin
`dose by approx. 50% and improves blood sugar control after only four
`weeks‘ treatment.
`In well controlled patients, beneficial metabolic effects
`can be detected after only one week on an insulin sensitizer.
`Page 3 of 3
`
`pFrl08
`M. Walz, H. Kolb and S. Martin
`German Diabetes Research Institute at the Heinrich—Heine-University of
`Diisscldorf, Gemian Diabetes Centre, Dusseldorf, Germany
`
`Downregulation of the pancreatic IFN-Iy expression in NOD mice
`treated with an 11,4-lg fusionproteiu
`
`The nonobese diabetic (NOD) mouse spontaneously dcvclops
`autoimmune diabetes which is associated with T cell infiltration of
`pancreatic islets leading to the destruction of insulin-producing 0 cells.
`More recently, the importance of a preferential activation of the Thl
`subset of T cells leading to a secretion of prointlamrnatory cytokincs was
`shown.
`We have constructed a fusion protein consisting of the mouse IL-4 and
`the Fc-domain of IgG2a. Bioactixity of the recombinant protein was
`initially shovm by its ability to stimulate IL-4-dependent cytotoxic T
`lytnphocytcs (CTL-44). IL-4-lg chimeric proteins were then tested in
`NOD mice which were treated with cyclophosphamide to synchronize
`the progression of insulitis. PBS, 20 ng rll.-4 or 50 ng IL-1-lg was
`administered (i.p.). At different time points, animals were sacrificed,
`pancrcata and spleen were removed for histopathology and RNA
`isolation.
`Quantitative PCR was performed from pancreatic RNA using the
`TaqMan (Perkin Elmer). RNA samples were nonnalized for B-actin and
`the expression of IFN-y, IL-12pl0 and IL-10 was analyzed. Expression
`of the Th1 cytokine IFN-y was reduced by 50% after treatment with IL-
`4. Only subtle differences were found for the expression levels of IL-
`I2p40 and IL-10. Histopathology revealed :1 different fonn of infiltration
`when compared to PBS-treated animals.
`Our results demonstrate that the IL-4-Ig fusion protein has a biological
`activity comparable to rI.L-4, as demonstrated in vitro and by
`downregulation of the 'I‘l11-specific cytokine expression The IL-Hg
`chimeric protein may be a powerful tool for the prevention of 13 cell
`destruction.
`
`Page 3 of 3