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(12) Patent Application Publication (10) Pub. No.: US 2011/0224301 A1 ZAMORA Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/0224301 A1 ZAMORA Et Al US 20110224301A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0224301 A1 ZAMORA et al. (43) Pub. Date: Sep. 15, 2011 (54) HMGB1 EXPRESSION AND PROTECTIVE Publication Classification ROLE OF SEMAPMOD IN NEC (51) Int. Cl. (75) Inventors: Ruben ZAMORA, Pittsburgh, PA st iOS CR (US); Henri R. FORD, La Canada, (2006.01) CA (US); Thais A6IP3L/2 (2006.01) SIELECK-DZURDZ, Kennett A6IP33/6 (2006.01) Square, PA (US); Vidal F. DE LA CRUZ, Phoenixville, PA (US) (52) U.S. Cl. ........................................................ S14/615 (73) Assignee: CYTOKINE PHARMASCIENCES, INC., King (57) ABSTRACT of Prussia, PA (US) Methods are described, which include the administration of (21) Appl. No.: 12/879,144 semapimod or guanylhydraZone containing compounds, salt thereof, or a combination of the compound and a salt thereof 22) Filed1C Sep.ep. 10,1U, 2010 forOr the 1inhibiti 1t1on, treatment, and/ord/ prevention off any o f NEC, a condition associated with the release of HMGB1, a Related U.S. Application Data condition associated with the release of iNOS protein, a con dition associated with the release of Bax protein, a condition (63) sity pig, S. 21,666 filed on associated with the release of Bad protein, a condition asso • us s • L vs - s -- a-- s- u. I • ciated with the release of COX-2 protein, or a condition (60) Provisional application No. 60/685,875, filed on Jun. associated with the release of RAGE, or a combination 1, 2005. thereof to a subject in need thereof. Patent Application Publication Sep. 15, 2011 Sheet 1 of 12 US 2011/0224301 A1 Fig. 1. BF FFH HMGB1 - Otis " – 30 kDa - 10 kDa 7kDa B-actin -> 30 kDa 10 kDa 7 kDa Patent Application Publication Sep. 15, 2011 Sheet 2 of 12 US 2011/0224301 A1 Fig. 2. 100 FFH CD FFH + Semapimod - 80 S. O L Z 60 an O (9 ss 40 U 20 O O.1 0.25 0.50 0.75 1 Semapimod mg/kg, IP Patent Application Publication Sep. 15, 2011 Sheet 3 of 12 US 2011/0224301 A1 Fig. 3a. BF FFH FFH Semapimod HMGB-1 -> 2.5 2.0 - 1.5 - k, 10 - 0.5 OO BF FFH FFH + Semapimod Patent Application Publication Sep. 15, 2011 Sheet 4 of 12 US 2011/0224301 A1 , 's t! y F-Jaw: rt W. - A. Sisi.a. A. : ".Y. y; -e. & ( : , tri.A. Fig 3b. Patent Application Publication Sep. 15, 2011 Sheet 5 of 12 US 2011/0224301 A1 Fig. 3c. BF FFH FFH + Semapimod 45 kDa - in c - up RAGE to st state 'P' me ... me a memouseumsmo B-actin - ""rnhaupuapulus BF FFH O FFH + Semapimod Patent Application Publication Sep. 15, 2011 Sheet 6 of 12 US 2011/0224301 A1 Fig. 4a. BF FFH FFH + Semapimod Bad --> an an - e. qug sm a r sale or 23 kDa B-actin -> Nandanmummum 18 15 1.2 0.9 0.6 0.3 0.0 BF FFH FFH + Semapimod Patent Application Publication Sep. 15, 2011 Sheet 7 of 12 US 2011/0224301 A1 Fig. 4b. BF FFH FFH + Semapimod Bax -> e is as as - 21 kDa B-actin -> OC O.30 0.25 O20 0.15 0.10 O,05 OOO BF FFH FFH + Semapimod Patent Application Publication Sep. 15, 2011 Sheet 8 of 12 US 2011/0224301 A1 Fig. 5a. BF FFH FFH + Semapimod iNOS --> xx * * * * * oneeasis. - - -- 130 kDa B-actin - -u 18 1.5 1.2 O.9 O.6 O.3 0.0 BF FFH FFH + Semapimod Patent Application Publication Sep. 15, 2011 Sheet 9 of 12 US 2011/0224301 A1 Fig. 5b. BF FFH FFH + Semapimod COX-2-> . dous mole-72 kDa 2.0 1 5 - 10 0.5 BF FFH FFH+ Semapimod Patent Application Publication Sep. 15, 2011 Sheet 10 of 12 US 2011/0224301 A1 Fig. 6a. 2.5 12 5O 10 O. 5 Ctrl O 0.1 0.5 1 5 10 SemapimodulM) Patent Application Publication Sep. 15, 2011 Sheet 11 of 12 US 2011/0224301 A1 Fig. 6b. Ctrl LPS ONOO Semapimod - H pp38 -> n up up Patent Application Publication Sep. 15, 2011 Sheet 12 of 12 US 2011/0224301 A1 Fig. 7. Control NEC HMGB-1 -> m an amumumap (-30 kDa Bactin ru- urun Control NEC US 2011/0224301 A1 Sep. 15, 2011 HMGB1 EXPRESSION AND PROTECTIVE (1) have been implicated in the pathogenesis of NEC. In order ROLE OF SEMAPMOD IN NEC to understand the pathogenesis of NEC, others have relied on intravenous administration of pro-inflammatory cytokines or CROSS REFERENCE TO RELATED invasive Surgical procedures, such as occlusion of the mesen APPLICATIONS teric vessels, to reproduce the morphological and clinical 0001. This application is based on, and claims priority to, changes seen in infants with NEC (16). However, these arti U.S. Provisional Application Ser. No. 60/685,875, filed Jun. ficial insults do not parallel the human disease. To understand 1, 2005, the entire contents of which are hereby incorporated the pathogenesis of this disease, the present inventors have by reference. developed a consistent and reproducible rat model that relies on formula feeding and hypoxia, two major risk factors for BACKGROUND NEC (32). 0012. The present inventors modified an experimental Field model (32) so that newborn rats were fed with formula twice 0002 The present invention relates to guanylhydrazone a day and exposed to hypoxia for a longer period of time (10 moiety-containing compounds and their use in the preven min. instead of 3 min.). Examining a larger number of animals tion, treatment, and inhibition of conditions, such as inflam the present inventors observed a higher mortality rate in the matory conditions. This work was Supported in part by the FFH animals as compared to the BF group. As used herein, RO1-AI-14032 grant from the National Institutes of Health BF represents breast-fed animals left with their mothers (con (Bethesda, Md.). The government may have rights in this trols), and FFH are formula-fed pups exposed to hypoxia. invention. Although malnutrition could be a contributing factor (the Volume of formula consumed by the neonatal rats is less than DESCRIPTION OF THE FIGURES the volume of milk consumed by breast-fed pups), there was no apparent cause of death for most of the animals in the FFH 0003 FIG. 1 shows that HMGB1 is elevated in formula group. The significant difference in mortality could only be fed animals exposed to hypoxia. attributed to aspiration during gavage. The longer exposure to 0004 FIG. 2 shows that administration of semapimod in vivo is protective in an experimental NEC model. hypoxia, however, exacerbated the inflammatory changes 0005 FIG. 3 shows that administration of semapimod in seen in the intestine of the FFH group and rendered the vivo decreases the expression of HMGB1 and its receptor neonatal rats more Susceptible to gut barrier failure as shown RAGE in ileal samples from formula-fed animals exposed to by the increased incidence of NEC starting at day 3 after birth. hypoxia. 0013 The present inventors have shown that NEC is char 0006 FIG. 4 shows that administration of semapimod in acterized by the presence of a number of pro-inflammatory vivo decreases the expression of the Bcl-2 family members cytokines, both in experimental and in human NEC (32: 33). Bad and Bax in an experimental NEC model in rats. There, the present inventors have examined the expression of 0007 FIG. 5 shows that administration of semapimod in the protein called high mobility group box 1 (HMGB1) in the vivo decreases the expression of iNOS and COX-2 in an small intestine of newborn rats with NEC. Wang et al. have experimental NEC model in rats. identified and characterized the high mobility group box-1 0008 FIG. 6 shows that semapimod decreases the activa protein (HMGB-1, previously known as HMG-1 or amphot tion of p38 MAP kinase by LPS in vitro. erin) as a potential late mediator of lethality in a mouse model 0009 FIG. 7 shows HMGB1 protein expression in human (44) and a regulator of human monocyte proinflammatory NEC. cytokine synthesis (3). This protein belongs to the HMGB group, one of the three superfamilies of the HMG nuclear DESCRIPTION OF THE SEVERAL proteins Subdivided according to their characteristic func EMBODIMENTS tional sequence motifs. The functional motif of this family is called the HMG-box and according to the revised nomencla 0010 Necrotizing enterocolitis (NEC) is the most fre ture of the HMG nuclear proteins, the HMG-1 has been quent and the most lethal disease that affects the gastrointes renamed to HMGB1 (9). HMGB1 is 30 kDa nuclear and tinal tract of the premature infant (16). The overall mortality cytosolic protein member of the high-mobility group protein rate for patients with NEC ranges from 10 to 70% (22) and Superfamily that has been widely studied as a transcription as approaches 100% for patients with the most severe form of well as growth factor. HMGB1 is also defined as a cytokine the disease, which is characterized by involvement of the because it stimulates proinflammatory responses in mono entire bowel (pan-necrosis) (37). Survivors may develop cytes/macrophages, is produced during systemic and local short-bowel syndrome, recurrent bouts of central line associ inflammatory responses, has been identified as a late mediator ated sepsis, malabsorption and malnutrition, liver failure as a of lethal systemic inflammation (e.g. endotoxaemia and sep result of longstanding administration of total parenteral nutri sis), and is required for the full expression of inflammation in tion, and eventually may require liver-Small bowel transplan animal models of endotoxemia, sepsis and arthritis (2: 45).
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