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Objective To investigate the safety, pharmacokinetics (PK), binding activity and immunogenicity of CR002, a human monoclonal antibody (mAb) directed against platelet-derived growth factor-D (PDGF-D), administered as a single intravenous (i.v.) infusion over a range of doses. Subjects 40 healthy male subjects received increasing doses of CR002 at 0.3, 1, 3, 10, 30 mg/kg or placebo. Method This was a randomized, double-blind, placebo-controlled, dose-escalation Phase I study. The trial had a duration of 90 days, with dosing on Day 1 and follow-up visits on Days 2, 4, 7, 14, 21, 30, 45 and 90. Serum was collected for PK, binding activity and immunogenicity analysis at screening and up to Day 90. Safety was recorded throughout the study by performing laboratory tests, recording vital signs and electrocardiograms (ECGs), by monitoring the occurrence of adverse events (AEs). The use of concomitant medications was also recorded. Results All 40 subjects received CR002 or placebo, and completed the trial. No dose-limiting toxicities (DLTs) occurred, the maximum tolerated dose (MTD) was not reached and was estimated as > 30 mg/kg. There were no deaths during this study and no SAEs or other significant AEs reported. The most frequent drug-related treatment-emergent AE (TEAE) was headache in 4 of 30 subjects (13.3%) in the CR002 group vs. 0 of 10 subjects in the placebo group. CR002 exhibited linear PK parameters, had a long half-life (t1/2 in the range 15.5 â 48.1 days) and a volume of distribution at steady state in the range 4.7 â 6.5. Free PDGF-D in the serum bound to CR002 in a reversible manner, as shown in the lowest dose cohort. However, levels of total circulating PDGF-D remained constant throughout the study. There were no anti-CR002 antibodies detected in subjects dosed with CR002. Conclusions CR002 was safe and well-tolerated at all doses tested as a single i.v. administration. The MTD was estimated to be above 30 mg/kg, the highest dose tested. CR002 had a long half-life, low clearance and a limited tissue distribution. Although total levels of PDGF-D at all dose levels remained relatively constant, there was no detectable circulating free PDGF-D after CR002 administration. At the lowest CR002 dose tested (0.3 mg/kg), PDGF-D was detectable again by Day 21 and the levels increased near to pre-infusion levels by Day 90. In this study, CR002 was not immunogenic during the 90-day study period.

The present study aims to evaluate the effects of metronidazole, probiotics oligosaccharide on indigenous microflora and bacterial translocation (BT) in protein malnourished rats. Thirty male Wistarrats were divided into three groups: protein malnourished rats PM (group1, n = 10) were fed with maize only, protein malnourished rats (group 2, n = 10) were received metronidazole and protein malnourished rats (group 3, n = 10) were received both metronidazole and probiotics-oligosaccharide for fifteen days. Metronidazole (1000 mg/kg/day) was given via an orogastric feeding tube to the second and third groups. Lyophilized probiotics-oligosaccharide (0.5 mg/g body weight/day) was given in two doses via the same route to the third group. All animals were sacrificed after fifteen days of protein malnutrition and cultures of the mesenteric lymph nodes (MLNs), liver, spleen and cecal contents were done. Theincidence of bacterial translocation (BT) was 30% (3/10) in protein malnourished group 1,60% (06/10) in group 2 where protein malnutrition was associated with metronidazole and 25% (2.5/10) in group 3whose animals were subjected to protein malnutrition associated with metronidazole and probiotics oligosaccharide. A significant increase in the BT incidence was found in group 2 (P < 0.05), while a significant decrease was found in group 3 when compared to group 1. The total bacterial count of cecal flora was significantly low in group 3 than in group 1 (P < 0.01). These results suggest that the incidence of BT in protein malnutrition is increased by using an antibiotic while probioticsoligosaccharide decreases this incidence in protein malnutrition induced by antibiotic. Thus, weconclude that probiotics-oligosaccharide can effectively protect the intestinal mucosa and prevent BT in protein malnourished infants.

This study was designed to assess the effects of protein malnutrition (PM) associated with antibiotic on growth weight, cecal bacterial overgrowth and enterobacteria translocation. Eighteen Gnotobioticyoung Wistar rats (135 ± 2.35 g) were treated orally with antibiotic and submitted to dietary restriction based on maize diet in order to determine gram-negative enteric overgrowth in the ceca, therebypromoting the translocation of these bacteria from the gastrointestinal tract. The control group (n= 6) was fed conventional diet, the malnourished rats (n= 6) were fed only maize (10 g/rat/day) and themetronidazole treated malnourished rats (n= 6) were fed only maize (10 g/rat/day) and treated orally with metronidazole (1 mg/ml) for 10 days. The PM associated or not with metronidazole increased the entericbacilli populations in the ceca and promotes their translocation to the mesenteric lymph nodes. There was a direct relationship between cecal bacterial overgrowth, the numbers of viable enterobacteria ofthis strain present in the mesenteric lymph nodes (MLN) and protein malnutrition associated with metronidazole. This study provides confirmation that PM and PM associated with metronidazoledecrease body weight and promotes cecal bacterial overgrowth and enterobacteria translocation in the MLN and liver.

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