Supplementary MaterialsAdditional file 1 Patient flow charts. an antimicrobial, the only undesirable effect being a possible elevation of transaminases, which may be related to hLF1-11 although the current data do not allow conclusive interpretation of treatment relationship. A lower dose is recommended for the forthcoming multiple dosing studies in HSCT patients. Trial registration ClinicalTrials.gov: nct00509938. Background The treatment of patients with haematological malignancies with haematopoietic stem cell transplantation (HSCT) is often accompanied by life threatening complications as a result of the damage caused by the conditioning regimens to the mucosal barrier, and the innate and adaptive, humoral and cellular immune defences [1-3]. Despite many advances in supportive care, transplantation-related morbidity and mortality due to bacterial and fungal infections and uncontrolled inflammation remains high [4,5]. A troublesome fact is the increasing resistance against several important antimicrobial drugs including quinolones, azoles Dabrafenib novel inhibtior and cephalosporins, making control of bacterial and fungal infections in HSCT a difficult task [6-8]. Therefore, the discovery of a broad array of naturally occurring antimicrobial peptides (AMPs) is interesting, although few AMPs have been studied so far and even less have been studied in clinical settings [9-11]. Human lactoferrin is a natural defence protein present in body fluids and secretions as well as neutrophils Dabrafenib novel inhibtior [12,13], and has pleiotropic functions including broad spectrum antimicrobial activity, antitumour activity, regulation of cell growth and differentiation, and modulation of inflammatory, humoral and cellular immune responses [14-17]. Levels of lactoferrin are decreased following HSCT [18], contributing to the overall immune deficiency. Correcting this deficit might ameliorate immunity in HSCT recipients [19]. Human lactoferrin 1-11 (hLF1-11) is a lactoferrin derivative being developed for the treatment of bacterial and fungal infections in HSCT recipients. It contains the N-terminal moiety of hLF, consisting of 11 amino acids, that is essential for the antimicrobial and anti-inflammatory activity [14,15]. Preclinical studies have shown promising antimicrobial activity even in the setting of immunodeficiency justifying further investigation for clinical application [20-24]. Being a derivative of a ‘natural’ human protein, hLF1-11 might have the advantage of fewer side effects and less formation of antibodies and antimicrobial resistance, especially since antimicrobial peptides are unlikely to induce resistance because of the evolutionary difficulty in changing bacterial membrane structure [11]. We report on the first three studies conducted in humans with ascending doses of hLF1-11 in healthy volunteers and in patients receiving autologous HSCT following conditioning with high-dose melphalan (HDM) for multiple myeloma or lymphoplasmocytic lymphoma. Methods Study design The 3 studies were conducted sequentially and included a total of 56 subjects (placebo: 12; hLF1-11: 44) as follows. Study 1: single intravenous administration of ascending hLF1-11 doses (0.005, Dabrafenib novel inhibtior 0.05, 0.5 and 5 mg) in healthy volunteers; study 2: multiple intravenous administration of two ascending hLF1-11 doses (0.5 and 5 mg daily for 5 days) in healthy volunteers; study 3: single intravenous administration of a fixed hLF1-11 dose (5 mg) in patients undergoing an autologous HSCT (Table ?(Table1,1, Additional file 1). JTK12 Table 1 Entry demographics and dosing schedule. thead SubjectsMean age (SD), yearsMean height (SD), cmMean weight (SD), kgMean BMI (SD), kg/m2Male/female, nDosingDose (mg)Placebo, nhLF1-11, nAll, n /thead Study 1Healthy volunteers24 (5)185 (6)79 (9)23 (3)32/0Single0.0052680.052680.52685.0268Study 2Healthy volunteers32 (12)183 (7)78 (12)23 (3)16/0Multiple0.52685.0268Study 3HSCT patients53 (8)178 (7)78 (14)24 (3)7/1Single5.0-88124456 Open in a separate window BMI = body mass index; hLF, human lactoferrin; HSCT = haematopoietic stem cell transplant. Blinding and subject selection Studies 1 and 2 were conducted in healthy volunteers, both were randomised, placebo controlled, enrolled 48 volunteers in total (placebo: 12; antimicrobial peptide (AP): 36) (Table Dabrafenib novel inhibtior ?(Table1)1) and were conducted at the Phase-I Clinical Pharmacology Unit, Xendo Drug Development BV, Groningen, The Netherlands, with prior approval by the appropriate Institutional Review Board (IRB). Entry criteria were similar for studies 1 and 2, namely subjects considered healthy during medical Dabrafenib novel inhibtior screening by a qualified physician, medical history, physical examination, vital signs, blood and urine evaluations, and 12-lead electrocardiogram (ECG). Age and body mass index (BMI) entry criteria were 18 to 45 years (study 1) and 1 to.