Ototopical drops containing a novel antibacterial synthetic peptide: safety and efficacy in adults with chronic suppurative otitis media

ObjectiveChronic suppurative otitis media (CSOM) is a chronic infectious disease with worldwide prevalence that causes hearing loss and decreased quality of life. As current (antibiotic) treatments often unsuccessful and antibiotic resistance is emerging, alternative agents and/or strategies are urgently needed. We considered the synthetic antimicrobial and anti-biofilm peptide P60.4Ac to be an interesting candidate because it also displays anti-inflammatory activities including lipopolysaccharide-neutralizing activity. The aim of the present study was to investigate the safety and efficacy of ototopical drops containing P60.4Ac in adults with CSOM without cholesteatoma.MethodsWe conducted a range-finding study in 16 subjects followed by a randomized, double blinded, placebo-controlled, multicentre phase IIa study in 34 subjects. P60.4Ac-containing ototopical drops or placebo drops were applied twice a day for 2 weeks and adverse events (AEs) and medication use were recorded. Laboratory tests, swabs from the middle ear and throat for bacterial cultures, and audiometry were performed at intervals up to 10 weeks after therapy. Response to treatment was assessed by blinded symptom scoring on otoscopy.ResultsApplication of P60.4Ac-containing ototopical drops (0.25-2.0 mg of peptide/ml) in the ear canal of patients suffering from CSOM was found to be safe and well-tolerated. The optimal dose (0.5 mg of peptide/ml) was selected for the subsequent phase IIa study. Safety evaluation revealed only a few AEs that were unlikely related to study treatment and all, except one, were of mild to moderate intensity. In addition to this excellent safety profile, P60.4Ac ototopical drops resulted in a treatment success in 47% of cases versus 6% in the placebo group.ConclusionThe efficacy/safety balance assessed in the present study provides a compelling justification for continued clinical development of P60.4Ac in therapy-resistant CSOM.Development and application of statistical models for medical scientific researc

Synthesis and systematic evaluation of symmetric sulfonated centrally C-C bonded cyanine near-infrared dyes for protein labelling

<p>The most commonly used near-infrared cyanine dyes contain an aryl ether that is not fully stable towards nucleophiles. Replacement of the aryl ether by a more stable carbon-carbon bond can improve the stability. In this work we have synthesized a series of four negatively-charged symmetrical C-C bond-containing Cy7 derivatives and compared them to the known dyes indocyanine green (ICG) and IRDye 800CW. The extent of stacking of these C-C bond-containing dyes was higher than reported for aryl ether dyes, but stacking could be minimized by altering the surface charge of the molecules and by introducing sulfonate groups. Furthermore, the degree of stacked dye in an antibody-dye conjugate was similar to the degree of stacking of free dye under labeling conditions. In our view, C-C bond-containing Cy7 dyes provide a chemical platform, based on which one can improve the photophysical properties and stacking behavior, thereby generating interesting additions to the conjugation toolbox available for e.g. antibodies.</p

Synthesis and systematic evaluation of symmetric sulfonated centrally C-C bonded cyanine near-infrared dyes for protein labelling

The most commonly used near-infrared cyanine dyes contain an aryl ether that is not fully stable towards nucleophiles. Replacement of the aryl ether by a more stable carbon-carbon bond can improve the stability. In this work we have synthesized a series of four negatively-charged symmetrical C-C bond-containing Cy7 derivatives and compared them to the known dyes indocyanine green (ICG) and IRDye 800CW. The extent of stacking of these C-C bond-containing dyes was higher than reported for aryl ether dyes, but stacking could be minimized by altering the surface charge of the molecules and by introducing sulfonate groups. Furthermore, the degree of stacked dye in an antibody-dye conjugate was similar to the degree of stacking of free dye under labeling conditions. In our view, C-C bond-containing Cy7 dyes provide a chemical platform, based on which one can improve the photophysical properties and stacking behavior, thereby generating interesting additions to the conjugation toolbox available for e.g. antibodies.</p

A novel approach towards the synthesis of pyrophosphate analogues of farnesyl pyrophosphate

The synthesis of two new analogues (i.e. 3 and 4) of farnesyl pyrophosphate (FPP) containing a phosphonophosphate and a phosphonophosphonate moiety was accomplished via the phosphonomorpholidate. The latter was easily obtained by treatment of a phosphonic chloride with morpholine

Enhanced Cross-Presentation and Improved CD8(+) T Cell Responses after Mannosylation of Synthetic Long Peptides in Mice

Tumorimmunolog

Development of a Nose Cream Containing the Synthetic Antimicrobial Peptide P60.4Ac for Eradication of Methicillin-Resistant Staphylococcus aureus Carriage

Pathogenesis and treatment of chronic pulmonary disease

Near-Infrared Fluorescence Imaging of Both Colorectal Cancer and Ureters Using a Low-Dose Integrin Targeted Probe

Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Cysteine Cathepsins in Breast Cancer: Promising Targets for Fluorescence-Guided Surgery

The majority of breast cancer patients is treated with breast-conserving surgery (BCS) combined with adjuvant radiation therapy. Up to 40% of patients has a tumor-positive resection margin after BCS, which necessitates re-resection or additional boost radiation. Cathepsin-targeted near-infrared fluorescence imaging during BCS could be used to detect residual cancer in the surgical cavity and guide additional resection, thereby preventing tumor-positive resection margins and associated mutilating treatments. The cysteine cathepsins are a family of proteases that play a major role in normal cellular physiology and neoplastic transformation. In breast cancer, the increased enzymatic activity and aberrant localization of many of the cysteine cathepsins drive tumor progression, proliferation, invasion, and metastasis. The upregulation of cysteine cathepsins in breast cancer cells indicates their potential as a target for intraoperative fluorescence imaging. This review provides a summary of the current knowledge on the role and expression of the most important cysteine cathepsins in breast cancer to better understand their potential as a target for fluorescence-guided surgery (FGS). In addition, it gives an overview of the cathepsin-targeted fluorescent probes that have been investigated preclinically and in breast cancer patients. The current review underscores that cysteine cathepsins are highly suitable molecular targets for FGS because of favorable expression and activity patterns in virtually all breast cancer subtypes. This is confirmed by cathepsin-targeted fluorescent probes that have been shown to facilitate in vivo breast cancer visualization and tumor resection in mouse models and breast cancer patients. These findings indicate that cathepsin-targeted FGS has potential to improve treatment outcomes in breast cancer patients.Personalised Therapeutic

Real-time near-infrared fluorescence imaging using cRGDZW800-1 for intraoperative visualization of multiple cancer types

Surgical oncolog