This Thesis deals with the design, synthesis and biological evaluation of peptide-based drugs. In chapters 1-4, the development of peptides derived from natural gluten which can serve as drugs to... Show moreThis Thesis deals with the design, synthesis and biological evaluation of peptide-based drugs. In chapters 1-4, the development of peptides derived from natural gluten which can serve as drugs to combat the symptoms of celiac disease is described. These symptoms are caused by a misdirected immune response towards dietary gluten in genetically predisposed individuals. Peptides which can inhibit this immune response possibly can be used as an addition to the gluten-free diet, which is the only therapy available today. In Chapters 5 and 6, the synthesis and biological evaluation analogs of the antibiotic peptide Gramicidin S is described. Gramicidin S is a naturally occurring antibiotic peptide. It is very effective against bacteria, but also exhibits toxicity towards human red blood cells which limits its use to topical applications. Analogs of this natural peptide may lead to efficient antibiotics which are broadly applicable. Show less
The work described in this thesis focussed on the modes of action of maggot therapy in chronic wounds, especially related to the inflammatory phase of wound healing. For this purpose, the effect of... Show moreThe work described in this thesis focussed on the modes of action of maggot therapy in chronic wounds, especially related to the inflammatory phase of wound healing. For this purpose, the effect of maggot excretions and/or secretions on microbiological, haematological and immunological processes was investigated. The results showed that maggot excretions/secretions breakdown biofilms of both Gram-positive and Gram-negative bacteria, exposing them to the immune system, antibiotics, and ingestion and subsequent degradation by the maggots. Furthermore, proteases in maggot secretions enhance debridement by increasing the fibrinolytic activity of wound components and by degrading matrix components directly. Additionally, maggot secretions inhibit the pro-inflammatory responses of phagocytes but do not affect their ability to ingest and intracellularly kill micro-organisms. Finally, secretions induce the production of growth factors essential for angiogenesis. In conclusion, the results described in this thesis provide new insights into the modes of action of maggot therapy in chronic wounds. The success of maggot therapy may be explained by the broad spectrum of processes that are modulated by maggot secretions. Show less
Antimicrobial resistance of bacteria is a worldwide and ever-growing problem, directly linked to the use of antimicrobial drugs. Resistant bacteria emerge under the selective pressure of... Show moreAntimicrobial resistance of bacteria is a worldwide and ever-growing problem, directly linked to the use of antimicrobial drugs. Resistant bacteria emerge under the selective pressure of antibiotics. In hospitals, where large-scale usage of antibiotics is common, bacteria frequently become resistant to several antibiotics which causes serious problems for the treatment of patients with infections by these microorganisms. Well-known (multi)-resistant bacteria causing problems in many countries all over the world are methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, penicillin-resistant pneumococci, extended-spectrum betalactamase-producing Klebsiella pneumoniae, carbapenem-resistant Acinetobacter baumannii, and multiresistant Mycobacterium tuberculosis Show less
Groep B streptokokken (GBS) zijn belangrijke veroorzakers van ernstige infecties rondom de bevalling. Ter preventie van GBS-ziekte bij het kind worden antibiotica aan ongeveer 20% van alle... Show moreGroep B streptokokken (GBS) zijn belangrijke veroorzakers van ernstige infecties rondom de bevalling. Ter preventie van GBS-ziekte bij het kind worden antibiotica aan ongeveer 20% van alle zwangeren toegediend. Ondanks de toediening van antibiotica worden er soms kinderen ziek. Onderzoek naar de farmacokinetiek (lotgevallen van geneesmiddelen in het lichaam) en de huidige dosering van deze antibiotica tijdens de bevalling werd nog niet eerder verricht. Antibiotica zoals amoxicilline en clindamycine, die tijdens de bevalling worden toegediend, moeten bij de moeder een voldoende tijd een werkzame bloedspiegel hebben, de moederkoek passeren en ook bij het kind een voldoende tijd een werkzame bloedspiegel bereiken. Uit ons onderzoek blijkt, dat voor amoxicilline de farmacokinetiek bij vrouwen met gebroken vliezen voor aanvang van de bevalling vergelijkbaar is met die bij niet-zwangeren. Verschillende situaties bleken geen invloed te hebben op de farmacokinetiek van amoxicilline. Wanneer gebruik wordt gemaakt van een farmacokinetisch computermodel, waarin de bloedspiegels van amoxicilline van moeder, de navelstreng en het kind verwerkt zijn, lijkt de begin dosis van 2 gram amoxicilline afdoende voor het voorkomen van GBS-ziekte. Doseringen penicilline G die gebruikt worden voor de behandeling van GBS-ziekte bij vroegtijdig geboren kinderen zijn ook afdoende. Over clindamycine kunnen geen definitieve conclusies getrokken worden. Show less
