Rate-controlled rectal drug delivery in man with a hydrogel preparation

Cylindrical hydrogels of hydroxyethyl methacrylate (HEMA) and ethylene glycol dimethacrylate (EGDMA) as crosslinking agent were prepared by radical polymerization at 70°C. After washing they were soaked in an aqueous drug solution of antipyrine or theophylline. The in vitro drug release experiments were performed in 100 ml isotonic glucose at 37°C. Rectal administration of a hydrogel preparation containing antipyrine was performed in two subjects for 72 h. With a theophylline-containing hydrogel preparation rectal drug administration was performed in six volunteers for 24 h. Plasma and saliva samples were taken regularly and the in vivo drug release was determined by means of a deconuolution procedure. In vitro 1.12g antipyrine had been released according to a matrix-type profile for 72 h, whereas it was calculated that this was 1.13 and 1.09 g in vivo in the two subjects. The release profile in vivo was very similar to that in vitro. The theophylline hydrogel preparation released in vitro a total of 288 ± 6 mg of drug in 24 h and in vivo this amount was calculated to be 288 ± 11 mg (mean ± s.d.). Near-constant plasma theophylline concentrations were obtained after administering the hydrogel preparation. In all six subjects the cumulative drug profile was in almost perfect agreement with that observed in vitro. Hydrogels offer interesting perspectives as rate-controlled rectal drug delivery systems because of the predictable release profile in vivo on the basis of observations in a simple in vitro model

Poly(amido amine)s as Gene Delivery Vectors: Effects of Quaternary Nicotinamide Moieties in the Side Chains

To evaluate the effect of quaternary nicotinamide pendant groups on gene delivery properties, a series of poly(amido amine) (co)polymers were synthesized by Michael addition polymerization of N, N-cystaminebisacrylamide with variable ratios of 1-(4-aminobutyl)-3-carbamoylpyridinium (Nic-BuNH2), and tert-butyl-4-aminobutyl carbamate (BocNH-BuNH2), yielding poly(amido amine)s (NicX-NHBoc) with X=0, 10, 30, and 50 % of quaternary nicotinamide groups in the polymer side chains. Deprotection of the pendant Boc-NH groups afforded an analogous series of polymers (NicX-NH2) with higher charge density (due to the presence of protonated primary amino groups in the side chains) and subsequent acetylation yielded a series of polymers (NicX-NHAc) of lower hydrophobicity than the Boc-protected polymers. The polymers with the Boc-protected or the acetylated amino groups showed high buffer capacity in the range pH 5.1-7.4, which is a property that can contribute to endosomal escape of polyplexes. The presence of quaternary nicotinamide groups has distinct beneficial effects on the gene vector properties of these polymers. The polymers containing 30 % of quaternary nicotinamide groups in their side chains condense DNA into small, nanosized particles (200 nm) with positive surface charge (+15 mV). Fluorescence experiments using ethidium bromide as a competitor showed that the quaternary nicotinamide groups intercalate with DNA, contributing to a more intimate polymer-DNA binding and shielding. Polyplexes of nicotinamide-functionalized poly(amido amine)s NicX-NHBoc and NicX-NHAc, formed at 12/1 polymerDNA mass ratio, efficiently transfect COS-7 cells with efficacies up to four times higher than that of PEI (Exgen 500), and with essentially absence of cytotoxicity. NicX-NH2 polymers, possessing protonated primary amino groups in their side chains, have a higher cytotoxicity profile under these conditions, but at lower 3/1 polymer-DNA mass ratio also these polymers are capable of efficient transfection, while retaining full cell viability

Synthesis and biological evaluation of immunoconjugates of adriamycin and a human IgM linked by poly[N5-(2-hydroxyethyl)-l-glutamine

The synthesis and purification of radiolabelled immunoconjugates, composed of a human IgM monoclonal antibody (IgM 16.88) directed against an intracellular tumour-associated antigen, the drug carrier poly[N5-(2-hydroxyethyl)--glutamine] (PHEG) and the cytostatic drug adriamycin (ADR) are described. The immunoconjugates were constructed to allow selective release of ADR in the putatively acidic environment of the tumour through a novel acid-labile maleamic acid linker. The conjugate of PHEG and the acid-labile ADR derivative effectively released ADR in cytotoxic amounts at a pH of 6.0 as judged from incubation in buffer and from inhibition of the growth of HT-29 colon tumour cells in vitro. Immunoconjugates were prepared by coupling of PHEG-ADR having a hydrolytically stable amide bond with 131I-labelled antibody through thioether bond formation involving a single thiol group at the C-terminus of the polymer chain and maleimido groups introduced onto th

Midwives' work-related fear and anxiety and its impact on their wellbeing and performance. A qualitative study of perceived anxiety in community midwives

INTRODUCTION: Working with acute situations is usually part of midwifery practice. In the Netherlands the community midwives work in a context where they are mostly the sole decision-makers and policymakers and often do not have the support of a multidisciplinary team during a birth. How Dutch community midwives maintain their emotional hygiene is not known. This study aims to explore how Dutch midwives perceive fear and its influence on their performance.METHODS: This is a qualitative study with semi-structured interviews of 19 Dutch community midwives between October 2018 and January 2019.RESULTS: Four themes were identified: 1) midwives' perceptions of fear and anxiety, 2) how years of experience affect fear and anxiety, 3) influence of the work content; and 4) implications for performance. Midwives perceived fear in acute situations where maternal and/or fetal complications were imminent. Participants perceived anxiety either as helpful or a hindrance. Awareness of these feelings helps them to regulate whether or not to give in to these feelings.CONCLUSIONS: Our findings suggest similar perspectives on fear in Dutch community midwives compared to previous outcomes. In the Netherlands, midwives seem reluctant to talk about fear and anxiety in the profession. The awareness of these emotions occurring while working is essential for the wellbeing of midwives, as well as the importance of knowing how to act on fear and anxiety.</p