Drug delivery during breastfeeding: investigations of formulations and clinical feasibility

Research presented in this thesis was jointly supervised by the Department of Chemical Engineering and Biotechnology (School of Technology) and the Department of Paediatrics (School of Clinical Medicine).At an age when breastfeeding is the optimal nutritional support for infants, oral drug delivery can be challenging. In the past, the concept of drug delivery during breastfeeding was developed as a means to address challenges in low-income countries by facilitating administration using solid dosage forms without the need for clean water. Hereby, a silicone nipple shield, containing a formulation inside its teat, is meant to be worn by a mother during breastfeeding, enabling drug delivery to the sucking infant through the flow of human milk. Furthering past research, this doctoral work aimed to investigate novel dosage forms for this application, including a fibrous matrix and a gel formulation, as well as the clinical potential, feasibility, and acceptability of therapeutic delivery during breastfeeding. In a clinical context, a descriptive qualitative study revealed the need for alternative infant oral drug delivery technologies in high-resource settings, and parents' and nursing staff's positive response to the concept of drug delivery during breastfeeding. Findings were supported by the anecdotal evidence of difficulties in infant compliance and accurate dosing, and indicated high relevance for a use case in neonatal intensive care. Formulation investigations included zinc sulphate loaded non-woven fibre mats, and iron sulphate loaded liquid-core alginate hydrogels, using a modified and a commercially available nipple shield design. While full release during breastfeeding simulation was not achieved, both formulations enabled superior delivery of their loaded therapeutic dose compared to previously studied dosage forms. In addition, a clinical feasibility study involving the delivery of vitamin B12 from a commercially available nipple shield during breastfeeding was conducted, supported by a qualitative mixed methods approach. Results illustrated the successful delivery of vitamin B12 to breastfed infants and unanimous maternal advocacy for the availability of therapeutic delivery during breastfeeding in the future.University of Cambridge's W.D. Armstrong Fund (W.D. Armstrong Studentship for the Application of Engineering in Medicine) University of Cambridge's Kurt Hahn Trust (Kurt Hahn Scholarship) German Academic Scholarship Foundation (PhD Scholarship

Grün in der Stadt

Die vorliegende Arbeit behandelt das Thema Natur in der Stadt und ihre Bedeutung für die Lebensqualität von Städtern. Ziel der Untersuchung war, die häufig berichtete positive Wirkung von Natur und naturnahen Elementen im städtischen Raum auf die subjektive Lebensqualität empirisch zu untermauern. Von besonderem Interesse war das Vorkommen sowie die Nutzung von Natur und Grünräumen und ob sich Unterschiede in der subjektiven Lebensqualität der Stadtbewohner hinsichtlich der zwei Konstrukte ergeben. Des Weiteren wurde untersucht, welche Bedeutung öffentlich zugängliche Grünräume im Gegensatz zu privaten Grünstrukturen für die Lebensqualität von Städtern haben. Dazu wurde versucht „Grün“ bzw. „Natur“ in der Stadt messbar zu machen. Mit Hilfe eines teils selbst konstruierten Fragebogens wurde eine schriftliche Erhebung in der Stadt Wien, als repräsentatives Beispiel für eine Großstadt, durchgeführt. Die Bedeutung des Öffentlichen Grünraums für die Lebensqualität der Stadtbewohner konnte sowohl hinsichtlich des Vorkommens, als auch hinsichtlich der Nutzung bestätigt werden. Das Vorhandensein von Straßenbegrünung und nahe der Wohnumgebung gelegenen Parks, scheint für die umweltbezogene Lebensqualität besonders wichtig zu sein. In Bezug auf die Nutzung Öffentlicher Grünräume erwies sich insbesondere die Berufstätigkeit, und somit die verfügbare Zeit der befragten Personen als relevant. In Bezug auf die Privaten Grünstrukturen und ihre Bedeutung für die Lebensqualität konnten in dieser Untersuchung, entgegen den Vorhersagen aus der Literatur, keinerlei Auswirkungen des Vorkommens Privater Grünstrukturen auf die subjektive Lebensqualität festgestellt werden. Die Nutzung Privater Grünstrukturen zeigte sich, unter Auspartialisierung des Geschlechtereffektes, bestimmend für die globale, psychische und soziale Dimension der Lebensqualität

Subcutaneous vitamin B12 administration using a portable infusion pump in cobalamin-related remethylation disorders: a gentle and easy to use alternative to intramuscular injections

BACKGROUND Cobalamin (cbl)-related remethylation disorders are a heterogeneous group of inherited disorders comprising the remethylation of homocysteine to methionine and affecting multiple organ systems, most prominently the nervous system and the bone marrow. To date, the parenteral, generally intramuscular, lifelong administration of hydroxycobalamin (OHCbl) is the mainstay of therapy in these disorders. The dosage and frequency of OHCbl is titrated in each patient to the minimum effective dose in order to account for the painful injections. This may result in undertreatment, a possible risk factor for disease progression and disease-related complications. RESULTS We describe parenteral administration of OHCbl using a subcutaneous catheter together with a portable infusion pump in a home therapy setting in four pediatric patients with remethylation disorders, two patients with cblC, one patient with cblG, and one patient with cblE deficiency, in whom intramuscular injections were not or no longer feasible. The placement of the subcutaneous catheters and handling of the infusion pump were readily accomplished and well accepted by the patients and their families. No adverse events occurred. The use of a small, portable syringe driver pump allowed for a most flexible administration of OHCbl in everyday life. The concentrations of total homocysteine levels were determined at regular patient visits and remained within the therapeutic target range. This approach allowed for the continuation of OHCbl therapy or the adjustment of therapy required to improve metabolic control in our patients. CONCLUSIONS Subcutaneous infusion using a subcutaneous catheter system and a portable pump for OHCbl administration in combined and isolated remethylation disorders is safe, acceptable, and effective. It decreases disease burden in preventing frequent single injections and providing patient independence. Thus, it may promote long-term adherence to therapy in patients and parents

Effects of mild hypothermia on hemodynamics in cardiac arrest survivors and isolated failing human myocardium

Post-cardiac arrest myocardial dysfunction is a common phenomenon after return of spontaneous circulation (ROSC) and contributes to hemodynamic instability and low survival rates after cardiac arrest. Mild hypothermia for 24 h after ROSC has been shown to significantly improve neurologic recovery and survival rates. In the present study we investigate the influence of therapeutic hypothermia on hemodynamic parameters in resuscitated patients and on contractility in failing human myocardium. We analyzed hemodynamic data from 200 cardiac arrest survivors during the hypothermia period. The initial LVEF was 32.6 ± 1.2% indicating a significantly impaired LV function. During hypothermia induction, the infusion rate of epinephrine could be significantly reduced from 9.1 ± 1.3 μg/min [arrival intensive care unit (ICU) 35.4°C] to 4.6 ± 1.0 μg/min (34°C) and 2.8 ± 0.5 μg/min (33°C). The dobutamine and norepinephrine application rates were not changed significantly. The mean arterial blood pressure remained stable. The mean heart rate significantly decreased from 91.8 ± 1.7 bpm (arrival ICU) to 77.3 ± 1.5 bpm (34°C) and 70.3 ± 1.4 bpm (33°C). In vitro we investigated the effect of hypothermia on isolated ventricular muscle strips from explanted failing human hearts. With decreasing temperature, the contractility increased to a maximum of 168 ± 23% at 27°C (n = 16, P < 0.05). Positive inotropic response to hypothermia was accompanied by moderately increased rapid cooling contractures as a measure of sarcoplasmic reticulum (SR) Ca2+ content, but can be elicited even when the SR Ca2+ release is blocked in the presence of ryanodine. Contraction and relaxation kinetics are prolonged with hypothermia, indicating increased Ca2+ sensitivity as the main mechanism responsible for inotropy. In conclusion, mild hypothermia stabilizes hemodynamics in cardiac arrest survivors which might contribute to improved survival rates in these patients. Mechanistically, we demonstrate that hypothermia improves contractility in failing human myocardium most likely by increasing Ca2+-sensitivity

An Inverse Thermogelling Bioink Based on an ABA-Type Poly(2-oxazoline) Amphiphile

Hydrogels are key components in several biomedical research areas such as drug delivery, tissue engineering, and biofabrication. Here, a novel ABA-type triblock copolymer comprising poly(2-methyl-2-oxazoline) as the hydrophilic A blocks and poly(2-phenethyl-2-oxazoline) as the aromatic and hydrophobic B block is introduced. Above the critical micelle concentration, the polymer self-assembles into small spherical polymer micelles with a hydrodynamic radius of approx 8-8.5 nm. Interestingly, this specific combination of hydrophilic and hydrophobic aromatic moieties leads to rapid thermoresponsive inverse gelation at polymer concentrations above a critical gelation concentration (20 wt %) into a macroporous hydrogel of densely packed micelles. This hydrogel exhibited pronounced viscoelastic solid-like properties, as well as extensive shear-thinning, rapid structure recovery, and good strain resistance properties. Excellent 3D-printability of the hydrogel at lower temperature opens a wide range of different applications, for example, in the field of biofabrication. In preliminary bioprinting experiments using NIH 3T3 cells, excellent cell viabilities of more than 95% were achieved. The particularly interesting feature of this novel material is that it can be used as a printing support in hybrid bioink systems and sacrificial bioink due to rapid dissolution at physiological conditions.Peer reviewe

Drug delivery from a solid formulation during breastfeeding-A feasibility study with mothers and infants.

Funder: University of Cambridge WD Armstrong TrustFunder: University of Cambridge Kurt Hahn TrustFunder: Studienstiftung des Deutschen Volkes; funder-id: http://dx.doi.org/10.13039/501100004350BACKGROUND: Breastfeeding is critical to health outcomes, particularly in low-resource settings where there is little access to clean water. For infants in their first twelve months of life, the delivery of medications is challenging, and use of oral syringes to deliver liquid formulations can pose both practical and emotional challenges. OBJECTIVE: To explore the potential to deliver medicine to infants via a solid formulation during breastfeeding. METHODS: Single center feasibility study within a tertiary level neonatal unit in the UK, involving twenty-six breastfeeding mother-infant dyads. A solid formulation of Vitamin B12 was delivered to infants during breastfeeding. Outcomes included the quantitative change in serum vitamin B12 and assessment of maternal expectations and experiences. RESULTS: Delivery of Vitamin B12 through a solid formulation that dissolved in human milk did not impair breastfeeding, and Vitamin B12 levels rose in all infants from a mean baseline (range) 533 pg/mL (236-925 pg/mL) to 1871 pg/mL (610-4981 pg/mL) at 6-8 hours post-delivery. Mothers described the surprising ease of 'drug' delivery, with 85% reporting a preference over the use of syringes. CONCLUSIONS: Solid drug formulations can be delivered during breastfeeding and were preferred by mothers over the delivery of liquid formulations via a syringe

The complete genome sequence and comparative genome analysis of the high pathogenicity Yersinia enterocolitica strain 8081

The human enteropathogen, Yersinia enterocolitica, is a significant link in the range of Yersinia pathologies extending from mild gastroenteritis to bubonic plague. Comparison at the genomic level is a key step in our understanding of the genetic basis for this pathogenicity spectrum. Here we report the genome of Y. enterocolitica strain 8081 (serotype 0:8; biotype 1B) and extensive microarray data relating to the genetic diversity of the Y. enterocolitica species. Our analysis reveals that the genome of Y. enterocolitica strain 8081 is a patchwork of horizontally acquired genetic loci, including a plasticity zone of 199 kb containing an extraordinarily high density of virulence genes. Microarray analysis has provided insights into species-specific Y. enterocolitica gene functions and the intraspecies differences between the high, low, and nonpathogenic Y. enterocolitica biotypes. Through comparative genome sequence analysis we provide new information on the evolution of the Yersinia. We identify numerous loci that represent ancestral clusters of genes potentially important in enteric survival and pathogenesis, which have been lost or are in the process of being lost, in the other sequenced Yersinia lineages. Our analysis also highlights large metabolic operons in Y. enterocolitica that are absent in the related enteropathogen, Yersinia pseudotuberculosis, indicating major differences in niche and nutrients used within the mammalian gut. These include clusters directing, the production of hydrogenases, tetrathionate respiration, cobalamin synthesis, and propanediol utilisation. Along with ancestral gene clusters, the genome of Y. enterocolitica has revealed species-specific and enteropathogen-specific loci. This has provided important insights into the pathology of this bacterium and, more broadly, into the evolution of the genus. Moreover, wider investigations looking at the patterns of gene loss and gain in the Yersinia have highlighted common themes in the genome evolution of other human enteropathogens

Gene drives for schistosomiasis transmission control.

Schistosomiasis is one of the most important and widespread neglected tropical diseases (NTD), with over 200 million people infected in more than 70 countries; the disease has nearly 800 million people at risk in endemic areas. Although mass drug administration is a cost-effective approach to reduce occurrence, extent, and severity of the disease, it does not provide protection to subsequent reinfection. Interventions that target the parasites' intermediate snail hosts are a crucial part of the integrated strategy required to move toward disease elimination. The recent revolution in gene drive technology naturally leads to questions about whether gene drives could be used to efficiently spread schistosome resistance traits in a population of snails and whether gene drives have the potential to contribute to reduced disease transmission in the long run. Responsible implementation of gene drives will require solutions to complex challenges spanning multiple disciplines, from biology to policy. This Review Article presents collected perspectives from practitioners of global health, genome engineering, epidemiology, and snail/schistosome biology and outlines strategies for responsible gene drive technology development, impact measurements of gene drives for schistosomiasis control, and gene drive governance. Success in this arena is a function of many factors, including gene-editing specificity and efficiency, the level of resistance conferred by the gene drive, how fast gene drives may spread in a metapopulation over a complex landscape, ecological sustainability, social equity, and, ultimately, the reduction of infection prevalence in humans. With combined efforts from across the broad global health community, gene drives for schistosomiasis control could fortify our defenses against this devastating disease in the future