Inter-subject variability in oral drug absorption

A low and highly variable bioavailability is often the main reason for the failure of the development of a drug intended for oral delivery. Focusing on absorption instead of bioavailability from oral administration enables the identification and understanding of key causes of low and erratic absorption to improve drug performance in early development. In the work carried out as part of this thesis, the in silico estimation of drug absorption (fa*fg) was carried out. The use of a population pharmacokinetic approach was proposed, as implemented in NONMEM, to estimate fa*fg and variability from phase I clinical studies (AstraZeneca database). This work enabled the identification of the rate limiting step in oral drug absorption, and allowed for comparisons of fa*fg and inter-subject variability for different drug formulations. Solubility/dissolution and permeability were investigated in vitro in terms of their variability for two model drugs – dipyridamole and furosemide. Physiological parameters such as bile salt concentrations and pH were simulated in vitro to understand their effects on the absorption process. Dipyridamole saturated solubility and dissolution are pH and bile salt dependent. However, when both dissolution and permeability were tested simultaneously, it was found that pH plays an important factor in the permeation of dipyridamole rather than bile salt concentration. This can explain to some extent the variability between individuals in the absorption of dipyridamole. Furosemide solubility experiments showed that pH, buffer capacity and, to a lesser extent, bile salt concentration affect its saturated solubility. Surprisingly, almost complete drug release was observed under all simulated conditions with a clinical dose. Similarly, the permeation of furosemide did not differ under different conditions. It was suggested that with this clinical dose, other physiological parameters contribute to variability in furosemide absorption, such as gastric emptying time. Moreover, the efficacy of three formulations (solid dispersion, Self Micro Emulsifying Drug Delivery systems and nano-particles) in increasing solubility\ dissolution in vitro and in vivo in the rat model was compared. Lack of IVIVC was observed. It was suggested that the missing link is the human absorption estimation that can be resolved by the proposed population pharmacokinetics approach presented herein

The explicit freedoms in our model democracy

Liberty isn't like a tap; it isn't something that can be turned on and off at will. Much the same can be said for freedom of speech, including the freedom of the media, and the freedom of citizens to use the media to express their views

All disease begins in the gut: Influence of gastrointestinal disorders and surgery on oral drug performance

The term "disease" conjures up a plethora of graphic imagery for many, and the use of drugs to combat symptoms and treat underlying pathology is at the core of modern medicine. However, the effects of the various gastrointestinal diseases, infections, co-morbidities and the impact of gastrointestinal surgery on the pharmacokinetic behaviour of drugs have been largely overlooked. The better elucidation of disease pathology and the role of underlying cellular and molecular mechanisms have increased our knowledge as far as diagnoses and prognoses are concerned. In addition, the recent advances in our understanding of the intestinal microbiome have linked the composition and function of gut microbiota to disease predisposition and development. However, this knowledge applies less so in the context of drug absorption and distribution mechanisms for orally administered dosage forms. Here, we revisit and re-evaluate the influence of a portfolio of gastrointestinal diseases and surgical effects on the functionality of the gastrointestinal tract, their implications for drug delivery and attempt to uncover significant links for clinical practice

A model for legal compliance in the South African banking sector : an information security perspective

In the past, many organisations used to keep their information on paper, which resulted in the loss of important information. In today’s knowledge era the information super-highway facilitates highly connected electronic environments where business applications can communicate on an intra- as well as inter-organizational level. As business expanded more into the cyber-world, so did the need to protect the information they have. Technology advances did not only bring benefits, it also increased the vulnerability of companies’ information. Information, the lifeblood of an organization, must be protected from threats such as hackers and fraud, amongst others. In the highly regulated financial sector, the protection of information is not only a best practice, but a legal obligation carrying penalties for non-compliance. From a positive aspect, organisations can identify security controls that can help them to secure their information, with the aid of legal sources. But organisations find themselves burdened by a burgeoning number of legal sources and requirements, which require vast resources and often become unmanageable. This research focuses on finding a solution for South African banks to comply with multiple legal sources, as seen from an information security perspective

Erasmus in crisistijd. Stefan Zweig en zijn "Triumph und Tragik des Erasmus von Rotterdam"

__Abstract__ Rede uitgesproken bij de openbare aanvaarding van het ambt van bijzonder hoogleraar vanwege de Erasmusstichting met als leeropdracht cultuurgeschiedenis, in het bijzonder de intellectuele geschiedenis van de late 15e tot de late 17e eeuw, bij de Erasmus School of History, Culture and Communication van de Erasmus Universiteit Rotterdam op 12 december 2013. Mijnheer de Rector Magnificus, dames en heren, Als Amsterdammer uit de Watergraafsmeer uitverkoren om een leer-stoel te bekleden namens een stichting die de naam draagt van de grote Rotterdammer, tevens de naamgever van deze universiteit, is het een beetje opletten wat je ex cathedra over Erasmus zegt; al te onaardige dingen worden je mogelijk al snel nagedragen. Maar zelfs met dit in het achterhoofd is er denk ik weinig mis mee om te constateren dat Desiderius Erasmus een leven heeft geleid dat arm was aan uiterlijke hoogtepunten. Dat heeft biografen er niettemin nooit van weerhouden om zich te wagen aan het vervaardigen van weer een nieuwe levensbeschrijving. Vanaf de korte vita die de eerste onder hen, Erasmus' goede vriend Beatus Rhenanus, nog in het sterfjaar 1536 liet verschijnen, tot aan het dit najaar verschenen hoorcollege op vier CD's van Hans Trapman, gaat het inmiddels om een hoeveelheid werken waarmee een flinke boekenkast te vullen valt

Robotic Trachelectomy After Supracervical Hysterectomy for Benign Gynecologic Disease

A renewed interest in the supra cervical approach to hysterectomy has created a cohort of patients with a retained cervix at risk of persistent symptoms requiring a subsequent trachelectomy. The objective of this study was to evaluate the efficacy of robotic trachelectomy after a previous supracervical hysterectomy

Gut reaction: impact of systemic diseases on gastrointestinal physiology and drug absorption

It was in 400 BC that Hippocrates reportedly stated that "death sits in the colon". The growth in our knowledge of the intestinal microbiome and the gut-brain axis, their function and imbalance, has distinctly uncovered the complex relationship between the gut to disease predisposition and development, heralding the problem and the solution to disease pathology. Human studies of new drug molecules are typically performed in healthy volunteers and their specific disease indication. Approved drugs, however, are used by patients with diverse disease backgrounds. Here, we review the current literature of the gastrointestinal tract reacting to systemic disease pathology that elicits physiological and functional changes that consequently affect oral drug product performance