Zambon (Netherlands)

Biliary atresia, severe FIC1 and severe BSEP deficiency (also known as PFIC1 and PFIC2) are rare cholestatic childhood diseases. The aim of this thesis was to identify novel targets of intervention for improving the prognosis of patients suffering these diseases. The studies conducted in this thesis demonstrate that national or global collaboration allows to obtain novel insights in the natural history of rare liver diseases and their responsiveness to specific treatments. These insights have already led to patient-tailored changes in treatments for these diseases and are expected to have more impact in the near future, not only for the care and counselling of individual patients but also for understanding the pathophysiology of these rare diseases. The studies underline the value, if not the necessity, of collaborative efforts of clinicians, authorities and patient advocates for improving the prognosis of patients with rare diseases and for the advancement of science.

INTRODUCTION The E dry ® spray dried particle engineering technique can be used to generate inhaled drugs using existing compounds and inhalers, yet with optimal size and de-agglomeration characteristics. For Z7200 (budesonide (BUD)/formoterol fumarate (FF) 80/2.25µg) it was demonstrated via in-vitro and in-silico testing that the E dry technology allows for comparable lung deposition with half the delivered dose compared to the reference product (Symbicort® Turbohaler®: 160/4.5µg). The aim of this work was to investigate if the pharmacodynamic effects of Z7200 are also comparable to the ones of its reference product. METHODS A double blind, double dummy, randomized, two way cross over study was performed to compare the acute effects of Z7200 and Symbicort in 20 asthma patients. Drug effects were analyzed by FRI changes in airway volumes and resistances, lung function and patient feeling. RESULTS Both products showed improved lung function for all measured variables; see figure1 for the FRI airway volume and FEV1. Patient feeling did not improve with either product. Also, no statistically significant differences in treatment effect were found between the test and reference product. CONCLUSIONS This work shows that there was no difference in efficacy parameters between Z7200 and Symbicort®, notably considering the delivered dose of the test product was half of the that of the reference product.

Introduction: Heterozygous familial hypercholesterolemia (HeFH) increases the risk of cardiovascular disease. Traditionally it has been reported that the most affected territory is the coronary arteries tree. However, there are very few data from large cohorts of HeFH and even fewer data comparing them with a control population. Hypotesis: To analyse the prevalence and location of cardiovascular disease in individuals with HeFH and their families with negative genetic diagnosis in a large study. Methods: Data from the study, which recruited 3745 individuals aged 18 and olderbetween January 2004 and November 2013 were analysed. Out of them, 2752 were genetically diagnosesof HeFH and 993 were family members without the mutation. Results: Median age of individuals with HeFH was 44 years (18-89) and 40 (18-87) in unaffected relatives. One thousand, two hundred and sixty four (45.90%) HeFH and 463 (46.60%) controls were male. Table and figure show atherothrombotic disease prevalence in different locations. Conclusions: The prevalence of atherothrombotic disease is higher in individuals with HeFH than in their unaffected relatives. In HeFH patients, the predominant involvement is at the level of the coronary tree.

Objectives: Deactivation of endotheliumderived relaxing factor due to an increased oxygen radical load during sepsis may contribute to an impairment in microcirculatory blood flow. We investigated whether treatment with the sulfhydryl donor and oxygen radical scavenger, N-acetylcysteine, would improve wholebody oxygen consumption (V̇o2), gastric intramucosal pH, and veno-arterial CO2 gradient (veno-arterial Pco2) during septic shock. Design: Prospective, randomized, doubleblind study conducted over 2 yrs. Setting: Septic shock patients admitted to the intensive care unit. Patients: Fifty-eight patients requiring hemodynamic monitoring (radial and pulmonary artery catheters) due to septic shock, were included in this study. All patients were examined within 72 hrs after the onset of sepsis. They were optimally resuscitated by conventional means with volume and inotropic agents, and exhibited stable clinical conditions (hemodynamic values, body temperature, hemoglobin, Fio2). Interventions: A gastric tonometer was inserted to measure the gastric intramucosal pH. Subjects randomly received either 150 mg/kg of intravenous N-acetylcysteine or placebo over a 15-min period, then a continuous infusion of 12.5 mg/hr of N-acetylcysteine or placebo over ˜90 mins. Measurements: Infusion measurements were begun 60 mins after the beginning of infusion and lasted ˜30 mins. The infusion was then discontinued and 2 hrs later the final measurements were taken. Main Results: Basic patient characteristics (age, sex, Acute Physiology and Chronic Health Evaluation [APACHE] II scores, Multiple Organ Failure scores) did not differ significantly, nor did pre- and 2-hr postinfusion measurements differ between any of the groups. Thirteen (45%) patients responded (i.e., showed an increase in V̇o2 >10%, reaching a mean of 19%) to the N-acetylcysteine infusion. The N-acetylcysteine responders also showed an increase in gastric intramucosal pH, a decrease in veno-arterial Pco2, an increase in oxygen delivery, cardiac index, stroke index, and left ventricular stroke work index, as well as a significant decrease in systemic vascular resistance in comparison to baseline. The N-acetylcysteine nonresponders, as well as the patients in the placebo group, did not show any significant changes in any of these variables. The N-acetylcysteine responders had a higher survival rate (69%) than the nonresponders (19%) and were studied earlier after onset of sepsis (37 hrs) than the nonresponders (61 hrs). The only significant difference between the entire N-acetylcysteine group (which included responders plus nonresponders) and the placebo group was an increased V̇o2 in the entire N-acetylcysteine group during infusion measurements. Conclusions: N-acetylcysteine provided a transient improvement in tissue oxygenation in about half of the septic shock patients, as indicated by an increase in V̇o2 and gastric intramucosal pH and a decrease in veno-arterial Pco2. The higher survival rate in the N-acetylcysteine responders and the fact that half of the patients receiving N-acetylcysteine did not respond, suggests that, in some patients, sepsis irreversibly damages the microvasculature to the extent that N-acetylcysteine has no effect. If analyzed by intention to treat, the N-acetylcysteine did not produce effects that were significantly different from the placebo. Whether the N-acetylcysteine challenge was merely diagnostic or whether N-acetylcysteine can be effective in the treatment of sepsis deserves further investigation. (Crit Care Med 1994; 22:1738–1746)