The Lantern Vol. 25, No. 3, Summer 1957

• Thunder Rock • Observation Concerning the Life of an International Nomad • The Dingleworm Dilemmahttps://digitalcommons.ursinus.edu/lantern/1072/thumbnail.jp

CYP2C-dependent drug metabolism in vivo; influence of genetics and drug interactions

Cytochrome P450 enzymes (CYPs) are responsible for the metabolism of the majority of therapeutic drugs. This thesis focuses on one of the CYP subfamilies, CYP2C, especially CYP2C9 and CYP2C19, which are responsible for the metabolism of 15– 20% of all drugs. All CYP2C enzymes are polymorphic, i.e. there are genetic variants, which have functional consequences for drug metabolism. Individuals can be classified according to their CYP2C metabolic capacity in extensive (EMs), intermediate (IMs) and poor metabolisers (PMs). Recently, a novel variant of the CYP2C19 gene was described in individuals with high metabolic capacity. This allele, CYP2C19*17, has been claimed to cause ultrarapid metabolism (UM) of CYP2C19 substrates. The aim of this thesis is to explore some of the aspects underlying varying metabolic capacity between, and within, individuals with the focus on genetics and drug–drug interactions. The thesis is based on five published papers. In Paper I we explored the influence of the genetic variant CYP2C9*3 on the CYP2C9 dependent metabolism of the anti-inflammatory and analgesic drug celecoxib. We found a seven-fold higher median exposure at steady-state in homozygous carriers of the CYP2C9*3 allele compared to homozygous wild-type subjects. This might be one factor behind the increased risk of cardiovascular events that has been observed in long-term users of celecoxib in a dose-dependent fashion. Paper II and III focused on the CYP2C19*17 allele that has been associated with extensive metabolism of CYP2C19 substrates. We showed a 52% lower exposure of omeprazole in homozygous *17 carriers compared to homozygous wild-type subjects after a single dose of 40 mg. Regarding steady-state levels of escitalopram (5 mg twice daily for a week), we noted a trend towards a 21% lower exposure in CYP2C19*17 homozygous individuals. However, this did not reach statistical significance in this study that was powered for a 40% difference. The clinical impact (or lack of impact) of this allele for various clinically important CYP2C19 substrates will be discussed in the thesis. A clinical consultation was the starting point for Paper IV in which we described eight cases of increased anticoagulant effect of warfarin in connection with concomitant use of noscapine; a cough medicine available over-the-counter. These cases were reported to the Swedish adverse drug reactions (ADR) register and we could show that they yielded a statistically significant signal worthy of further investigation. In vitro experiments were performed, showing that noscapine strongly inhibited CYP2C9 and CYP3A4, the key enzymes in warfarin metabolism. Besides noscapine, another OTC drug, glucosamine, has attracted interest for suspected interaction with warfarin. In Paper V we addressed the pharmacokinetic aspect of these interactions by giving a cocktail of four probe drugs before and during noscapine or glucosamine. Compared to baseline phenotyping, significant inhibition of both CYP2C9 (4.9-fold increase in the urinary losartan/E3174 ratio; 95% CI 2.8 - 8.4) and CYP2C19 (3.6-fold increase in the plasma omeprazole/5-hydroxyomeprazole ratio; 95% CI 2.6 - 4.8) was seen during noscapine treatment. This is likely to explain the observed interaction with warfarin. No enzyme inhibition was seen with glucosamine and a metabolic interaction between warfarin and glucosamine seems highly unlikely

Syringomatous Tumour Presenting as Inversion of a Supernumerary Nipple

Syringomatous tumour (SyT) is a rare type of benign locally infiltrative tumour with debated origin. Because of the growth pattern, SyT can be mistaken for a malignant tumour, and it is therefore important to keep this diagnosis in mind. This case presents a woman with two supernumerary nipples on each side of the abdomen. One of the nipples was inverted with a small palpable firm mass in close relation to the nipple, leading to referral to the breast surgery department. SyT occurring in a supernumerary nipple and presenting with the symptoms described in this case has to our knowledge never been described previously

The Lantern Vol. 25, No. 2, Spring 1957

• Samarra Train • Caleb: A Story of the Civil War • Pursued • Coup d\u27Etat • Medieval Portraits, Somewhat Diagrammatic • London: 1951, 1952 • Spot: A Tale of the Sea • The Big Mistake • Poetry and College Poetryhttps://digitalcommons.ursinus.edu/lantern/1071/thumbnail.jp

Population pharmacokinetics of apramycin from first-in-human plasma and urine data to support prediction of efficacious dose

BACKGROUND: Apramycin is under development for human use as EBL-1003, a crystalline free base of apramycin, in face of increasing incidence of multidrug-resistant bacteria. Both toxicity and cross-resistance, commonly seen for other aminoglycosides, appear relatively low owing to its distinct chemical structure. OBJECTIVES: To perform a population pharmacokinetic (PPK) analysis and predict an efficacious dose based on data from a first-in-human Phase I trial. METHODS: The drug was administered intravenously over 30 min in five ascending-dose groups ranging from 0.3 to 30 mg/kg. Plasma and urine samples were collected from 30 healthy volunteers. PPK model development was performed stepwise and the final model was used for PTA analysis. RESULTS: A mammillary four-compartment PPK model, with linear elimination and a renal fractional excretion of 90%, described the data. Apramycin clearance was proportional to the absolute estimated glomerular filtration rate (eGFR). All fixed effect parameters were allometrically scaled to total body weight (TBW). Clearance and steady-state volume of distribution were estimated to 5.5 L/h and 16 L, respectively, for a typical individual with absolute eGFR of 124 mL/min and TBW of 70 kg. PTA analyses demonstrated that the anticipated efficacious dose (30 mg/kg daily, 30 min intravenous infusion) reaches a probability of 96.4% for a free AUC/MIC target of 40, given an MIC of 8 mg/L, in a virtual Phase II patient population with an absolute eGFR extrapolated to 80 mL/min. CONCLUSIONS: The results support further Phase II clinical trials with apramycin at an anticipated efficacious dose of 30 mg/kg once daily

The complex crisis: analysis of an impending rockslide in Sunnmøre

Årsstudium i krisehåndtering, 2013Indre Sunnmøre er et av Norges mest besøkte turiststeder, og av de mest kjente områdene internasjonalt. Den trolske naturen målbinder de fleste som ser kontrastene mellom fjord og fjell. Naturen er også lunefull, og i dette området lever man med vissheten om at fjellet vil skape en naturkatastrofe på et eller annet tidspunkt. Samtidig vet man at man bor i et av de tryggeste områdene i Norge, fordi man blir passet på hele døgnet. Her sitter noen av de mest kompetente menneskene på fjellskred i Europa og følger med utviklingen. Utvikler ting seg så blir folk varslet – både innbyggere og de som tilfeldigvis befinner seg i området og har mobil. I tillegg har man egne tyfonanlegg med tale som varsler. Det er ikke mange som kan føle seg så ivaretatt. Man er dermed trygg på at beskjed blir gitt i god tid, og man får folk ut av området før skredet kommer. Utfordringen i det videre er knyttet til håndtering av selve hendelsen. Hvor godt forberedt er samfunnet og de ulike aktørene som skal samhandle

Buzz vs. Sales: Big Social Data Analytics of Style Icon Campaigns and Fashion Designer Collaborations on H&M’s Facebook Page

This paper examines the relationship between social media engagement and financial performance of the global fast fashion company, H&M. We analyze big social data from Facebook on the seven H&M style collections that occurred during 2012 and 2013 to investigate if style icon campaigns have a larger effect on quarterly sales than designer collaborations. We find that style icons such as David Beckham generate more social buzz than designer collaborations. Social Set Analysis of the Facebook data shows that the overlap between the users H&M reach with their different style collections is fairly small. The deviations between forecasted quarterly sales and actual quarterly sales are analyzed. Our results show that that style icon campaigns have a larger impact on sales than designer collaborations and reveal that the quarters with the largest deviations coincide with the quarter in which H&M ran a style icon campaign. We discuss the implications of our findings and outline directions for future research