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- McCrae, Cristopher, et al.
(author)
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Lanosterol Synthase Regulates Human Rhinovirus Replication in Human Bronchial Epithelial Cells
- 2018
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In: American Journal of Respiratory Cell and Molecular Biology. - 1044-1549. ; 59:6, s. 713-722
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Journal article (peer-reviewed)abstract
- Human rhinovirus (RV) infections are a significant risk factor for exacerbations of asthma and chronic obstructive pulmonary disease. Thus, approaches to prevent RV infection in such patients would give significant benefit. Through RNA interference library screening, we identified lanosterol synthase (LSS), a component of the cholesterol biosynthetic pathway, as a novel regulator of RV replication in primary normal human bronchial epithelial cells. Selective knock down of LSS mRNA with short interfering RNA inhibited RV2 replication in normal human bronchial epithelial cells. Small molecule inhibitors of LSS mimicked the effect of LSS mRNA knockdown in a concentration-dependent manner. We further demonstrated that the antiviral effect is not dependent on a reduction in total cellular cholesterol but requires a 24-hour preincubation with the LSS inhibitor. The rank order of antiviral potency of the LSS inhibitors used was consistent with LSS inhibition potency; however, all compounds showed remarkably higher potency against RV compared with the LSS enzyme potency. We showed that LSS inhibition led to an induction of 24(S),25 epoxycholesterol, an important regulator of the sterol pathway. We also demonstrated that LSS inhibition led to a profound increase in expression of the innate antiviral defense protein, IFN-beta. We found LSS to be a novel regulator of RV replication and innate antiviral immunity and identified a potential molecular mechanism for this effect, via induction of 24(S),25 epoxycholesterol. Inhibition of LSS could therefore be a novel therapeutic target for prevention of RV-induced exacerbations.
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- Bernander, R., et al.
(author)
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Genome ploidy in different stages of the Giardia lamblia life cycle
- 2001
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In: CELLULAR MICROBIOLOGY. - : BLACKWELL SCIENCE LTD. - 1462-5814. ; 3:1, s. 55-62
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Journal article (peer-reviewed)abstract
- The early diverging eukaryotic parasite Giardia lamblia is unusual in that it contains two apparently identical nuclei in the vegetative trophozoite stage. We have determined the nuclear and cellular genome ploidy of G. lamblia cells during all stages of
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- Stangier, J., et al.
(author)
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Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement
- 2005
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In: J Clin Pharmacol. - 0091-2700. ; 45:5, s. 555-63
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Journal article (peer-reviewed)abstract
- Dabigatran etexilate is an oral low-molecular-weight direct thrombin inhibitor. Following oral administration, dabigatran etexilate is rapidly converted to its active form, dabigatran. The authors investigated the absorption, distribution, and elimination of a single 150-mg dose capsule formulation of dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. In an open-label, 3-way crossover study, dabigatran etexilate was administered to 18 male volunteers in the fasted state, after administration of food and with coadministration of the proton pump inhibitor, pantoprazole. In a subsequent multicenter, open-label study, 59 patients received a single dose of dabigatran etexilate, administered 1 to 3 hours following total hip replacement. In healthy volunteers, food had no effect on the extent of absorption of dabigatran etexilate, although there was reduced interindividual variability for dabigatran maximum plasma concentration and AUC(0-infinity). A decrease in the mean dabigatran AUC(0-infinity) (904 to 705 ng*h/mL) occurred with coadministration of pantoprazole. In patients undergoing total hip replacement, immediate onset of absorption was seen with the maximum plasma concentration of dabigatran occurring after 6 hours. The AUC(0-24) of dabigatran was 88% of the steady-state AUC using a preliminary tablet formulation and 106% of that seen in the healthy volunteer study. Compared with healthy volunteers, the postoperative profile was flattened with delayed peak concentrations. In summary, administration of the dabigatran etexilate capsule with food has no effect on the extent of dabigatran absorption, with a moderate decrease when coadministered with pantoprazole. Adequate plasma concentrations of dabigatran were seen with early postoperative administration of the dabigatran etexilate capsule. These pharmacokinetic characteristics confirm the suitability of this oral solid dosage form for use in future clinical trials.
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