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Microplastics (MPs) in the environment are becoming a growing concern worldwide. Produced by the weathering of plastic waste or through intentional manufacturing, these microscopic synthetic particles are associated with adverse health effects in humans, animals, and even microbes. Due to their small size, MPs have an exceptionally large surface area that, in combination with their intrinsic hydrophobicity and natural weathering, gives them an increased affinity for toxins. Indeed, MPs can contain up to a million times the concentration of heavy metals, organic pollutants, and toxic secondary metabolites compared to their environment. Internalisation of or adherence to MPs by microorganisms has been linked to a decreased growth rate, altered gene expression, lower photosynthetic efficiency, and even cell death. However, despite their toxicity, the microbial utilisation of MPs as tools for protection, carbon and nutrient acquirement, and gene transfer through biofilm formation has now been recognised. Furthermore, microbe-mediated depolymerisation and mineralisation of MPs through the emergence of plastic-degrading enzymes and oxygen radicals highlights the employment of microorganisms as potential solution for the removal of MPs from the biosphere. Yet, it is unlikely that efficient degradation pathways for different types of plastic will evolve naturally in the near future, meaning that alternative approaches must be considered to clean-up the planet. Ultimately, this literature review presents the state of the art on MPs as microbial toxins and tools while exposing the MP-degradation potential of microorganisms and their role in decontaminating the environment.

Item does not contain fulltext, Tabaksverslaving wordt, in tegenstelling tot verslaving aan alcohol en drugs, vaak ten onrechte gezien als een ongezonde leefstijl. Tabaksverslaving is een verslaving zoals alle andere, waarbij biologische, psychologische en sociale factoren een interacterende rol spelen. De DSM-5 geeft criteria voor een 'Stoornis in het gebruik van tabak'. Patiënten met een ernstige tabaksverslaving hebben intensievere, gespecialiseerde behandeling nodig. Door tabaksverslaving niet langer te beschouwen als een leefstijlprobleem maar als een verslavingsziekte, zal de bereidheid van zorgmedewerkers om het probleem bespreekbaar te maken, groter worden. Dat vergroot ook de bereidheid van rokers om in behandeling te gaan. Leefstijlgeneeskunde en verslavingsgeneeskunde omarmen elkaar. Vanuit het oogpunt van preventie is dat geheel terecht. Preventie van het gebruik van verslavende stoffen kan veel narigheid voorkomen. Tabaksverslaving wordt echter, in tegenstelling tot verslaving aan alcohol en drugs, vaak ten onrechte gezien als een ongezonde leefstijl, een leefstijlprobleem. In dit artikel betogen wij dat een verschuiving in de visie op tabaksverslaving van leefstijlprobleem naar echte verslaving bijdraagt aan betere zorg voor patiënten met een tabaksverslaving.

Contains fulltext : 236277.pdf (Publisher’s version ) (Closed access), Tabaksverslaving wordt, in tegenstelling tot verslaving aan alcohol en drugs, vaak ten onrechte gezien als een ongezonde leefstijl. Tabaksverslaving is een verslaving zoals alle andere, waarbij biologische, psychologische en sociale factoren een interacterende rol spelen. De DSM-5 geeft criteria voor een 'Stoornis in het gebruik van tabak'. Patiënten met een ernstige tabaksverslaving hebben intensievere, gespecialiseerde behandeling nodig. Door tabaksverslaving niet langer te beschouwen als een leefstijlprobleem maar als een verslavingsziekte, zal de bereidheid van zorgmedewerkers om het probleem bespreekbaar te maken, groter worden. Dat vergroot ook de bereidheid van rokers om in behandeling te gaan. Leefstijlgeneeskunde en verslavingsgeneeskunde omarmen elkaar. Vanuit het oogpunt van preventie is dat geheel terecht. Preventie van het gebruik van verslavende stoffen kan veel narigheid voorkomen. Tabaksverslaving wordt echter, in tegenstelling tot verslaving aan alcohol en drugs, vaak ten onrechte gezien als een ongezonde leefstijl, een leefstijlprobleem. In dit artikel betogen wij dat een verschuiving in de visie op tabaksverslaving van leefstijlprobleem naar echte verslaving bijdraagt aan betere zorg voor patiënten met een tabaksverslaving.

Contains fulltext : 236277.pdf (Publisher’s version ) (Closed access), Tabaksverslaving wordt, in tegenstelling tot verslaving aan alcohol en drugs, vaak ten onrechte gezien als een ongezonde leefstijl. Tabaksverslaving is een verslaving zoals alle andere, waarbij biologische, psychologische en sociale factoren een interacterende rol spelen. De DSM-5 geeft criteria voor een 'Stoornis in het gebruik van tabak'. Patiënten met een ernstige tabaksverslaving hebben intensievere, gespecialiseerde behandeling nodig. Door tabaksverslaving niet langer te beschouwen als een leefstijlprobleem maar als een verslavingsziekte, zal de bereidheid van zorgmedewerkers om het probleem bespreekbaar te maken, groter worden. Dat vergroot ook de bereidheid van rokers om in behandeling te gaan. Leefstijlgeneeskunde en verslavingsgeneeskunde omarmen elkaar. Vanuit het oogpunt van preventie is dat geheel terecht. Preventie van het gebruik van verslavende stoffen kan veel narigheid voorkomen. Tabaksverslaving wordt echter, in tegenstelling tot verslaving aan alcohol en drugs, vaak ten onrechte gezien als een ongezonde leefstijl, een leefstijlprobleem. In dit artikel betogen wij dat een verschuiving in de visie op tabaksverslaving van leefstijlprobleem naar echte verslaving bijdraagt aan betere zorg voor patiënten met een tabaksverslaving.

The mainstream bioethical discourse on germline editing, intervening in the genome of a human embryo, has tended to focus on arguments of safety, benefits, autonomy and social justice, and to be universalist in kind. Rehmann-Sutter has recently argued that attention should be paid to the lifeworld and relational perspective of parent and child, because they will be most directly affected by the technology. In this thesis, Rehmann-Sutter’s argument of relationality, which holds that what is morally troublesome about germline editing is that it might negatively change the parent-child relationship, is critically discussed. Rehmann-Sutter bases this argument on a theoretical framework that takes into account a biology and phenomenology of the germline. The germline is conceptualised as a vulnerable entity that is the embodiment of the relationship between generations, relating them backwards and forwards in time. While Rehmann-Sutter’s claim that germline editing burdens the parents with a plethora of choice is rejected, it is argued that germline editing might be experienced by parent and child as intrusive in a manner that other reproductive technologies might not be. It is concluded that, in opting for germline editing, parents should make a decision that allows for a loving parent-child relationship to be maintained.

The mainstream bioethical discourse on germline editing, intervening in the genome of a human embryo, has tended to focus on arguments of safety, benefits, autonomy and social justice, and to be universalist in kind. Rehmann-Sutter has recently argued that attention should be paid to the lifeworld and relational perspective of parent and child, because they will be most directly affected by the technology. In this thesis, Rehmann-Sutter’s argument of relationality, which holds that what is morally troublesome about germline editing is that it might negatively change the parent-child relationship, is critically discussed. Rehmann-Sutter bases this argument on a theoretical framework that takes into account a biology and phenomenology of the germline. The germline is conceptualised as a vulnerable entity that is the embodiment of the relationship between generations, relating them backwards and forwards in time. While Rehmann-Sutter’s claim that germline editing burdens the parents with a plethora of choice is rejected, it is argued that germline editing might be experienced by parent and child as intrusive in a manner that other reproductive technologies might not be. It is concluded that, in opting for germline editing, parents should make a decision that allows for a loving parent-child relationship to be maintained.

Contains fulltext : 190027.pdf (publisher's version ) (Closed access)

Contains fulltext : 193417.pdf (publisher's version ) (Open Access), By analogy with the journal's title Pain Research and Management, this review describes TMD Research and Management. More specific are the (1) research aspects of "occlusion," still one of the most controversial topics in TMD, and (2) as much as possible evidence-based management aspects of "TMD" for the dental practitioner. Research. The disorders temporomandibular dysfunction and the synonymous craniomandibular dysfunction are still being discussed intensely in the literature. Traditionally, attention is mostly devoted to occlusion and its relationship with these disorders. The conclusions reached are often contradictory. Considering the definitions of temporomandibular and craniomandibular dysfunctions/disorders and "occlusion," a possible explanation for this controversy can be found in the subsequent methodological problems of the studies. Based on a Medline search of these terms over the past 40 years related to contemporary terms such as "Evidence Based Dentistry" and "Pyramid of Evidence," these methodological aspects are examined, resulting in recommendations for future research and TMD-occlusal therapy. Management. To assist the dental practitioner in his/her daily routine to meet the modern standards of best practice, 7 guidelines are formulated that are explained and accompanied with clinical examples for an evidence-based treatment of patients with this disorder in general dental practices.

Contains fulltext : 190048.pdf (publisher's version ) (Closed access)

In the wake of the Six Day War in 1967, Israel became an occupying power with the conquest of the Golan Heights, Sinai Peninsula, Gaza Strip and West Bank, including East Jerusalem. Since the 1970s, comparisons have increasingly been drawn by authorities in the UN, human rights organisations, political commentators and protest movements, between the South African system of apartheid and Israeli policies in the occupied territories. This thesis explores the historical development of the Israel apartheid analogy and its use in public discourse. Not only by analysing secondary literature, but also by conducting a case study, in which articles are examined from high circulation Israeli and Palestinian centrist newspapers the Jerusalem Post and Al-Quds, in the period between January 1st 2017 and May 15th 2018. Analysis of the research data suggests that the apartheid analogy is part of the Palestinian injustice frame, which serves as a powerful delegitimisation and mobilisation tool in the dynamic and continuous contest over meaning. Scope and depth of the present study are limited and future research may therefore include a larger selection of data from a wider range of sources, over a longer period of time. Additionally it would be interesting to investigate the interplay between positive frames and public discourse in protracted conflict situations, as a potential means for conflict management and peace building.

Contains fulltext : 190027.pdf (publisher's version ) (Closed access)

Contains fulltext : 193417.pdf (publisher's version ) (Open Access), By analogy with the journal's title Pain Research and Management, this review describes TMD Research and Management. More specific are the (1) research aspects of "occlusion," still one of the most controversial topics in TMD, and (2) as much as possible evidence-based management aspects of "TMD" for the dental practitioner. Research. The disorders temporomandibular dysfunction and the synonymous craniomandibular dysfunction are still being discussed intensely in the literature. Traditionally, attention is mostly devoted to occlusion and its relationship with these disorders. The conclusions reached are often contradictory. Considering the definitions of temporomandibular and craniomandibular dysfunctions/disorders and "occlusion," a possible explanation for this controversy can be found in the subsequent methodological problems of the studies. Based on a Medline search of these terms over the past 40 years related to contemporary terms such as "Evidence Based Dentistry" and "Pyramid of Evidence," these methodological aspects are examined, resulting in recommendations for future research and TMD-occlusal therapy. Management. To assist the dental practitioner in his/her daily routine to meet the modern standards of best practice, 7 guidelines are formulated that are explained and accompanied with clinical examples for an evidence-based treatment of patients with this disorder in general dental practices.

Contains fulltext : 190048.pdf (publisher's version ) (Closed access)

Contains fulltext : 190027.pdf (publisher's version ) (Closed access)

Contains fulltext : 193417.pdf (publisher's version ) (Open Access), By analogy with the journal's title Pain Research and Management, this review describes TMD Research and Management. More specific are the (1) research aspects of "occlusion," still one of the most controversial topics in TMD, and (2) as much as possible evidence-based management aspects of "TMD" for the dental practitioner. Research. The disorders temporomandibular dysfunction and the synonymous craniomandibular dysfunction are still being discussed intensely in the literature. Traditionally, attention is mostly devoted to occlusion and its relationship with these disorders. The conclusions reached are often contradictory. Considering the definitions of temporomandibular and craniomandibular dysfunctions/disorders and "occlusion," a possible explanation for this controversy can be found in the subsequent methodological problems of the studies. Based on a Medline search of these terms over the past 40 years related to contemporary terms such as "Evidence Based Dentistry" and "Pyramid of Evidence," these methodological aspects are examined, resulting in recommendations for future research and TMD-occlusal therapy. Management. To assist the dental practitioner in his/her daily routine to meet the modern standards of best practice, 7 guidelines are formulated that are explained and accompanied with clinical examples for an evidence-based treatment of patients with this disorder in general dental practices.

In the wake of the Six Day War in 1967, Israel became an occupying power with the conquest of the Golan Heights, Sinai Peninsula, Gaza Strip and West Bank, including East Jerusalem. Since the 1970s, comparisons have increasingly been drawn by authorities in the UN, human rights organisations, political commentators and protest movements, between the South African system of apartheid and Israeli policies in the occupied territories. This thesis explores the historical development of the Israel apartheid analogy and its use in public discourse. Not only by analysing secondary literature, but also by conducting a case study, in which articles are examined from high circulation Israeli and Palestinian centrist newspapers the Jerusalem Post and Al-Quds, in the period between January 1st 2017 and May 15th 2018. Analysis of the research data suggests that the apartheid analogy is part of the Palestinian injustice frame, which serves as a powerful delegitimisation and mobilisation tool in the dynamic and continuous contest over meaning. Scope and depth of the present study are limited and future research may therefore include a larger selection of data from a wider range of sources, over a longer period of time. Additionally it would be interesting to investigate the interplay between positive frames and public discourse in protracted conflict situations, as a potential means for conflict management and peace building.

Contains fulltext : 169944.pdf (publisher's version ) (Closed access), BACKGROUND: Atazanavir is boosted with the cytochrome P450 (CYP) 3A4 inhibitor ritonavir. When combined with the CYP3A4 substrate daclatasvir, the daclatasvir dosage should be reduced from 60 to 30 mg once daily. Recently, cobicistat was licensed as a CYP3A booster and used with atazanavir. OBJECTIVES: To determine whether the fixed-dose combination of atazanavir/cobicistat has an influence on daclatasvir pharmacokinetics comparable to that of the separate agents atazanavir and ritonavir. METHODS: A prospective, open-label, two-period, randomized, cross-over trial was performed in 16 healthy subjects (NCT02565888). Treatment consisted of 300/100 mg of atazanavir/ritonavir plus 30 mg of daclatasvir once daily (reference) and a second period of 300/150 mg of atazanavir/cobicistat plus 30 mg of daclatasvir once daily (test). A 24 h pharmacokinetic, steady-state curve was recorded for all drugs. Geometric mean ratios (GMRs) with 90% CI were calculated for daclatasvir and atazanavir AUCtau and Cmax to compare the effect of both treatments (test versus reference). Laboratory safety and adverse events were evaluated throughout the trial. RESULTS: All 16 healthy subjects completed the study. Median (range) age and BMI were 48.5 (21-55) years and 24.5 (19.0-29.2) kg/m2, respectively. Pharmacokinetic parameters of ritonavir and cobicistat were comparable to those in the literature. The GMRs (90% CI) of daclatasvir AUCtau and Cmax (test versus reference) were 101% (92%-111%) and 97% (89%-106%), respectively. Atazanavir GMRs (90% CI) of AUCtau and Cmax were 82% (75%-79%) and 74% (68%-81%), respectively. No serious adverse events were reported. CONCLUSIONS: Atazanavir/cobicistat and atazanavir/ritonavir had a similar influence on daclatasvir pharmacokinetics in healthy volunteers. Daclatasvir at 30 mg once daily is the correct dose when combined with atazanavir/cobicistat.

Item does not contain fulltext, BACKGROUND: To describe the use of nonantiretroviral comedication and combination antiretroviral therapy (cART) in patients coinfected with HIV/hepatitis C virus (HCV) and to predict the potential for drug-drug interactions (DDIs) with direct-acting antivirals (DAAs) against HCV. METHODS: This is a retrospective, cross-sectional study, using the Dutch, nationwide ATHENA observational HIV cohort database. All patients with a known HIV/HCV coinfection on January 1, 2015, were included. Comedication and cART registered in the database were listed. The potential for DDIs between DAAs and comedication/cART were predicted using http://hep-druginteractions.org. DDIs were categorized as: (1) no clinically relevant DDI; (2) possible DDI; (3) contraindication; or (4) no information available. RESULTS: We included 777 patients of whom 488 (63%) used nonantiretroviral comedication. At risk for a category 2/3 DDI with nonantiretroviral comedications were 299 patients (38%). Most DDIs were predicted with paritaprevir/ritonavir, ombitasvir +/- dasabuvir (47% of the drugs) and least with grazoprevir/elbasvir (11% of the drugs). Concerning cART, daclatasvir/sofosbuvir is the most favorable combination as no cART is contraindicated with this combination. In genotype 1/4 patients, grazoprevir/elbasvir is least favorable as 75% of the patients must alter their cART. CONCLUSIONS: This study showed that comedication use in the aging HIV/HCV population is frequent and diverse. There is a high potential for DDIs between DAAs and comedication/cART.

Contains fulltext : 176887.pdf (publisher's version ) (Closed access), AIM: The aim of the present study was to evaluate the effect of the proposed organic cation transporter (OCT) inhibitor daclatasvir on the pharmacokinetics and pharmacodynamics of the OCT substrate metformin. METHODS: This was an open-label, two-period, randomized, crossover trial in 20 healthy subjects. Treatment A consisted of metformin and treatment B consisted of metformin + daclatasvir. Pharmacokinetic curves were recorded at steady-state. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) were calculated for metformin area under the concentration-time curve from 0 h to 12 h (AUC0-12 ), maximum plasma concentration (Cmax ) and final plasma concentration (Clast ). An oral glucose tolerance test was performed, measuring insulin, glucose and lactate levels. RESULTS: The GMRs (90% CI) of metformin AUC0-12 , Cmax and Clast (B vs. A) were 109% (102-116%), 108% (101-116%) and 112% (103-122%). The geometric mean AUC0-2 for insulin, glucose and lactate during treatments A and B were 84 h. mEl-1 and 90 h. mEl-1 , 13.6 h. mmol l-1 and 13.4 h. mmol l-1 , and 3.4 h. mmol l-1 and 3.5 h. mmol l-1 , respectively. CONCLUSIONS: Bioequivalence analysis showed that daclatasvir does not influence the pharmacokinetics of metformin in healthy subjects. Pharmacodynamic parameters were also comparable between treatments.

Contains fulltext : 182656.pdf (Publisher’s version ) (Closed access), BACKGROUND: In the era of highly effective direct-acting antivirals (DAAs) for treatment of patients with chronic hepatitis C virus (HCV) infection, ribavirin (RBV) is still considered beneficial in certain patients. AIM: To assess the association between RBV steady-state plasma levels and sustained virological response (SVR). METHODS: Consecutive HCV-infected patients treated with DAAs plus RBV from four Dutch academic medical centres were enrolled. RBV steady-state plasma levels were prospectively measured at treatment week 8 using validated assays. Logistic regression analyses were performed to assess the influence of RBV steady-state plasma level on SVR, and RBV therapeutic range was explored using area under the ROC curve analyses. RESULTS: A total of 183 patients were included, of whom 85% had one or more difficult-to-cure characteristics (ie treatment experienced, HCV genotype 3, cirrhosis). The majority was treated with a sofosbuvir-based regimen and 163 (89%) patients achieved SVR. Median RBV dose was 12.9 (interquartile range 11.2-14.7) mg/kg/d, and median RBV steady-state plasma level was 2.66 (1.95-3.60) mg/L. In multivariable analyses, higher RBV steady-state plasma level (adjusted odds ratio 1.79 [95% CI 1.09-2.93]) was an independent predictor of SVR. With regard to the optimal RBV therapeutic range, 2.28 mg/L was the optimal lower cut-off for achieving SVR and 3.61 mg/L was the upper cut-off for preventing significant anaemia (Haemoglobin < 10 g/dL). CONCLUSION: In this cohort of mainly difficult-to-cure patients treated with DAAs plus RBV, higher RBV steady-state plasma level was an independent predictor of SVR.

Radboud University, 1 december 2017, Promotores : Burger, D.M., Drenth, J.P.H. Co-promotor : Kanter, C.T.M.M. de, Contains fulltext : 173898.pdf (publisher's version ) (Open Access)

Contains fulltext : 169944.pdf (publisher's version ) (Closed access), BACKGROUND: Atazanavir is boosted with the cytochrome P450 (CYP) 3A4 inhibitor ritonavir. When combined with the CYP3A4 substrate daclatasvir, the daclatasvir dosage should be reduced from 60 to 30 mg once daily. Recently, cobicistat was licensed as a CYP3A booster and used with atazanavir. OBJECTIVES: To determine whether the fixed-dose combination of atazanavir/cobicistat has an influence on daclatasvir pharmacokinetics comparable to that of the separate agents atazanavir and ritonavir. METHODS: A prospective, open-label, two-period, randomized, cross-over trial was performed in 16 healthy subjects (NCT02565888). Treatment consisted of 300/100 mg of atazanavir/ritonavir plus 30 mg of daclatasvir once daily (reference) and a second period of 300/150 mg of atazanavir/cobicistat plus 30 mg of daclatasvir once daily (test). A 24 h pharmacokinetic, steady-state curve was recorded for all drugs. Geometric mean ratios (GMRs) with 90% CI were calculated for daclatasvir and atazanavir AUCtau and Cmax to compare the effect of both treatments (test versus reference). Laboratory safety and adverse events were evaluated throughout the trial. RESULTS: All 16 healthy subjects completed the study. Median (range) age and BMI were 48.5 (21-55) years and 24.5 (19.0-29.2) kg/m2, respectively. Pharmacokinetic parameters of ritonavir and cobicistat were comparable to those in the literature. The GMRs (90% CI) of daclatasvir AUCtau and Cmax (test versus reference) were 101% (92%-111%) and 97% (89%-106%), respectively. Atazanavir GMRs (90% CI) of AUCtau and Cmax were 82% (75%-79%) and 74% (68%-81%), respectively. No serious adverse events were reported. CONCLUSIONS: Atazanavir/cobicistat and atazanavir/ritonavir had a similar influence on daclatasvir pharmacokinetics in healthy volunteers. Daclatasvir at 30 mg once daily is the correct dose when combined with atazanavir/cobicistat.

Item does not contain fulltext, BACKGROUND: To describe the use of nonantiretroviral comedication and combination antiretroviral therapy (cART) in patients coinfected with HIV/hepatitis C virus (HCV) and to predict the potential for drug-drug interactions (DDIs) with direct-acting antivirals (DAAs) against HCV. METHODS: This is a retrospective, cross-sectional study, using the Dutch, nationwide ATHENA observational HIV cohort database. All patients with a known HIV/HCV coinfection on January 1, 2015, were included. Comedication and cART registered in the database were listed. The potential for DDIs between DAAs and comedication/cART were predicted using http://hep-druginteractions.org. DDIs were categorized as: (1) no clinically relevant DDI; (2) possible DDI; (3) contraindication; or (4) no information available. RESULTS: We included 777 patients of whom 488 (63%) used nonantiretroviral comedication. At risk for a category 2/3 DDI with nonantiretroviral comedications were 299 patients (38%). Most DDIs were predicted with paritaprevir/ritonavir, ombitasvir +/- dasabuvir (47% of the drugs) and least with grazoprevir/elbasvir (11% of the drugs). Concerning cART, daclatasvir/sofosbuvir is the most favorable combination as no cART is contraindicated with this combination. In genotype 1/4 patients, grazoprevir/elbasvir is least favorable as 75% of the patients must alter their cART. CONCLUSIONS: This study showed that comedication use in the aging HIV/HCV population is frequent and diverse. There is a high potential for DDIs between DAAs and comedication/cART.

Contains fulltext : 176887.pdf (publisher's version ) (Closed access), AIM: The aim of the present study was to evaluate the effect of the proposed organic cation transporter (OCT) inhibitor daclatasvir on the pharmacokinetics and pharmacodynamics of the OCT substrate metformin. METHODS: This was an open-label, two-period, randomized, crossover trial in 20 healthy subjects. Treatment A consisted of metformin and treatment B consisted of metformin + daclatasvir. Pharmacokinetic curves were recorded at steady-state. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) were calculated for metformin area under the concentration-time curve from 0 h to 12 h (AUC0-12 ), maximum plasma concentration (Cmax ) and final plasma concentration (Clast ). An oral glucose tolerance test was performed, measuring insulin, glucose and lactate levels. RESULTS: The GMRs (90% CI) of metformin AUC0-12 , Cmax and Clast (B vs. A) were 109% (102-116%), 108% (101-116%) and 112% (103-122%). The geometric mean AUC0-2 for insulin, glucose and lactate during treatments A and B were 84 h. mEl-1 and 90 h. mEl-1 , 13.6 h. mmol l-1 and 13.4 h. mmol l-1 , and 3.4 h. mmol l-1 and 3.5 h. mmol l-1 , respectively. CONCLUSIONS: Bioequivalence analysis showed that daclatasvir does not influence the pharmacokinetics of metformin in healthy subjects. Pharmacodynamic parameters were also comparable between treatments.

Radboud University, 01 december 2017, Promotores : Burger, D.M., Drenth, J.P.H. Co-promotor : Kanter, C.T.M.M. de, Contains fulltext : 173898.pdf (publisher's version ) (Open Access)

Contains fulltext : 182656.pdf (Publisher’s version ) (Closed access), BACKGROUND: In the era of highly effective direct-acting antivirals (DAAs) for treatment of patients with chronic hepatitis C virus (HCV) infection, ribavirin (RBV) is still considered beneficial in certain patients. AIM: To assess the association between RBV steady-state plasma levels and sustained virological response (SVR). METHODS: Consecutive HCV-infected patients treated with DAAs plus RBV from four Dutch academic medical centres were enrolled. RBV steady-state plasma levels were prospectively measured at treatment week 8 using validated assays. Logistic regression analyses were performed to assess the influence of RBV steady-state plasma level on SVR, and RBV therapeutic range was explored using area under the ROC curve analyses. RESULTS: A total of 183 patients were included, of whom 85% had one or more difficult-to-cure characteristics (ie treatment experienced, HCV genotype 3, cirrhosis). The majority was treated with a sofosbuvir-based regimen and 163 (89%) patients achieved SVR. Median RBV dose was 12.9 (interquartile range 11.2-14.7) mg/kg/d, and median RBV steady-state plasma level was 2.66 (1.95-3.60) mg/L. In multivariable analyses, higher RBV steady-state plasma level (adjusted odds ratio 1.79 [95% CI 1.09-2.93]) was an independent predictor of SVR. With regard to the optimal RBV therapeutic range, 2.28 mg/L was the optimal lower cut-off for achieving SVR and 3.61 mg/L was the upper cut-off for preventing significant anaemia (Haemoglobin < 10 g/dL). CONCLUSION: In this cohort of mainly difficult-to-cure patients treated with DAAs plus RBV, higher RBV steady-state plasma level was an independent predictor of SVR.

Item does not contain fulltext, BACKGROUND: To describe the use of nonantiretroviral comedication and combination antiretroviral therapy (cART) in patients coinfected with HIV/hepatitis C virus (HCV) and to predict the potential for drug-drug interactions (DDIs) with direct-acting antivirals (DAAs) against HCV. METHODS: This is a retrospective, cross-sectional study, using the Dutch, nationwide ATHENA observational HIV cohort database. All patients with a known HIV/HCV coinfection on January 1, 2015, were included. Comedication and cART registered in the database were listed. The potential for DDIs between DAAs and comedication/cART were predicted using http://hep-druginteractions.org. DDIs were categorized as: (1) no clinically relevant DDI; (2) possible DDI; (3) contraindication; or (4) no information available. RESULTS: We included 777 patients of whom 488 (63%) used nonantiretroviral comedication. At risk for a category 2/3 DDI with nonantiretroviral comedications were 299 patients (38%). Most DDIs were predicted with paritaprevir/ritonavir, ombitasvir +/- dasabuvir (47% of the drugs) and least with grazoprevir/elbasvir (11% of the drugs). Concerning cART, daclatasvir/sofosbuvir is the most favorable combination as no cART is contraindicated with this combination. In genotype 1/4 patients, grazoprevir/elbasvir is least favorable as 75% of the patients must alter their cART. CONCLUSIONS: This study showed that comedication use in the aging HIV/HCV population is frequent and diverse. There is a high potential for DDIs between DAAs and comedication/cART.

Contains fulltext : 176887.pdf (publisher's version ) (Closed access), AIM: The aim of the present study was to evaluate the effect of the proposed organic cation transporter (OCT) inhibitor daclatasvir on the pharmacokinetics and pharmacodynamics of the OCT substrate metformin. METHODS: This was an open-label, two-period, randomized, crossover trial in 20 healthy subjects. Treatment A consisted of metformin and treatment B consisted of metformin + daclatasvir. Pharmacokinetic curves were recorded at steady-state. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) were calculated for metformin area under the concentration-time curve from 0 h to 12 h (AUC0-12 ), maximum plasma concentration (Cmax ) and final plasma concentration (Clast ). An oral glucose tolerance test was performed, measuring insulin, glucose and lactate levels. RESULTS: The GMRs (90% CI) of metformin AUC0-12 , Cmax and Clast (B vs. A) were 109% (102-116%), 108% (101-116%) and 112% (103-122%). The geometric mean AUC0-2 for insulin, glucose and lactate during treatments A and B were 84 h. mEl-1 and 90 h. mEl-1 , 13.6 h. mmol l-1 and 13.4 h. mmol l-1 , and 3.4 h. mmol l-1 and 3.5 h. mmol l-1 , respectively. CONCLUSIONS: Bioequivalence analysis showed that daclatasvir does not influence the pharmacokinetics of metformin in healthy subjects. Pharmacodynamic parameters were also comparable between treatments.

Radboud University, 01 december 2017, Promotores : Burger, D.M., Drenth, J.P.H. Co-promotor : Kanter, C.T.M.M. de, Contains fulltext : 173898.pdf (publisher's version ) (Open Access)

Contains fulltext : 182656.pdf (Publisher’s version ) (Closed access), BACKGROUND: In the era of highly effective direct-acting antivirals (DAAs) for treatment of patients with chronic hepatitis C virus (HCV) infection, ribavirin (RBV) is still considered beneficial in certain patients. AIM: To assess the association between RBV steady-state plasma levels and sustained virological response (SVR). METHODS: Consecutive HCV-infected patients treated with DAAs plus RBV from four Dutch academic medical centres were enrolled. RBV steady-state plasma levels were prospectively measured at treatment week 8 using validated assays. Logistic regression analyses were performed to assess the influence of RBV steady-state plasma level on SVR, and RBV therapeutic range was explored using area under the ROC curve analyses. RESULTS: A total of 183 patients were included, of whom 85% had one or more difficult-to-cure characteristics (ie treatment experienced, HCV genotype 3, cirrhosis). The majority was treated with a sofosbuvir-based regimen and 163 (89%) patients achieved SVR. Median RBV dose was 12.9 (interquartile range 11.2-14.7) mg/kg/d, and median RBV steady-state plasma level was 2.66 (1.95-3.60) mg/L. In multivariable analyses, higher RBV steady-state plasma level (adjusted odds ratio 1.79 [95% CI 1.09-2.93]) was an independent predictor of SVR. With regard to the optimal RBV therapeutic range, 2.28 mg/L was the optimal lower cut-off for achieving SVR and 3.61 mg/L was the upper cut-off for preventing significant anaemia (Haemoglobin < 10 g/dL). CONCLUSION: In this cohort of mainly difficult-to-cure patients treated with DAAs plus RBV, higher RBV steady-state plasma level was an independent predictor of SVR.

Contains fulltext : 165932.PDF (publisher's version ) (Open Access)

Contains fulltext : 171181.pdf (Publisher’s version ) (Open Access), Hepatitis C virus (HCV)-infected patients often suffer from liver cirrhosis, which can be complicated by renal impairment. Therefore, in this review we describe the treatment possibilities in HCV patients with hepatic and renal impairment. Cirrhosis alters the structure of the liver, which affects drug-metabolizing enzymes and drug transporters. These modifications influence the plasma concentration of substrates of drugs metabolized/transported by these enzymes. The direct-acting antivirals (DAAs) are substrates of, for example, cytochrome P450 enzymes in the liver. Most DAAs are not studied in HCV-infected individuals with decompensated cirrhosis, and therefore awareness is needed when these patients are treated. Most DAAs are contraindicated in cirrhotic patients; however, patients with a Child-Pugh score of B or C can be treated safely with a normal dose sofosbuvir plus ledipasvir or daclatasvir, in combination with ribavirin. Patients with renal impairment (glomerular filtration rate [GFR] <90 mL/min) or who are dependent on dialysis often tolerate ribavirin treatment poorly, even after dose adjustments. However, most DAAs can be used at the normal dose because DAAs are not renally excreted. To date, grazoprevir plus elbasvir is the preferred DAA regimen in patients with renal impairment as data are pending for sofosbuvir patients with GFR <30 mL/min (as for ledipasvir and velpatasvir). However, sofosbuvir has been used in a small number of patients with severe renal impairment and, based on these trials, we recommend sofosbuvir 400 mg every day when no other DAA regimen is available. Ledipasvir and velpatasvir are not recommended in patients with severe renal impairment.

Item does not contain fulltext, BACKGROUND: Monitoring ribavirin concentrations during hepatitis C treatment with dual therapy can help optimize treatment response and minimize anaemia. A defined therapeutic range for ribavirin during direct-acting antiviral-based therapies is lacking. This analysis explores whether a therapeutic range for ribavirin concentrations can be defined in patients treated with boceprevir- or telaprevir-based triple therapies. METHODS: Treatment-naive patients from ADVANCE, ILLUMINATE, OPTIMIZE and SPRINT-2, and treatment-experienced patients from RESPOND-2 were included. Multivariable logistic regression analyses were performed to evaluate whether ribavirin concentrations were an independent predictor of sustained virological response or anaemia. Optimal cutoff values and the percentage of patients within the proposed therapeutic range were determined, along with the associated chance of response. RESULTS: Overall, 1,502 patients were included. In both regimens, ribavirin concentrations were significantly associated with anaemia (haemoglobin level <10 g/dl) at all time points (1.75 < odds ratio [OR] <2.45) and sustained virological response was associated with ribavirin concentrations at week 8 (OR=1.43 for telaprevir and 1.78 for boceprevir). A therapeutic range for ribavirin at week 8 of 2.2-3.5 mg/l was defined for telaprevir treatment. Of the 48% of patients with a concentration within this range, 81% achieved sustained virological response and only 5.1% reported anaemia. For boceprevir treatment, the week 8 optimal range was defined as 2.2-3.6 mg/l and 50% of patients had a concentration within this range, of whom 69% achieved sustained virological response and 46% developed anaemia. CONCLUSIONS: We established the therapeutic range for ribavirin in boceprevir- and telaprevir-based therapy that balances safety and efficacy.

Contains fulltext : 165932.PDF (publisher's version ) (Open Access)

Contains fulltext : 171181.pdf (Publisher’s version ) (Open Access), Hepatitis C virus (HCV)-infected patients often suffer from liver cirrhosis, which can be complicated by renal impairment. Therefore, in this review we describe the treatment possibilities in HCV patients with hepatic and renal impairment. Cirrhosis alters the structure of the liver, which affects drug-metabolizing enzymes and drug transporters. These modifications influence the plasma concentration of substrates of drugs metabolized/transported by these enzymes. The direct-acting antivirals (DAAs) are substrates of, for example, cytochrome P450 enzymes in the liver. Most DAAs are not studied in HCV-infected individuals with decompensated cirrhosis, and therefore awareness is needed when these patients are treated. Most DAAs are contraindicated in cirrhotic patients; however, patients with a Child-Pugh score of B or C can be treated safely with a normal dose sofosbuvir plus ledipasvir or daclatasvir, in combination with ribavirin. Patients with renal impairment (glomerular filtration rate [GFR] <90 mL/min) or who are dependent on dialysis often tolerate ribavirin treatment poorly, even after dose adjustments. However, most DAAs can be used at the normal dose because DAAs are not renally excreted. To date, grazoprevir plus elbasvir is the preferred DAA regimen in patients with renal impairment as data are pending for sofosbuvir patients with GFR <30 mL/min (as for ledipasvir and velpatasvir). However, sofosbuvir has been used in a small number of patients with severe renal impairment and, based on these trials, we recommend sofosbuvir 400 mg every day when no other DAA regimen is available. Ledipasvir and velpatasvir are not recommended in patients with severe renal impairment.

Item does not contain fulltext, BACKGROUND: Monitoring ribavirin concentrations during hepatitis C treatment with dual therapy can help optimize treatment response and minimize anaemia. A defined therapeutic range for ribavirin during direct-acting antiviral-based therapies is lacking. This analysis explores whether a therapeutic range for ribavirin concentrations can be defined in patients treated with boceprevir- or telaprevir-based triple therapies. METHODS: Treatment-naive patients from ADVANCE, ILLUMINATE, OPTIMIZE and SPRINT-2, and treatment-experienced patients from RESPOND-2 were included. Multivariable logistic regression analyses were performed to evaluate whether ribavirin concentrations were an independent predictor of sustained virological response or anaemia. Optimal cutoff values and the percentage of patients within the proposed therapeutic range were determined, along with the associated chance of response. RESULTS: Overall, 1,502 patients were included. In both regimens, ribavirin concentrations were significantly associated with anaemia (haemoglobin level <10 g/dl) at all time points (1.75 < odds ratio [OR] <2.45) and sustained virological response was associated with ribavirin concentrations at week 8 (OR=1.43 for telaprevir and 1.78 for boceprevir). A therapeutic range for ribavirin at week 8 of 2.2-3.5 mg/l was defined for telaprevir treatment. Of the 48% of patients with a concentration within this range, 81% achieved sustained virological response and only 5.1% reported anaemia. For boceprevir treatment, the week 8 optimal range was defined as 2.2-3.6 mg/l and 50% of patients had a concentration within this range, of whom 69% achieved sustained virological response and 46% developed anaemia. CONCLUSIONS: We established the therapeutic range for ribavirin in boceprevir- and telaprevir-based therapy that balances safety and efficacy.

Contains fulltext : 165932.PDF (publisher's version ) (Open Access)

Contains fulltext : 171181.pdf (Publisher’s version ) (Open Access), Hepatitis C virus (HCV)-infected patients often suffer from liver cirrhosis, which can be complicated by renal impairment. Therefore, in this review we describe the treatment possibilities in HCV patients with hepatic and renal impairment. Cirrhosis alters the structure of the liver, which affects drug-metabolizing enzymes and drug transporters. These modifications influence the plasma concentration of substrates of drugs metabolized/transported by these enzymes. The direct-acting antivirals (DAAs) are substrates of, for example, cytochrome P450 enzymes in the liver. Most DAAs are not studied in HCV-infected individuals with decompensated cirrhosis, and therefore awareness is needed when these patients are treated. Most DAAs are contraindicated in cirrhotic patients; however, patients with a Child-Pugh score of B or C can be treated safely with a normal dose sofosbuvir plus ledipasvir or daclatasvir, in combination with ribavirin. Patients with renal impairment (glomerular filtration rate [GFR] <90 mL/min) or who are dependent on dialysis often tolerate ribavirin treatment poorly, even after dose adjustments. However, most DAAs can be used at the normal dose because DAAs are not renally excreted. To date, grazoprevir plus elbasvir is the preferred DAA regimen in patients with renal impairment as data are pending for sofosbuvir patients with GFR <30 mL/min (as for ledipasvir and velpatasvir). However, sofosbuvir has been used in a small number of patients with severe renal impairment and, based on these trials, we recommend sofosbuvir 400 mg every day when no other DAA regimen is available. Ledipasvir and velpatasvir are not recommended in patients with severe renal impairment.

Item does not contain fulltext, BACKGROUND: Telaprevir is a protease inhibitor used in the treatment of hepatitis C virus infection. Analytical methods for telaprevir should separate the compound from its R-diastereomer VRT-127394, which is 30-fold less active. The objective of this work was to develop liquid chromatography-tandem mass spectrometer (LC-MS/MS) assays for telaprevir both in plasma and in dried blood spot (DBS), capable of stabilizing the equilibrium and chromatographically separating the 2 epimers. METHODS: Human plasma was acidified with formic acid and frozen within 1 hour after collection to stabilize the equilibrium between the 2 telaprevir diastereomers ex vivo in plasma. After protein precipitation, the sample was analyzed with LC-MS/MS. For the DBS assay, sampling paper was impregnated with citric acid solution to achieve stabilization of the epimers on the sampling paper. DBS samples were extracted before LC-MS/MS analysis. LC-MS/MS analysis comprised online solid-phase extraction and separation on a C18 column, with the mass spectrometer operating in TurboIonSpray-negative ionization mode and performing multiple reaction monitoring. RESULTS: The assays were linear over the concentration range of 0.1-10 mg/L in plasma and DBS. Accuracies ranged from 97% to 106% in plasma and from 93% to 99% in DBS. Within- and between-day coefficients of variation were <7.9% in plasma and <9.3% in DBS. Human whole blood samples with hematocrit values of 27%-47% gave reproducible quantitation results in the DBS assay, and spot volume did not affect results of the DBS assay either. Acidified plasma with telaprevir was stable for 5 hours at 20 degrees C, and telaprevir on impregnated DBS paper was stable for at least 3 months at 4 degrees C or at 20 degrees C. CONCLUSIONS: An assay was developed and validated for the determination of telaprevir in human plasma, separating telaprevir from its R-diastereomer VRT-127394. In addition, a DBS assay was developed, which avoids immediate centrifuging

Item does not contain fulltext, BACKGROUND: Adequate ribavirin exposure is essential for optimal sustained virological response (SVR) rates in chronic HCV treatment. It has been proposed that the area under the concentration-time curve up to 4 h after intake of ribavirin (AUC0-4 h) of the first weight-based ribavirin dose should be >/=1.755 mg*h/l to guarantee the highest chance of SVR. Our ARRIBA concept comprises a test dose of ribavirin to select the optimal starting dose to achieve adequate exposure. This study aims to evaluate whether adequate exposure can be achieved after dose advice based on the AUC0-4 h of a single weight-based ribavirin test dose. METHODS: (Formerly) HCV-infected subjects received a single weight-based ribavirin test dose (<75 kg: 400 mg; >/=75 kg: 600 mg) and the AUC0-4 h was calculated. If ribavirin AUC0-4 h was >/=1.755 mg*h/l, subjects received the same dose 4 weeks later; if the AUC0-4 h was <1.755 mg*h/l, an adjusted dose was administered. The ribavirin AUC0-4 h was recorded again. The primary outcome was the proportion of subjects with an AUC0-4 h >/=1.755 mg*h/l after the second dose. RESULTS: A total of 26 subjects were included. The geometric mean (95% CI) ribavirin AUC0-4 h was 1.67 (1.44-1.92) mg*h/l with 9 subjects (35%) reaching the target AUC on day 1. Thus, on day 29, 17 subjects (65%) received an adjusted dose. The geometric mean (95% CI) AUC0-4 h increased to 1.90 (1.62-2.21) mg*h/l and then 16 subjects (62%) had an AUC0-4 h >/=1.755 mg*h/l, which is significantly higher than day 1 (P<0.05). CONCLUSIONS: Our ARRIBA concept of a ribavirin test dose, with dose adjustment if necessary, leads to an increased proportion of patients with an AUC>/=1.755 mg*h/l compared to traditional weight-based ribavirin dosing.

Item does not contain fulltext, BACKGROUND: Hepatitis C virus (HCV)/HIV-coinfected patients respond worse to dual therapy with ribavirin (RBV)/peginterferon compared with HCV-monoinfected patients. Several trials found that lower RBV plasma concentrations are associated with impaired virological response rates. The aim of this study was to determine RBV plasma concentrations in a cohort of HCV-monoinfected and HCV/HIV-coinfected patients. Our hypothesis is that HCV/HIV-coinfected patients have lower RBV plasma concentrations, which may in part explain their inferior response to dual therapy. METHODS: A retrospective cohort study was performed in chronic HCV-monoinfected and HCV/HIV-coinfected patients who received peginterferon and weight-based RBV. Plasma RBV concentrations were determined at weeks 4 and 12 by a validated high-performance liquid chromatography assay. RBV concentrations were compared between monoinfected and coinfected patients. We calculated the proportion of patients with a subtherapeutic RBV plasma concentration defined as <2.0 mg/L. RESULTS: A total of 61 HCV-infected patients were included, of whom 21 (34%) were coinfected with HIV. Although there was no difference in the weight-based dose of RBV between monoinfected and coinfected patients, RBV exposure was significantly lower in HCV/HIV-coinfected patients than in HCV-monoinfected patients: the mean +/- SD RBV plasma concentrations were 1.82 +/- 0.63 mg/L versus 2.25 +/- 0.80 mg/L (P = 0.04) at week 4 and 2.14 +/- 0.65 mg/L versus 2.62 +/- 0.81 mg/L (P = 0.05) at week 12, respectively. The percentage of patients with subtherapeutic plasma concentrations of RBV in coinfected patients versus monoinfected patients was 62% versus 46% (P = 0.240) at week 4 and 50% versus 16% (P = 0.01) at week 12 of treatment, respectively. CONCLUSIONS: HIV/HCV-coinfected patients yield significantly lower plasma concentrations of RBV than HCV-monoinfected patients. This puts them at an increased risk of not achieving sustained virological respo

Radboud Universiteit Nijmegen, 21 augustus 2015, Promotores : Burger, D.M., Drenth, J.P.H. Co-promotor : Dofferhoff, A.S.M., Contains fulltext : 142579.pdf (publisher's version ) (Open Access)

Item does not contain fulltext, BACKGROUND: Telaprevir is a protease inhibitor used in the treatment of hepatitis C virus infection. Analytical methods for telaprevir should separate the compound from its R-diastereomer VRT-127394, which is 30-fold less active. The objective of this work was to develop liquid chromatography-tandem mass spectrometer (LC-MS/MS) assays for telaprevir both in plasma and in dried blood spot (DBS), capable of stabilizing the equilibrium and chromatographically separating the 2 epimers. METHODS: Human plasma was acidified with formic acid and frozen within 1 hour after collection to stabilize the equilibrium between the 2 telaprevir diastereomers ex vivo in plasma. After protein precipitation, the sample was analyzed with LC-MS/MS. For the DBS assay, sampling paper was impregnated with citric acid solution to achieve stabilization of the epimers on the sampling paper. DBS samples were extracted before LC-MS/MS analysis. LC-MS/MS analysis comprised online solid-phase extraction and separation on a C18 column, with the mass spectrometer operating in TurboIonSpray-negative ionization mode and performing multiple reaction monitoring. RESULTS: The assays were linear over the concentration range of 0.1-10 mg/L in plasma and DBS. Accuracies ranged from 97% to 106% in plasma and from 93% to 99% in DBS. Within- and between-day coefficients of variation were <7.9% in plasma and <9.3% in DBS. Human whole blood samples with hematocrit values of 27%-47% gave reproducible quantitation results in the DBS assay, and spot volume did not affect results of the DBS assay either. Acidified plasma with telaprevir was stable for 5 hours at 20 degrees C, and telaprevir on impregnated DBS paper was stable for at least 3 months at 4 degrees C or at 20 degrees C. CONCLUSIONS: An assay was developed and validated for the determination of telaprevir in human plasma, separating telaprevir from its R-diastereomer VRT-127394. In addition, a DBS assay was developed, which avoids immediate centrifuging